Electrophilic Aromatic Substitution Reactions - ACS Publications


a concise overview of the main features of such diagrams will be presented based ..... 10, and cause thereby a split of the merged TS into two separat...
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Electrophilic Aromatic Substitution Reactions: Mechanistic Landscape, Electrostatic and Electric-Field Control of Reaction Rates and Mechanistic Crossovers Thijs Stuyver, David Danovich, Frank De Proft, and Sason Shaik J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 May 2019 Downloaded from http://pubs.acs.org on May 29, 2019

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Electrophilic Aromatic Substitution Reactions: Mechanistic Landscape, Electrostatic and Electric-Field Control of Reaction Rates and Mechanistic Crossovers Thijs Stuyver,*a,b David Danovich,a Frank De Proft,b and Sason Shaik*a

a.

Department of Organic Chemistry and the Lise Meitner-Minerva Centre for Computational Quantum Chemistry, The Hebrew University, Jerusalem 91904, Israel

b.

Algemene Chemie, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium

Abstract: This study investigates the rich mechanistic landscape of the iconic electrophilic aromatic substitution (EAS) reaction class, in the gas phase, in solvents, and under the stimulation by oriented external electric fields. The study uses DFT calculations, which are complemented by a qualitative valence bond (VB) perspective. We construct a comprehensive and unifying framework, which elucidates the many surprising mechanistic features, uncovered in recent years, of this class of reactions. For example, one of the puzzling issues which have attracted significant interest recently are the findings of a variety of concerted mechanisms which do not involve the formation of s-complex intermediates, in apparent contradiction to the generally accepted textbook mechanism. Our VB modeling elucidates the existence of both the concerted and stepwise mechanisms, and uncovers the root causes and necessary conditions for the appearance of these intermediates. Furthermore, our VB analysis offers insight into the potential of external electric fields as smart, green, and selective catalysts, which can control at will reaction rates, as well as mechanistic crossovers, for this class of reactions. Finally, we highlight how understanding of the electric fields effect on the EAS reaction could lead to the formulation of guiding principles for the design of improved heterogeneous catalysts. Overall,

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our analysis underscores the powerful synergy offered by combining MO and VB theory to tackle interesting and challenging mechanistic questions in chemistry.

Introduction Electrophilic aromatic substitution (EAS) reactions are arguably among the most iconic reactions in organic chemistry. Many concepts central to this branch of chemistry, such as the inductive-, mesomeric- and substituent-effects have emerged from the experimental study of the kinetics for this type of reactions.1 As such, EAS occupies a central role in most introductory and advanced organic chemistry textbooks and monographs. 2 Furthermore, EAS reactions afford a facile route to many key industrial products and intermediates such as ethylbenzene and chlorobenzene, explaining the continuing interest in expanding our understanding of its chemistry and mechanistic details.3 Traditionally, the mechanism of this industrially important type of reactions has been posited to involve the formation of both a p-complex as well as a s-complex intermediate, also known as a Wheland intermediate (cf. Figure 1).4

Figure 1. Textbook representation of a typical electrophilic aromatic substitution (EAS) reaction involving a dihalogen (X2) electrophile.

Experimental isolation of various long-lived s-complexes by Olah et al.5 – and more recently by both Rathore et al. 6 and Chowdhury and co-workers 7 – offered unequivocal evidence for the validity of this mechanism and contributed to the acceptance of its generality



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as the dominant pathway for all EAS reactions. The initial computational investigations into this type of reaction appeared to further confirm this point of view.8 Recently however, the assumed generality of this mechanism has been challenged,1,3, 9 , 10 , 11 , 12 , 13 , 14 , 15 when Schleyer and co-workers extensively scrutinized the mechanisms of chlorination, bromination and sulfonation of a set of aromatic compounds under a variety of conditions. Schleyer et al. found strong deviations from the above mentioned textbook mechanism, especially when the reaction is considered in apolar solvents and/or in the absence of an external catalyst.1,9,10,11,12,15 Their calculations on the chlorination of benzene and toluene for example pointed to a combination of different competing autocatalytic reaction pathways consisting of multiple concerted steps and involving an HCl product molecule, without the formation of a s-complex intermediate.12 Additionally, Schleyer and co-workers were unable to detect a direct (one-step) concerted substitution pathway for the chlorination reaction, even though a previous study by the same authors had revealed the existence of exactly such a pathway for the analogous bromination reaction.9 More recently, Van Lommel et al.3 argued that even in apolar solvents, the chlorination reaction of benzene can involve a transient s-complex alongside the fully concerted pathways discovered by Schleyer et al. Furthermore, Van Lommel et al. reported that the mechanistic choice (concerted or via a s-complex) is dependent on the charge-stabilization potential of the specific solvent involved.3 Other groups have waded into this controversy concerning the concerted versus stepwise nature of EAS reactions as well. Shernyukov et al. examined for example the noncatalytic bromination of benzene and identified concerted mechanisms analogous to the chlorination pathways identified by Van Lommel et al. However, in the case of the bromination reactions, the authors did not find a significant autocatalytic effect by HBr, but a remarkable rate



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enhancement of the reaction was observed when large Br-clusters were included in the computational model instead of Br2.14 The myriad of distinct reaction pathways proposed in recent years, as concisely summarized above, sketches an increasingly complex (and arguably bewildering) landscape for the EAS process. The various scenarios appear to even dispel altogether the traditional notion that all EAS reactions adhere to a uniform reaction paradigm, as describe in textbooks.2 Indeed, from the above outline one could infer that the EAS reaction pathways can only be explored and discussed on a system-by-system basis, with limited systematics or overarching framework. As such, one can pose the following question: "Despite this situation, is it still possible to paint a comprehensive and unifying picture of the electrophilic aromatic substitution reaction in which the diverse mechanistic features uncovered in recent years can be embedded? And furthermore, can one control the mechanistic choice?”. This will be the focus of this contribution. Below, we will demonstrate that qualitative valence bond (VB) models are ideally suited for such an endeavor and enable unrivaled insight into the mechanistic controversies raised above. Among others, we will discuss the general conditions under which a transition from a concerted to a stepwise mechanism in a chemical reaction can occur and use this knowledge to assess the existence of s-complexes in the EAS reaction under various conditions. Furthermore, our VB modeling and analysis also affords direct insight into the potential of external electric fields as smart – and green – catalysts for this reaction class.16, 17,18,19,20

Qualitative Valence Bond Theory Before we can get to this point, we first need to introduce some basic notions of qualitative VB theory, in order to facilitate the ensuing discussions.



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Qualitative VB analysis involves the construction of VB reactivity diagrams which reflect the shape of the potential energy surface (PES) associated to a given chemical system along a chosen reaction coordinate. A comprehensive guide on the systematic construction of VB diagrams for the treatment of chemical reactivity problems can be found in chapter 6 of ref. 21. An alternative introduction to this topic can be found in the recent tutorial in ref. 22. Here, a concise overview of the main features of such diagrams will be presented based on a simple model reaction: the hydrogen exchange reaction (cf. Fig. 2).

Figure 2. VB structures contributing to the state-wave-function throughout the H-exchange reaction. 1R and 2P are the covalent or HL structures describing the H-H bonds in the reactant (R) and product (P) respectively. The remaining structures (3-8) are ionic- and CT-structures, which mix into the wave-function to a variable extent throughout the transformation.

The first step towards the construction of a VB diagram involves the plotting of the diabatic energy curves corresponding to the electronic structure of the reactants and products for the considered reaction as a function of the reaction coordinate. For the simple model reaction considered here, the H-H bonds in the reactants (R) and products (P) can – in first

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instance – be approximated respectively by the Heitler-London (HL) VB structures 1R and 1P, wherein the arched lines connecting the electrons signify singlet-electron pairing. By definition, the optimal reactant geometry is the geometry stabilizing structure 1R the most, whereas the optimal product geometry is the geometry stabilizing structure 2P the most. These two limiting geometries are connected through the reaction coordinate. As one proceeds from the optimal reactant geometry towards the optimal product geometry, 1R will rise in energy. At the optimal product geometry, 1R can be considered as the promoted – or excited – state of the product P and is usually denoted by P*. Equivalently, 2P will also rise in energy as one moves away from the optimal product geometry and, at the optimal reactant geometry, this VB structure can be considered as the promoted state of the reactant R, denoted by R*. This way, one has obtained the rudimentary shape of two crossing diabatic energy curves in a simple valence bond state correlation diagram (VBSCD),22,23,24 cf. Fig. 3a. As explained in ref. 21-24, the promotion energy required to excite R to R* and P to P* can be expressed as the singlet-triplet excitation energy of the short (H-H) bond (corresponding to twice the bond energy). The magnitude of this promotion energy (together with the thermodynamic driving force of the reaction) determines the height of the crossing point between the two energy curves. Once the energy curves corresponding to the diabatic states have been constructed, one proceeds to consider the interaction between the individual diabatic states and complete thereby the shape of the adiabatic energy curve, which is the energy curve of the full wave function. At the optimal reactant geometry, the adiabatic energy curve essentially coincides with the diabatic curve R (R* does not contribute to the wave function in this geometry) and equivalently, at the optimal product geometry, the adiabatic curve essentially coincides with the diabatic curve P. However, at the crossing-point between the two diabatic energy curves (corresponding to the transition state (TS) geometry), 1R and 2P mix significantly, pushing the adiabatic energy curve



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below the crossing-point and leading to an avoided crossing in the VBSCD. The resulting energy hill corresponds to the observed barrier of the chemical reaction (Fig. 3a).

Figure 3. Generic VB reactivity diagrams, depicting the diabatic (in dotted lines) and adiabatic (in bold) energy curves along the reaction coordinate connecting the reactants (R) to the products (P). (a) The covalent structures (Fcov, i.e. 1R and 2P) describe the covalent bonds of R and P. The mixing of these two VB structures leads to the VB state shown in the bold curve, in which YTS denotes the transition state, B the resonance interaction between the two curves and GR and GP the promotion energies on the reactant and product side respectively. (b) the same VB diagram but now including the ionic- and CT-structures (Fion/YCT); the downward arrow indicates the lowering of YTS due to the admixture of these diabatic structures.

So far, we have limited our discussion of VB diagrams to the main HL structures. As evident from Fig. 2, other VB structures can be defined as well, namely the ionic- and charge transfer (CT)-states. These structures mix, in principle, with the HL-structures along the reaction coordinate. Ionic structures 3 and 4 contribute to the H-H Lewis-bond in 1R, while 5 and 6 contribute to the full Lewis-bond in 2P. Often these ionic structures are directly combined



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with the HL structures to form the so-called diabatic Lewis structures (vide infra). Structures 7 and 8 correspond to CT states because they involve an odd number of electrons in both the right-hand and left-hand bonds. At the optimal reactant or product geometries, 7 and 8 generally do not mix with the main structures 1R and 2P. In principle, this mixing becomes allowed at the TS geometry (cf. Fig. 3b), but is subject to HOMO-LUMO orbital symmetry match (which figure in allowed vs. forbidden reactions21, 22,24). The smaller the spacing between the diabatic curve associated to the Lewis- and the CTstates in the region around the TS geometry, the bigger the extent of interaction between them: the adiabatic curve is pushed progressively lower in this region as the CT state comes down in energy. Generally speaking, when the curve associated to one (or more) of the CT states in a VB diagram drops below the curves associated to the Lewis states of reactants and products in the TS region, then a kinetically stable intermediate, i.e. a local minimum in the PES, can be formed. Such a situation corresponds to a mechanistic cross-over (vide infra). Instead of a single hill-shaped feature along the reaction coordinate connecting the reactant and product, one now observes a double dip profile (cf. Fig. 4).



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Figure 4. The same generic VB diagram as in Figure 3, with the addition of the YCT curve, which drops below the crossing point of the diabatic reactant and product curves. As a consequence of the three state-curve mixing, an intermediate is formed halfway along the reaction coordinate instead of a transition state. As shown by the bold state-curve, the reactionmechanism has transformed from a concerted mechanism to a stepwise one.

Now that the main concepts of qualitative VB theory have been introduced, we can turn to a general analysis of EAS reactions. Initially, we will focus specifically on the archetypical chlorination reaction of benzene, but throughout our analysis, we will make excursions to some related EAS reactions as well to illustrate the unifying nature of the viewpoint presented.

Computational Methods All calculations were performed with Gaussian 0925 at B3LYP-3D/6-311++G**26 level of theory, unless stated otherwise. Solvent effects were determined with the SMD model.27 The effects of oriented external electric fields (OEEFs) were studied using the “Field = M ± N” keyword, which defines in Gaussian 09 the axis of the OEEF, its direction along that axis, and its magnitude. One should note that in Gaussian 09, the positive direction of the electric field vector is defined from the negative to the positive charge, which is opposite to the conventional definition in physics.16 As such, whenever the dipole moment (µ) and the field vector (F) are oppositely oriented relative to one another, the OEEF will stabilize the dipole. Electric fields were consistently aligned with the dipole moment of the system, in agreement with a recent study by Wang et al. in which OEEFs were posited to act as tweezers aligning the dipole moment of the molecular system with the electric field.18 Except for the rigid scans in Fig. 19 and 21, all molecular systems investigated were always (re)optimized in the presence of the respective solvent or electric field.



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The (Concerted) Pathways of the EAS Reaction In Fig. 5, a schematic representation of the electrophilic aromatic chlorination reaction is shown.

Figure 5. Schematic representation of an electrophilic aromatic substitution reaction between benzene and Cl2. Globally speaking, what happens throughout this reaction is the following; a C-H and a Cl-Cl bond are broken and a C-Cl and H-Cl bond are formed instead. Thus, one can formally construct a VBSCD for this reaction in terms of Lewis states as in Fig. 6.

Figure 6. The formal VBSCD diagram associated to the reaction depicted in Figure 5.



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The promotion energy separating the reactant ground state from the excited reactant state (GR), can be approximated as follows: G" = ∆𝐸&' 𝐶𝑙 − 𝐶𝑙 + ∆𝐸&' 𝐻- 𝐶. − 𝐻 ,

(1)

where ∆𝐸&' 𝐶𝑙 − 𝐶𝑙 and ∆𝐸&' 𝐻- 𝐶. − 𝐻 correspond to the singlet-triplet decoupling energies of the Cl-Cl bond and the phenylic C-H bond respectively (corresponding to twice the bonding energy, cf. ref. 21). Ignoring the effect of the CT states for a moment (even though they play a decisive role in this reaction; vide infra), the TS of this reaction should be located at the crossing between the reactant and the product state, as discussed in the previous section. At this crossing point, the reactant and product states are by definition degenerate. Apart from a fully dissociated structure in which all active bonds have been broken completely, the only geometric arrangement of the nuclei that can satisfy this condition is the one depicted in Fig. 7.

Figure 7. The concerted TS of the direct EAS reaction in Figure 5 in the absence of CT states.

So, if this reaction were to occur in this direct and concerted way, the TS would have to

adopt approximately this shape. Given the orbital symmetry mismatch in [2+2] cycloadditions,28 the proposed TS geometry in Fig. 7 can be expected to lead to only a limited resonance interaction B between the reactant and product state so that the adiabatic curve will pass only slightly below the crossing point drawn in Fig. 6 (for an in-depth discussion of the influence of orbital symmetry on the resonance interaction between diabatic curves, we refer to



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ref. 21 and 24). The final VB diagram for this direct concerted EAS reaction is shown in Fig. 8.

Figure 8. The full VB diagram of the reaction depicted in Figure 5 in the absence of CT states. It is important to note that a competing and structurally very similar concerted TS, which involves the concerted addition of the Cl2 molecule to the p-system of the benzene molecule instead of a direct substitution of the H substituent by one of the Cl atoms, should exist as well. This structurally related TS is part of an alternative multi-step reaction pathway of the EAS reaction, previously described by Van Lommel et al. (Fig. 9).3



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Figure 9. A summary of the alternative multistep pathway of the aromatic chlorination reaction.3 The structurally similar TS to the direct substitution one depicted in Fig. 7 has been framed. Below, the alternative reaction pathway involving this TS will be referred to in short as the CC-pathway.29 The promotion energy associated to the first step of this alternative mechanism will be significantly lower than the promotion energy associated to the direct concerted reaction (cf. Eq. 1), G" = ∆𝐸&' 𝐶𝑙 − 𝐶𝑙 + ∆𝐸&' 𝐶. 𝐻. ,

(2)

with ∆𝐸&' 𝐶. 𝐻. corresponding to a singlet-triplet excitation within the conjugated p-system in the phenyl ring. As such, this second TS can be expected to be lower in energy than the original one depicted in Fig. 7. Given the structural similarity between TS1 and TS2, an important question now comes to mind: "will the two concerted TSs be distinct saddle points in the PES or will they interact sufficiently to combine into a single (delocalized) TS?". Fig. 10 graphically depicts the two possible scenarios, along the red RC’ coordinate that connects the two TSs.



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Figure 10. (a) The two competing reaction pathways discussed above depicted in a single graph with RC 1 corresponding to the reaction coordinate associated to the direct concerted reaction pathway and RC 2 corresponding to the reaction coordinate associated to the first stage of the multistep pathway depicted in Fig. 9 (the CC-pathway). RC' corresponds to the auxiliary reaction coordinate which can be defined as connecting the two TS geometries. (b) Two possible energy profiles can be encountered along this auxiliary reaction coordinate: either a hill-shaped one (bottom left) or a single-valley-shaped one (bottom right). The latter profile



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corresponds to the formation of a single (delocalized) TS2’. Given its relative closeness in energy to TS2, the single TS2’ will resemble TS2 more than TS1.

Our calculations at the B3LYP-D3/6-311++G**-level of theory indicate that for the chlorination reaction, the two TSs indeed merge into a single one, as in the situation depicted in the bottom right of Figure 10. Nevertheless, it appears that one remains very close to the tipping point between the two situations for this reaction: reducing the basis set size to 3-21G for example enables the localization of two independent concerted TSs separated by only 2-3 kcal/mol, whereas a more extensive basis set leads – as stated above – to the collapse of both TSs into a single concerted one. As mentioned above, the observation that TS2 is lower in energy than TS1 could be straightforwardly predicted from Eqs. 1 and 2. Thus, given that TS2 is slightly lower in energy, it will be the main contributor to the merged minimum in the adiabatic curve along RC'. As such, the geometry of the merged TS will mainly resemble the geometry of the TS associated to the CC-pathway. This corresponds exactly to the previous findings by both Schleyer and his co-workers and Van Lommel et al.: they were both unable to locate a TS associated to a direct substitution pathway and were only able to report a stepwise concerted pathway involving the CC-addition as a first step.12,3 A further indication of the proximity to the tipping point between the co-existence of two TSs and a single merged one for the chlorination reaction can be found in the computational results for the analogous bromination reaction presented by Schleyer et al. in ref. 9. Thus, the replacing Cl2 by Br2 reduces the resonance interaction between the two diabatic curves along RC' in Fig. 10, and cause thereby a split of the merged TS into two separate saddle points in the PES. In their calculations at RB2-PLYP/6-311+G(2d,2p) level of theory, Schleyer and coworkers found TS1 to be 2.4 kcal/mol higher in energy than TS2. Calculations at B3LYP-D3/6-



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311++G**-level of theory within the context of the present study lead to an almost identical value for the energy difference between the TSs of 2.3 kcal/mol. Note that these numbers are in perfect agreement with our qualitative reasoning based on the promotion energies associated to the two competing reaction pathways as well as with our calculated difference between the TS1 and TS2 in the case of the chlorination reaction in the 3-21G basis set. Both of the concerted reaction pathways discussed above involved 4-membered TSs in a concerted mechanism (cf. Fig. 7 and Fig. 9). As mentioned above, the orbital interaction between the incoming reactants in such a geometry is generally limited, leading to a low resonance stabilization B.21 However, there is a straightforward way to mitigate this unfavorable orbital overlap at the transition state geometry: incorporation of another species, e.g. a product molecule of the EAS reaction (HCl in this case), in the mechanism so that a hexagon instead of a square can be formed in the TS geometry.21,24 Incorporation of an additional molecule in the mechanism will obviously cause the promotion energy associated with the reaction to increase since now an additional bond has to be "prepared" for reaction,

G",123 = G",456123 + ∆𝐸&' 𝐻 − 𝐶𝑙 ,

(3)

but this increase will be more than off-set by the lowering of the adiabatic curve caused by the improved mixing between the two states at the [4+2] transition state geometry.30 Given that the reactant state and product state should be degenerate at this geometry, the transition state for the autocatalytic direct concerted reaction pathway has to look approximately as in Fig. 11.



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Figure 11. The projected TS of the reaction depicted in Figure 5 in the presence of HCl.

The VB diagram for this reaction will then look approximately as in Fig. 12.

Figure 12. The full VB diagram of the reaction depicted in Figure 5 in in the presence of HCl.

A similar analysis could be performed for the concerted first step of the alternative stepwise mechanism shown in Fig. 9 as well. Thus, participation of a product HCl molecule



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into the reaction mechanism can be expected to lower the barrier of the concerted reaction pathways, i.e. the reaction is autocatalytic in nature. As mentioned before, this autocatalytic nature of the chlorination reaction has been corroborated by the previous calculations found in the study of Schleyer and co-workers and Van Lommel et al. respectively.12,3 Considering that both a distinct autocatalytic direct concerted pathway and an autocatalytic stepwise pathway have been identified in both of the computational studies mentioned above, one can conclude that the profile of the PES along the reaction coordinate connecting the two transition states (RC' in Fig. 10) has turned from a single-valley-shape into a hill-shape upon incorporation of the HCl molecule. As a final note on this topic, we would like to point out that the autocatalytic effect caused by a transition from a 4-membered to a 6-membered ring in the TS is not limited exclusively to the participation of product molecules in the mechanism; in their study on the mechanism of the sulfonation reaction of benzene, Schleyer and co-workers demonstrated that incorporation of two SO3 molecules in the mechanism can lead to an equivalent effect (Fig. 13).10 This result for the sulfonation reaction has since been corroborated by others groups, and additional related pathways involving TSs with 6 (or more) -membered rings have been proposed as well.13

Figure 13. The autocatalysed sulfonation reaction of benzene involving two SO3 molecules as first described by Schleyer et al. in ref. 10.



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Whence s-complexes? Up to this point, we have not taken the presence of ionic/CT states into account in our mechanistic analysis. Consequently, no s-complexes – whether they be transient species or actual intermediates – have appeared in our discussions so far. Indeed, as mentioned before, scomplexes can be directly connected to a CT state (Fig. 14).

Figure 14. The charge transfer state, involving electron transfer from the p-system of benzene to the Cl-Cl bond, thus giving rise to the formation of a s-complex, known as the Wheland intermediate, which is depicted on the right-hand side.

The extent to which the CT state depicted in Fig. 14 mixes into the adiabatic state along the reaction coordinate in Fig. 8 will determine whether s-complexes will play an important role in the mechanism of the EAS reaction or not. If the CT state remains significantly above the HL states associated with the reactant and product at every point along the reaction coordinate, then the picture sketched in the previous section is obtained: every reaction step of the mechanism is completely concerted and no s-complexes will appear in the ground state PES. However, as the CT state becomes stabilized and approaches the Lewis state-curves in the region around the TS geometry, its weight in the adiabatic curve will rise. Consequently, the concerted TS will become increasingly asynchronous, i.e. one of the Clatoms in the TS becomes increasingly distant from the benzene moiety and one can observe a gradual shift towards a s-complex-like geometry. Nevertheless, as long as the CT state does not cross below the HL states, the s-complex can only be transient in nature, meaning that a



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single barrier remains along the reaction coordinate. Once the CT state crosses the diabatic Lewis curves, the barrier in the adiabatic profile will split in two, leading to the formation of an actual s-complex intermediate (Fig. 15). From this point on, no direct concerted mechanism can be observed anymore; the original saddle point in the PES has collapsed into a local minimum.

Figure 15. Dependence of the mechanism of the EAS reaction on the height of the CT state: A high-lying CT state will lead to a concerted reaction pathway, while a low-lying CT state will give rise to a stepwise one with the formation of a s-complex (Wheland) intermediate.31



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One can straightforwardly see this transition at work when one considers the evolution in the geometry of the concerted TS for a set of solvents with increasing polarity. As one moves from the gas phase, over CCl4, to ether, the asynchronicity in the TS increases (cf. Fig. 16; one C-Cl distance shortens slightly from 1.93 Å to 1.85 Å, whereas the other C-Cl distance increases from 3.61 Å to 4.42 Å). Furthermore, the charge accumulation on the more distant Cl-atom becomes increasingly pronounced; in the gas phase this charge amounts to -0.44 e, in the presence of an ether solvent, this has increased to -0.72 e.

Figure 16. The evolution of the concerted TS as one increases the polarity of the solvent: the gas phase, CCl4 and ether. The C-Cl distance for the more distant Cl atom is denoted (in Å), as well as the charge of this distant Cl (in e). Calculations performed at B3LYP-3D/6-311++G** level of theory.

Beyond a critical polarity level of the solvent, the concerted TS disappears altogether as predicted by our VB modeling above. At this point, the concerted TS has morphed into a scomplex intermediate and a search for saddle points in the PES now leads to TSs connecting this stable intermediate to either the reactant or to the product (cf. Fig. 17). Furthermore, we see that the charge on the distant Cl continues to approach –e, indicating that the CT state becomes more and more dominant. Note that the solvents used in Fig. 17 constitute hypothetical



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limiting situations; in reality, the solubility of the non-polar reagents under consideration here is extremely low in either methanol or water.

Figure 17. (a) The first transition state obtained in polar solvent (methanol and water), corresponding to the formation of the s-complex intermediate; (b) The second transition state in which one of the Cl atoms migrates to the other face of the benzene-plane in the s-complex. The charge on the distant Cl for both solvents is mentioned at the bottom (in e). Calculations performed at B3LYP-3D/6-311++G** level of theory.

Do Concerted and Stepwise Mechanism Coexist? One can wonder now whether both a concerted and stepwise (polar) mechanism could co-exist and compete at some intermediate polarity of the solvent. Given the discussion above, one could expect that such a situation would arise from a crossing of the CT/ionic states and the HL states as the distant Cl is removed further and further form the benzene moiety in the concerted TS geometry (cf. Fig. 18).



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Figure 18. The dissociation profile of the concerted TS in the hypothetical situation in which two competing reaction pathways would exist. The second minimum is formed by the crossing of the FHL- and FCT/ion-curves along the reaction coordinate and corresponds to a (transient) scomplex.

While it is impossible to rule out completely the existence of such a situation under specific circumstances, we have not found any computational evidence for this situation in the solvents we tested. Thus, dissociation profiles calculated for a variety of solvents all lead to a single minimum which either corresponds to the concerted TS (though asynchronous) or to the s-complex intermediate (Fig. 19). As such, it seems that both minima generally collapse into one.



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Figure 19. A rigid scan along the C-Cl distance for the distant Cl performed on the gas phase TS geometry in the presence of different solvents. Calculations performed at B3LYP-3D/6311++G** level of theory.

The Effect of Oriented External -Electric Fields OEEFs are known to stabilize CT/ionic states relative to (unpolarized) Lewis ones.19 The extent of stabilization depends on the dipole moment of the ion pair of the CT structure,

Δ𝐸 = 𝐹.



𝜇 , 4.8

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where ΔE corresponds to the stabilization energy (expressed in eV), F to the electric field (in V Å-1) and 𝜇 to the dipole moment (in Debye). The dipole moment in its turn is proportional to the distance between the poles,

𝜇 = 4.8 𝑞 𝑅 ,

(6)

with q the charge of the poles (in e units) and 𝑅 the distance (in Å) between them. Thus, returning to the dissociation profile of Fig. 18, when an external electric field is oriented along the reaction coordinate in this profile (or the direction in which the Cl-atom is being displaced is aligned with the applied field, cf. Computational Methods section),19 then the CT/ionic curve will become increasingly stabilized as the Cl– displacement increases (Fig. 20), since the dipole moment of the system increases.

Figure 20. The dissociation of the concerted TS associated with the aromatic chlorination reaction in the presence of an external electric field aligned with the reaction coordinate.



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This is exactly what is found when one performs similar scans as in Fig. 19 but then with a varying field strength (Fig. 21).

Figure 21. A rigid scan performed on the gas-phase TS geometry in the presence of an external electric field of varying field strength. Calculations performed at B3LYP-3D/6-311++G** level of theory.

Thus, electric fields (of moderate field strength) lead to the formation of a barrier along the dissociation profile of the concerted TS. The minima in Fig. 20 and the upper panels of Fig. 21 correspond to the concerted TS which becomes increasingly asynchronous as the field strength is increased. Once the barrier in Fig. 21 is being crossed, the molecular system under consideration will dissociate completely. A s-complex will be formed, but its counter ion will be driven away towards infinity so that no actual stable intermediate can be formed. In an actual



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reaction medium, one can expect that the ejected counter ion will be able to react with other scomplexes surrounding it so that the full EAS reaction can still be completed. This expectation of the recombination of ejected ions with stable intermediates in the presence of a strong electric field is in agreement with previous findings by some of us,18,19 and with Car-Perinello Molecular Dynamics (CPMD)32 studies by Cassone et al. on the one-step synthesis of methane and formaldehyde as well as molecular hydrogen in liquid methanol.17 As such, the catalysis of the EAS reaction caused by the external field is essentially twofold: on the one hand the field leads to a reduction of the barrier associated to the direct concerted pathway and – at the same time – it introduces an alternative and competing scomplex mediated pathway which will gradually become dominant. At some critical field strength, the barrier along the dissociation profile will disappear altogether and the original direct concerted mechanism collapses into the stepwise s-complex mediated pathway discussed in the previous paragraph (cf. lower panel of Fig. 21). At this point, the only mechanism available to the molecular system is the direct nucleophilic cleavage of the Cl-Cl bond by which one of the Cl atom becomes attached to the benzene moiety (forming a scomplex) and the other is ejected towards “infinity”. As the field strength is increased further, the EEF-induced slope in the profile will become steeper and steeper, causing the barrier separating the onset of the slope and the global minimum in the PES associated to the reactant in its optimal geometry (the p-complex) to decrease in height. As a consequence, the transition state geometry of the Cl-Cl cleavage reaction step will start to resemble more and more that of the p-complex (Fig. 22). At a critical field strength, Cl-Cl cleavage will occur without a barrier and the formation of s-complexes will become a pure downhill process (Table 1).



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Figure 22. The TS geometry for the s-complex intermediate formation in the presence of an external electric field of varying field strength. Calculations performed at B3LYP-3D/6311++G** level of theory.

Table 1. The barrier height (DE≠), the C-Cl distance for the distant chlorine atom (r(C-Cl)), and charge of the distant Cl (q(Cl)) as a function of the applied field strength F.



F (VÅ-1)

DE≠ (kcal/mol)

r(C-Cl) (Å)

q(Cl) (e)

0.26

31.3

4.92

-0.64

0.39

19.8

4.30

-0.73

0.51

6.9

3.82

-0.82

0.57

2.3

3.55

-0.86

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From Table 1, we can project that in the gas phase, an electric field of slightly more than 0.57 V Å-1 is required to turn the EAS reaction into a spontaneous process. More broadly speaking, the analysis above demonstrates that OEEFs could in principle be used to catalyze EAS reactions in apolar solvents. The predictions made here about the effect of OEEFs can be verified experimentally; for an overview of the current state-of-the-art of experimental techniques available to harness electric fields in chemical synthesis we refer to the excellent review in ref. 20.

Can OEEF Effect be Made Scalable? It is important to note that most of the techniques explored so far suffer from scalability issues, hampering the adoption of electrostatic catalysis as a valuable industrial tool. One alternative, realistic approach to potentially achieve electrostatic catalysis on an industrial scale would be to employ so-called "pulsed electric fields" (PEF).33 PEF is a technology originating from the food processing industry in which electric fields are pulsed through a flow reactor. Currently, it is applied mainly as a tool to disintegrate the biological tissues of bacteria with the goal of improving the preservation time of food products, but the first steps towards an alternative use as an agent effecting catalysis in chemical synthesis have already been taken.34 Even though the experimental techniques to harness external electric fields in chemical synthesis explicitly are still in their infancy, a better understanding of the impact of electric fields on reactivity can have an impact on more established subdomains of chemistry as well. For example, it could facilitate the development of improved heterogeneous catalysts for EAS reactions,7 since it has been demonstrated that zeolite frameworks exhibit significant local electric fields (LEF), which – as amply discussed above – affect directly the reactivity.35 As such, optimization of the LEFs present in zeolites could improve the catalytic capability of these materials.36



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Conclusions Throughout this work, we have taken a closer look at the electrophilic aromatic substitution reaction. We have demonstrated that qualitative VB modeling enables the construction of a comprehensive and unifying framework through which the many (seemingly surprising) mechanistic features of this class of reactions can be understood. Among others, we discussed the conditions under which s-complexes can appear in the mechanism of the EAS reaction, an issue which has attracted significant interest in recent years and has been clouded in controversy. Additionally, our VB modeling and analysis offered direct insight into the potential of external electric fields as smart, green, and selective catalysts, which can control the mechanism and energy barrier of this class of reactions at will. Furthermore, we briefly discussed how a better understanding of the influence of electric fields on the EAS reaction can lead to the design of improved zeolitic catalysts in which the LEFs, inherently present in these materials, have been optimized. Overall, our analysis underscores the powerful synergy offered by combining MO and VB theory to tackle interesting and challenging mechanistic questions in chemistry.

Supporting Information The Supporting Information is available free of charge on the ACS Publications website at http://pubs.acs.org Geometries and electronic energies for all the calculated systems.

Author Information *[email protected] *[email protected]



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ORCID Thijs Stuyver: 0000-0002-8322-0572 David Danovich: 0000-0002-8730-5119 Frank De Proft: 0000-0003-4900-7513 Sason Shaik: 0000-0001-7643-9421 Notes The authors declare no competing financial interest.

Acknowledgements T.S. acknowledges the Research Foundation-Flanders (FWO) for a position as postdoctoral research fellow (1203419N). FDP acknowledges the Vrije Universiteit Brussel (VUB) and the Research Foundation Flanders (FWO) for continuous support to the ALGC research group. Among others, the Strategic Research Program funding of the VUB is thanked for financial support. FDP also acknowledges the Francqui foundation for a position as “Francqui research professor”. S.S. is supported by the Israel Science Foundation (ISF 520/18).



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