Electrophilic Aromatic Substitution: New Insights into an Old Class of

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Electrophilic Aromatic Substitution: New Insights into an Old Class of Reactions Boris Galabov,*,† Didi Nalbantova,† Paul von R. Schleyer,‡ and Henry F. Schaefer, III*,‡ †

Department of Chemistry and Pharmacy, University of Sofia, Sofia 1164, Bulgaria Center for Computational Quantum Chemistry, University of Georgia, Athens, Georgia 30602, United States

‡

S Supporting Information *

CONSPECTUS: 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 twostage 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.

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INTRODUCTION Although electrophilic aromatic substitution (EAS) reactions have been known since the 19th century, the interest in their chemistry is still continuing.1−4 Many key industrial products and process intermediates are obtained via EAS. Historically, the development of important quantitative concepts such as the inductive effect, the mesomeric effect, and field substituent effects are linked to kinetic studies of EAS reactions.5−10 The emergence of mechanistic organic chemistry also has been associated with kinetic and spectroscopic investigations of EAS processes. The classic two-stage mechanism for electrophilic aromatic substitutions is now well-established and has served as a backbone in understanding aromatic chemistry.6−14 This reaction route, comprising the formation of π- and σ-complex © XXXX American Chemical Society

intermediates (Scheme 1), is described in textbooks, monographs, and reviews.4−14 Our findings in a series of recent studies15−19 challenged the generality of this mechanistic paradigm. By combining theoretical modeling and experimental spectroScheme 1. Typical Depiction of the Arenium Ion Mechanism for EAS Reactions

Received: March 4, 2016

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Figure 1. Kinetics of consumption of Cl2 (the band at 330 nm) during the reaction with anisole recorded at 15 min intervals at 25 °C (A) in the absence of added HCl and (B) when HCl was added to the reaction mixture prior to Cl2 flow. Details of the concentrations are given in ref 16.

Scheme 2. Concerted and Addition−Elimination Pathways for Para Chlorination of Anisole in Nonpolar Media

Figure 2. Geometries of the transition states for (A) para substitution and (B) 3,4-cis addition in the chlorination of anisole catalyzed by HCl in simulated CCl4 solution at the B3LYP/6-311+G(2d,2p) level.

evaluation of the potential energy surfaces was accompanied by our NMR spectroscopic studies of the reaction at varying temperatures. Kinetics measurements conducted by UV/vis spectroscopy revealed the significant autocatalytic role of the HCl product (Figure 1), in accord with early experimental studies.21 The presence of excess HCl at the start of the reaction accelerates the rate of transformation. Therefore, we modeled the reaction pathway and systematically considered the catalytic role of HCl. Our G09 computations employed the B3LYP hybrid functional22−24 and the Perdew−Burke− Ernzerhof (PBE) functional25 combined with 6-311++G(2d,2p) basis sets.26,27 Single-point computations using the B2-PLYP hybrid functional28 also were conducted. All of the energies were also corrected with Grimme’s DFT-D3 dispersion corrections.29 Intrinsic reaction coordinate (IRC) computations connected all of the optimized structures along the reaction paths.30 Solvent effects were modeled using the IEF-PCM method.31 Sketches of the potential energy surfaces

scopic investigations, we have shown that some typical EAS reactions (halogenation, nitration, and sulfonation) may follow alternative pathways, depending on the type of reactant and medium and the presence or absence of catalysts. In this Account, we present the principal outcomes of these studies. Recent research on the topic from other laboratories is also discussed.

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HALOGENATION BY MOLECULAR CHLORINE AND BROMINE Halogenation is a prototypical electrophilic aromatic substitution reaction. The process can be facilitated by a variety of catalysts but also may proceed using molecular halogens.4,6−9,11,13,14 We are interested in examining the inherent mechanisms of the interaction of halogens with arenes not influenced by catalysts or polar solvents. We investigated15 by theoretical modeling the mechanism of the chlorination of anisole in the nonpolar medium CCl4.20 The computational B

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Figure 3. Sketches of potential energy surfaces for the HCl-catalyzed chlorination of toluene [at the B3LYP-D3/6-311+G(2d,2p) level] in simulated CCl4 solvent.

The structures of intermediates and transition states are quite analogous to those obtained in modeling of anisole chlorination. The theoretical results for benzene, toluene, and naphthalene excellently reflect the experimentally established reactivity trends in the literature4−9,11,13 for the electrophilic chlorination of these basic arenes. The concerted substitutions proceed via a single transition state and do not involve arenium ion σ-complex intermediates. Theoretical modeling of the reactions of benzene, naphthalene, anthracene, and phenanthrene with molecular bromine in a simulated (IEF-PCM) CCl4 solvent at the RB2-PLYP-D3/ 6-311+G(2d,2p) level arrived at analogous results for the mechanistic pathways.17 Some transition states were found to possess diradical character. In these cases, we applied an unrestricted broken-symmetry (UBS) methodology to evaluate the energies of these structures.17 No σ-complex intermediates were established along the direct substitution routes. Instead, following the barrierless formation of a π complex, the reactions proceed via a concerted process involving addition of halogen followed by elimination of HBr to reach the monosubstituted reaction product. Catalysis was not considered for the bromination reaction since the available literature kinetic data did not provide clear indications in this respect.37 The theoretically evaluated transition state energy barriers (Eel + ZPE + Edisp) were higher than expected compared with the experimental conditions for these reactions. A very recent combined experimental and theoretical investigation of benzene bromination by Shernyakov et al.38 provided further valuable insights into the chemistry of this reaction. These authors established that at high bromine concentration (5−14 M) in benzene medium the reaction proceeds at room temperature, yielding mostly bromobenzene. Theoretical modeling revealed significant reductions in free energy barriers when clusters of two to five bromine molecules are considered to react with the arene. The computations also showed competing direct concerted substitution and AE pathways, and the experiments established the presence of addition side products. These authors determined a small negative H/D kinetic isotope effect

for anisole chlorination are shown in Figure S1 in the Supporting Information. The theoretical results revealed that the process proceeds as a competition between direct substitution and addition−elimination (AE) pathways, as depicted in Scheme 2. Addition products of arene halogenation have been known since the 19th century32,33 and were confirmed in the work of de la Mare.14,33 Nonetheless, the prevailing opinion in recent decades is that halogenation and other electrophilic substitutions of aromatic compounds proceed via the classic two-stage SEAr mechanism (Scheme 1). Our results, however, clearly showed that the direct substitution and AE pathways compete during the chlorination of anisole. Moreover, the computations for anisole chlorination demonstrated that the barrier for the AE process is lower by about 3 kcal/mol (Figure S1). In contrast to the traditional view, our computational modeling revealed that the direct chlorination proceeds via a concerted mechanism involving a single transition state. The structures of the transition states for concerted para substitution and 3,4-cis addition are illustrated in Figure 2. A concerted mechanism for arene nitrosation was discussed by Skokov and Wheeler34 on the basis of computational modeling in the gas phase. Other authors also have confirmed these mechanistic features of nitrosation by EAS.35,36 The results from the theoretical modeling of anisole chlorination were substantiated by our experimental NMR investigations of the reaction.15 Though most of the anisole is converted into the expected o- and p-chloroanisole, about 7− 8% of the initial reactant is transformed into addition products containing four chlorine atoms (Figure S2). These compounds may only be formed following earlier addition of a single Cl2. We further conducted a theoretical investigation of the mechanisms of chlorination of benzene, toluene, and naphthalene with molecular chlorine in a simulated nonpolar solvent (CCl4).16 The results of computational modeling at the B3LYP-D3/6-311+G(2d,2p) level are in agreement with the above-discussed findings for anisole chlorination. Figure 3 shows a schematic representation of the derived alternative potential energy surfaces for the toluene + Cl2 reaction in CCl4. C

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The formation of the nitronium ion results from the equilibrium shown in Scheme 3. The conversion to nitronium ion is only partial. Thus, the reaction mixture contains various neutral and ionic species. The bisulfate ions and sulfuric acid can both act as proton-removing agents at the last stage of the reaction. However, the sulfuric acid is much more abundant and is favored as the proton-abstracting reactant considering the entropy contributions to the transition state energy. The inclusion of an explicit H2SO4 molecule in the computational modeling is an approximate approach. However, it reflects two important functions of the medium: the specific interaction of the nitronium ion with the solvent and the role of sulfuric acid as a proton-removing reagent. As mentioned above, the solvent also separates the nitronium ion from the bisulfate ion, which otherwise would collapse into each other and recombine immediately. Nonetheless, under real reaction conditions the immediate environment of the NO2+ ion would be much more complicated. This of course would be reflected in the energies of the considered critical structures along the reaction path. The results revealed that the nitration of benzene by mixed acid proceeds along the classic two-stage mechanism involving the intermediate formation of π- and σ-complex intermediates. The structures of the predicted intermediates and transition states are shown in Figure 4. The computations using

of 0.97 for the reaction. This result is in accord with both the asynchronous concerted substitution and AE pathways. Although the direct substitution proceeds along a concerted pathway, the breaking of the C−H bond takes place later than the highest point of the potential energy surface.

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BENZENE NITRATION WITH MIXED ACID The nitration of benzene by mixed acid is a reaction with wide industrial applications. Thus, the interest in its mechanism was brought to the attention of chemists as early as the beginning of the 20th century, when Euler39 suggested that NO2+ is the nitrating agent. This hypothesis was confirmed later in the studies of Bennett, Brand, and Williams,40 Westheimer and Kharash,41 and Hughes, Ingold, and Reed.42 According to these studies, the aromatic nitration pathway follows the classic twostep mechanism. Numerous experimental and theoretical studies have been devoted to detailed analysis of the aromatic nitration mechanism (for surveys, see, e.g., refs 9, 11, and 43). One of the interesting developments is the proposed single electron transfer (SET) mechanism for aromatic nitration.44−47 According to the SET mechanism, transfer of an electron from the aromatic π system to the nitronium unit takes place during the initial stage of π-complex formation, resulting in an ionradical intermediate. This intermediate is further transformed into an arenium ion (σ complex), leading eventually to the final nitro product. Theoretical studies of the nitration reaction have indeed confirmed the significant transfer of electronic charge in the π-complex formation step.47−50 The dominant opinion in later years is that aromatic nitration proceeds via the SET mechanism. However, recent computational modeling of benzene nitration by Parker et al.51 did not establish evidence for electron transfer and supports the classic Ingold−Hughes polar mechanism. It should be underlined that most of these studies considered the process in the gas phase, and solvent effects were not examined in detail. A proper treatment of solvent influences is particularly important for the most basic nitration reaction, the nitration of benzene by “mixed acid” (a mixture of concentrated nitric and sulfuric acids). The presence of NO2+ ions in the solution (Scheme 3) is only due to the solvent molecules, which keep the nitronium and bisulfate ions separate.

Figure 4. Optimized structures of intermediates and transition states along the reaction path for benzene nitration with NO2+ aided by H2SO4 in simulated polar solvent (ε = 109) at the M06-2X/6311+G(2d,2p) level.

Scheme 3. Nitronium Ion Formation in Mixed Acid Solution

alternative basis sets provided quite analogous results.18 Similar results for the structures of intermediates and transition states were also obtained using the B3LYP/6-311+G(2d,2p) method.18 Following the formation of an initial π complex, the reaction path reaches the transition state with highest barrier (TS1). The IRC computations show a smooth transition from TS1 to an arenium ion intermediate. An intriguing point in discussions of the mechanism of benzene nitration by mixed acid is the analysis of charge shifts between the reactants at the stage of π-complex formation. NBO54 and Hirshfeld55 atomic charges were evaluated for two types of π complexes: the complex resulting from the interaction of the nitronium ion and benzene in isolation (gas phase) and the complex established within our computational modeling (Figure 4). The results from the population analyses are presented in Figure 5. Both methods predict substantial electron density transfer (∼0.7e) from the aromatic

Our recent combined theoretical and experimental investigation of benzene nitration by mixed acid18 provided new insights into the chemistry of this key industrial process. We obtained for the first time experimental UV/vis spectroscopic evidence for the initial π-complex intermediate of this reaction. We also conducted broader theoretical modeling of the reaction by considering not only the bulk solvent effects but also the specific interactions of an explicit solvent (H2SO4) molecule with the critical structures along the reaction path. Our computations employed the G09 and Molpro programs. The M06-2X52 and B3LYP functionals combined with the 6311+G(2d,2p) and 6-311++G(2df,2p) basis sets were used in modeling the potential energy surfaces. Reactants, intermediates, transition states, and products were connected via IRC computations. We applied the CPCM method53 in modeling bulk solvent effects. D

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Figure 5. NBO (top, black) and Hirshfeld (bottom, gray) charges in the π complex formed during benzene nitration with NO2+ (A) in isolation (gas phase) at the B3LYP/6-311+(2d,2p) level and (B) in the presence of an explicit H2SO4 molecule in a simulated highly polar solvent (ε = 109) at the M06-2X/6-311+(2d,2p) level.

equilibrium between the acids (Scheme 3) continuously supplies NO2+ ions as the reaction proceeds. The nature of the found intermediate was examined by EOM CCSD/aug-ccpVDZ computations56 of the UV/vis spectral parameters of the two alternative π-complex structures. The theoretically evaluated band positions and intensities for the π complex illustrated in Figure 5A corresponding to the interaction of isolated NO2+ and benzene (Cs symmetry) are as follows: A′, 306 nm (oscillator strength f = 0.459); A″, 429 nm (f = 0.019). No absorption above 400 nm is found in the experimental spectrum (Figures 5 and S3). Thus, the gas-phase π complex (Figure 5A) does not correspond to what is present in the mixed acid medium. The calculated spectral parameters for the π-complex structure reflecting (though approximately) the explicit interaction of the nitronium ion with the solvent (C1 symmetry) (Figure 5B) are as follows: λmax(1) = 315 nm (f = 0.0126); λmax(2) = 311 nm ( f = 0.0122); λmax(3) = 309 nm ( f = 0.0050). These predictions are in satisfactory accord with the experimentally discovered spectral features of the intermediate.

ring to the nitronium unit for the complex in the gas phase. However, no signif icant charge transfer is predicted for the πcomplex structure evaluated with fuller consideration of the solvent effects (Figure 5). In this complex, the distance between the aromatic ring and the NO2+ unit is nearly 3 Å. This hampers the transfer of electronic charge between the principal reactants. The association of the nitronium ion with H2SO4 reduces the competitive interaction with the benzene π system. To verify these theoretical findings further, we conducted a UV/vis spectroscopic investigation of the nitration of benzene by mixed acid. Details of our experiments are provided elsewhere.18 The UV/vis spectrum of the nitrating acid (49 wt % sulfuric acid, 32.5 wt % nitric acid, and 18.5 wt % water) shows zero absorption beyond 320 nm. Addition of 0.02 M benzene results in the appearance of an increased absorption (a band shoulder) at 320 nm (Figure 6). This absorption is nearly

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SULFONATION WITH SULFUR TRIOXIDE Sulfonation is also among the most widely applied industrial EAS reactions.9,57,58 Sulfuric acid, fuming sulfuric acid, sulfur trioxide, and chlorosulfonic acid are most commonly employed as sulfonating agents. It is generally accepted that SO3 is the sulfonating agent in processes involving these alternative reagents. SO3 may attack as a free species or attached to a carrier. The classic kinetic studies of Cerfontain59,60 provided important insights into the mechanism of sulfonation with SO3 and underlined the importance of the medium in the course of the sulfonation reaction. On the basis of these investigations, Cerfontain proposed59 the reaction sequence for the process shown in Scheme 4. It is seen that along the examined pathways the formation of a σ-complex arenium ion−bisulfate zwitterion is postulated to be a key step. Further interaction with ArH converts it into benzenesulfonic acid. The different paths of the reaction depend on the medium. In a low-polarity noncomplexing solvent (weakly interacting with the reactants solvent59), Cerfontain considered that rate-controlling attack by a single SO3 results in the formation of a Wheland-type zwitterionic intermediate. Further interaction with a second SO3 molecule results in a second σ complex of 2:1 composition. Proton removal from the ipso position then leads to the pyrosulfonic acid product (Scheme 4). In complexing solvents

Figure 6. Kinetics of nitration of 0.02 M benzene (at 25 °C) with mixed acid in 1:1 HNO3/H2SO4 as followed by UV/vis spectroscopy.

twice as intense that of the nitrobenzene (0.02 M) reaction product in the same medium (Figure S3). The investigation of the reaction kinetics revealed that at ambient temperature (25 °C) the absorption at 320 nm gradually decreases to reach the intensity of the final product in 60 min (Figure 6). The 320 nm band shoulder may be associated with the π-complex intermediate. None of the other species that might be present in the reaction mixture possess absorption of comparable intensity in this spectral region (for more details, see Figure S3). The concentration of nitronium ions in the employed mixed acid solution is expected to be low. Nonetheless, the E

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(nitromethane, 1,4-dioxane), the second step was considered to be rate-controlling in accord with the measured second-order kinetics in SO3.59 We conducted DFT computations with the M06-2X functional and the 6-311+G(2d,2p) basis set on all of the critical structures along the potential energy surfaces for the sulfonation reaction paths of benzene, 1,4-dichlorobenzene, toluene, and naphthalene.19 The obtained results were further verified by SCS-MP2/6-311+G(2d,2p) computations. We investigated the mechanisms of sulfonation for reactants in isolation (gas phase) and by applying the IEFPCM method31 to simulate noncomplexing (CFCl3 and CCl4) and complexing (CH3 NO 2 ) solvents. Our theoretical modeling of the mechanism of sulfonation in the gas phase and in noncomplexing solvents produced unexpected shapes of the potential energy surfaces. No σ-complex intermediate could be located when exploring the interaction between the arene derivatives and a single SO3 molecule, even though we applied a variety of methods in the search for such species. Instead, a concerted transition state follows the formation of a reaction complex. However, the evaluated energies of these transition states were too high and do not correspond to the mild experimental conditions for these reactions. The TS energies became distinctly lower only when we considered the autocatalytic effect of a second SO3 molecule. Interaction with a preexisting SO3·SO3 dimer species in the solution or simple catalysis by a second SO3 led to significantly lower reaction barriers, in good accord with experiment. Notably, the experimentally found pyrosulfonic acid final product contains two SO3 units.59 Scheme 5 illustrates the concerted reaction

Figure 7. Sketches of the M06-2X/6-311+G(2d,2p) free energy surface profiles comparing the sulfonation of benzene with one SO3 (unfavorable, concerted) and the two alternative energetically more favorable alternative pathways with two SO3 molecules in modeled (IEF-PCM) CFCl3 and CH3NO2 solvents.

modeled potential energy surfaces for sulfonation of benzene with one SO3 in simulated CFCl3 solvent and that with two SO3 molecules in CFCl3 as well as the stepwise mechanistic path in CH3NO2 solvent. The remarkable effect of the nitromethane solvent is clearly seen. It changes the mechanistic pathway from concerted to stepwise and reduces the reaction barrier. The geometries of the transition states for concerted sulfonation (TS) and the stepwise process (TS1) in nitromethane are illustrated in Figure S4.

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QUANTIFYING REACTIVITY AND POSITIONAL SELECTIVITY Quantifying reactivity and regiospecificity has been of paramount interest throughout the history of research on electrophilic aromatic substitution reactions.4−14 This topic continues to be the focus of current research.4 Here we present briefly our recent approach based on the use of a theoretically evaluated quantity, electrophile affinity (Eα).62 Eα was successfully applied to characterize the effects of substituents and changing structure on EAS reactivity and regioselectivity. Our methodology is based on experimentally discovered correlations between the rates of some EAS processes and the stabilization energies associated with σ-complex formation.9,11 In harmony with these findings, we defined Eα as the computationally estimated energy of formation of an arenium ion σ-complex intermediate at individual positions of the arene:62

Scheme 5. Direct Mechanism for Sulfonation of Benzene with Two SO3 Molecules in Isolation (Gas Phase) or in a Nonpolar Medium

Eα = [Earene + Eelectrophile] − Earenium ion

(1)

It should be emphasized that the Eα approach is applicable only to reactions that follow the classic SEAr mechanisms. We have employed this methodology in characterizing the reactivity and positional selectivity for several EAS reactions.62,63 Good correlations between Eα and the partial rate factors (ln f values) for 11 chlorination reactions of benzene and methylbenzenes (correlation coefficient r = 0.992), nitration of substituted benzenes (r = 0.971 for 12 processes), and benzylation of benzene and substituted benzenes (r = 0.973 for 13 processes) were established. Here we illustrate the approach using our study of the application of Eα in quantifying the reactivity and positional selectivity for 37 brominations of

pathway for sulfonation of benzene with SO3 in noncomplexing solvents. Figure S4A illustrates the structure of the concerted transition state for the sulfonation of benzene with SO3. In contrast, in the complexing solvent nitromethane, the potential energy surface follows the classic stepwise SEAr mechanism involving the formation of an ArH+(SO3)2− σcomplex intermediate. Notably, under these conditions a coordinated attack by two SO3 molecules is still needed to reach acceptable reaction barriers. This mechanism is in accord with the established second-order kinetics in SO3 in nitromethane solvent.60,61 Figure 7 compares the theoretically F

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pathway can be quantified with the newly introduced theoretically estimated quantity, electrophile affinity (Eα). Eα measures the energy of formation of the σ-complex intermediates. These investigations have shown that with the aid of contemporary theoretical and experimental approaches unknown features of classic organic reactions may be revealed and some “old dogmas” questioned. Further research on electrophilic aromatic substitution reactions is expected to illuminate new sides of the chemistry of these fundamental processes.

benzene and various mono-, di-, and polysubstituted benzenes catalyzed by perchloric acid in water. The experimental relative rates of chlorination are from the studies of Dubois et al.64 The electrophile affinity values were calculated at the B3LYP/6311+G(2d,2p) level in simulated water solvent. The plot of the relationship between Eα and log krel is shown in Figure 8. An excellent correlation for these substitutions reflecting changes in both structure and position is obtained.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.accounts.6b00120. Computed potential energy surfaces for anisole chlorination, structures of anisole chlorination side products, additional UV/vis spectra for benzene nitration, geometries of transition states for benzene sulfonation, and references indicating where to find the Cartesian coordinates of optimized structures discussed in the text (PDF)

Figure 8. Plot of electrophile affinity Eα vs log krel for a set of 37 substitution processes in the bromination of benzene and variously substituted derivatives. Eα is the electrophile affinity evaluated for the modeled solutions in water.

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AUTHOR INFORMATION

Corresponding Authors

In a quite similar approach, Ashtekar et al.65 defined a theoretically evaluated halenium af f inity (HalA) to characterize and predict reaction chemoselectivity and reactivity for halofunctionalization reactions. Although a modest level of theory (B3LYP/6-31G*) is employed in evaluating the HalA scales, the study provides a valuable outlook for applications of such affinity parameters in explaining and devising electrophilic functionalization processes.

*E-mail: [email protected]fia.bg (B.G.). *E-mail: [email protected] (H.F.S.). Notes

The authors declare no competing financial interest. Biographies

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Boris Galabov received his Ph.D. from the University of Sofia in Bulgaria in 1975. He joined the academic staff of his alma mater and served as a lecturer and later as a professor in the Department of Chemistry, where he is currently Emeritus Professor of Organic Chemistry.

CONCLUSIONS AND OUTLOOK Combined theoretical and spectroscopic investigations of several electrophilic aromatic substitution reactions have revealed new mechanistic pathways for these important processes. It has been shown that in the absence of catalyst and in nonpolar media, the inherent chlorination and bromination of arenes proceed along two competitive mechanisms leading to the same reaction product: direct concerted substitution and a two-stage addition−elimination routes. Neither of these paths includes the formation of an arenium ion (σ-complex) intermediate, which is regarded as obligatory in the current literature. Our UV/vis spectroscopic study of the classic reaction of benzene nitration by mixed acid discovered the presence of a specific absorption associated with the first intermediate of the process, the π complex. Both theoretical computations and experiments showed that in contrast to the dominant opinions in the literature, no electron density transfer from the aromatic π system to the nitronium unit takes place at the stage of π-complex formation. We also showed by theoretical potential energy surface modeling that depending on the reaction medium, the sulfonation of arenes with sulfur trioxide in nonpolar (noncomplexing) media follows a single-stage concerted mechanism. In complexing solvents, the process proceeds along the classic two-stage SEAr mechanism. Both pathways involve two SO3 molecules in the rate-controlling stages. The reactivity and positional selectivity in EAS reactions that proceed along the classic mechanistic

Didi Nalbantova received her Ph.D. from the University of Sofia in 2013. Her research is focused on the application of quantum-chemistry methods and spectroscopic techniques in studying kinetics and mechanisms of organic reactions. Paul von R. Schleyer died on November 21, 2014, after brilliant careers at three different universities. At Princeton University he rose to become the Eugene Higgins Professor of Chemistry. At Erlangen he held the Chair of Organic Chemistry. At the University of Georgia he was the Graham Perdue Professor of Chemistry. His research has been cited more than 80 000 times with an H-index of 128. Henry F. Schaefer, III, served for 18 years as a professor at the University of California, Berkeley. He is currently Graham Perdue Professor and Director of the Center for Computational Quantum Chemistry at the University of Georgia.

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ACKNOWLEDGMENTS The research in Georgia was supported by the U.S. National Science Foundation (Grants CHE-1361178 to H.F.S. and CHE-1057466 to P.v.R.S.). The research in Sofia was supported by the National Science Fund (Bulgaria) (Grant DO02-124/08). We are greatly indebted to our co-workers Dr. Gergana Koleva, Prof. Svetlana Simova, Prof. Boriana Hadjieva, G

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Dr. Jing Kong, and Prof. Judy I. Wu for their critical contributions to the research described in this Account.

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DEDICATION In memory of Paul von Rague Schleyer. REFERENCES

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