Nucleophilic Aromatic Substitution Reactions Described by The Local Electron Attachment Energy

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Article
Nucleophilic Aromatic Substitution Reactions
Described by the Local Electron Attachment Energy
Joakim Halldin Stenlid, and Tore Brinck
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00059 • Publication Date (Web): 14 Feb 2017
Downloaded from http://pubs.acs.org on February 17, 2017
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Page 1 of 36 The Journal of Organic Chemistry
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Nucleophilic Aromatic Substitution Reactions
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Described by the Local Electron Attachment
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Energy
11 Joakim H. Stenlid and Tore Brinck*
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13 Applied Physical Chemistry, School of Chemical Science and Engineering, KTH Royal Institute
14 of Technology, SE-100 44 Stockholm, Sweden
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16 *E-mail: tore@kth.se
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19 Table of Content (TOC) graphics
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35 Abstract
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37 A local multi-orbital electrophilicity descriptor, the local electron attachment energy [E(r)], is
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39 used to study the nucleophilic aromatic substitution reactions of SNAr and VNS (vicarious
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41 nucleophilic substitution). The E(r) considers all virtual orbitals below the free electron limit and
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44 is determined on the molecular isodensity contour of 0.004 a.u. Good (R2=0.83) to excellent
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46 (R2=0.98) correlations are found between descriptor values and experimental reactivity data for
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48 six series of electron-deficient arenes. These include homo- and heteroarenes, rings of five to six
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51 atoms and a variation of fluorine, bromine and hydride leaving groups. The solvent, temperature
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53 and nucleophile are in addition varied between the series. The surface E(r) [ES(r)] is shown to
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provide better reactivity predictions than transition-state calculations for a concerted SNAr
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reaction with a bromine nucleofug, it gives substantially stronger correlations than LUMO
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6 energies and is over-all more reliable than the molecular electrostatic potential. With the use of
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8 ES(r) one can identify the various electrophilic sites within a molecule and correctly predict
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isomeric distributions. Since the calculations of ES(r) are computationally inexpensive, the
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13 descriptor offers fast but accurate reactivity predictions for the important nucleophilic aromatic
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15 substitution class of reactions. Applications in e.g. drug discovery, synthesis and toxicology
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18 studies are envisaged.
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23 Introduction
24 Nucleophilic aromatic substitutions (NAS) of electron deficient arenes are versatile and well-
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27 established synthetic tools, both for general synthesis as well as industrial purposes.1–5 In order
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29 to master this class of reactions, numerous methodologies have been derived over the years for a
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32 priori estimations of reactivity and regioselectivity. Experimental descriptors, e.g. the Hammett
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34 constants6–8 along with various empirical rules,2,9–12 as for instance the ortho/para directing
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ability of the nitro group, have been employed, as have many quantum chemical descriptors. The
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39 latter category includes the frontier molecular orbital approach (LUMO),13,14 Fukui functions,
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41 Parr’s electrophilicty index15,16 (and local hardness/softness),17 the so-called Iπ-repulsion
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44 model,18,19 relative energies of the σ-adduct intermediate20–23 (explained below) and the
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46 molecular surface electrostatic potential,24,25 among others. Quantum chemical approaches are
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49 especially useful for compounds with complex substituent patterns where the combined
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51 substituent effect is difficult to predict, and when no experimental data is available. This is for
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53 instance the case for previously unreported and/or short-lived compounds. However, few if any
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56 of the above methods are able to combine computational efficiency, accuracy and ease of
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automation in their predictions, which is often required for large-scale screenings or on-the-fly
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6 analysis.
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9 The arguable most well-recognized and versatile nucleophilic aromatic substitution reaction is
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11 the two-step addition-elimination reaction, known as SNAr. This type of reaction takes place
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between an electron deficient arene (e.g. nitro-arenes or pyridine derivatives) and a suitable
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16 nucleophile.3 The putative mechanism2,3,5 proceeds over a non-aromatic σ-adduct intermediate
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18 (also known as the σ-complex or the Meisenheimer complex), before a leaving group (often a
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21 halogen) is expulsed to regain the aromaticity as the product is formed. This mechanistic picture
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23 has, however, been questioned lately especially for weakly activated or deactivated substances
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25 with favorable leaving groups, e.g. bromide or chloride, where there are indications of a
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28 concerted reaction mechanism.20,26–28 A closely related, but less recognized, reaction type is the
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30 vicarious nucleophilic substitution (VNS).4,29–33 In the VNS reaction the sites occupied by
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33 hydrogen atoms are substituted. It has been found that addition to these sites proceed much faster
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35 than addition to e.g. halogenated sites. However, reaction via the SNAr mechanism at the
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hydrogen occupied sites would lead to an hydride anion leaving group, a much less favorable
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40 leaving group than those traditionally used in SNAr reactions. To circumvent this, special
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42 conditions typically have to be employed in order to facilitate the reaction; in the VNS reaction,
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45 for instance, one often uses the chloromethyl phenyl sulfone carbanion nucleophile that is able to
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47 directly abstract the hydrogen nucleofug as a proton instead of a hydride upon formation of the
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49 σH-adduct via a HCl β-elimination.30 A comparison between the SNAr and VNS mechanisms is
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52 given in Figure 1.
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17 Figure 1. Schematic comparison between the nucleophilic aromatic substitution (SNAr) and the vicarious nucleophilic
substitution (VNS) mechanisms 1-halo-4-nitrobenzene. To the left is the ES(r) at the 0.004 a.u. surface of X=F from series 5
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displayed. Coloring: red < -1.3 eV < yellow < -0.8 eV < green. ES,min are found at all ring carbons. The ortho (ES,min=-1.72 eV)
19 and meta (-1.22 eV) positions with respect to the nitro group are potentially VNS active while the para (-0.87 eV) position is a
20 SNAr site. ES,min are also found on the over the C-N bond between the ipso carbon and the nitro group (-1.47 eV) and on the
21 oxygen atoms of the nitro group (-1.25 eV). The ES(r) of 1-halo-4-nitrobenzene is discussed in more detail in the Introduction
22 section.
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25 In the present study the computationally inexpensive local electron attachment energy
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descriptor [E(r)],25 which is based merely on ground-states Kohn-Sham DFT calculations of the
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30 studied compounds, is used for estimations of both reactivity trends and regioselectivity for
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32 reactions with arenes that are active in the SNAr or VNS reactions. The E(r) descriptor is here
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35 compared to experimental data, but also to higher-level quantum chemical methods as well as
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37 other ground-state descriptors, e.g. the molecular electrostatic potential [V(r)]. For reactivity
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39 estimations, it has previously been shown25,34 that good correlations with experimental and
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42 computational data can be obtained by evaluating the E(r) and V(r) at molecular isodensity
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44 contours (here 0.004 a.u.) that typically lie close to the van der Waals radii of the atoms that
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constitutes the molecule. When E(r) and V(r) are analyzed at molecular surfaces they are
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49 denoted ES(r) and VS(r), respectively. Surface minima in E(r) [ES,min] and surface maxima in
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51 V(r) [VS,max] reflect sites susceptible to nucleophilic attack.
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54 The surface map of 1-Fluoro-4-nitrobenzene in Figure 1 serves as an example of the use of
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ES(r). This compound is active in both the SNAr and VNS reactions and ES,min are found in the
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vicinities of all ring carbons with the lowest surface minimum (ES,min=-1.72 eV) positioned ortho
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6 relative to the activating nitro group. The ortho position is also the preferred VNS site in this
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8 molecule, and the magnitude of the ES,min reflects the relative reactivity at this position, the ortho
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position of the less activated nitrobenzene compound is e.g. associated with a higher ES,min (-1.40
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13 eV). The meta carbons of 1-Fluoro-4-nitrobenzene are also potential VNS sites but have a higher
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15 ES,min (-1.22 eV) than the ortho carbons, in agreement with the experimentally well-established
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18 ortho directing effect of the nitro group. In addition, there is a surface minimum (-0.87 eV )
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20 associated with the para position that reflects the reactivity of SNAr. However, it must be
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22 emphasized that the relative reactivity of the ortho versus the para position is this molecule is not
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25 directly accessible by ES(r) due to the difference in leaving group. In comparison, we note that
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27 ES(r) is capable of ranking the ortho, meta, and para sites of nitrobenzene; here the ES,min are -
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1.40 eV (ortho), -1.00 eV (meta), and -1.12 eV (para), in line with the experimental and
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32 computational trends of reactivity for VNS found by Mąkosza and co-workers.4,33,35
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34 Furthermore, there is a ES,min of -1.47 eV associated with the C-N bond, corroborating an earlier
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37 proposal by Politzer and coworker that C-N bonds of nitroaromatics are sites susceptible to
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39 nucleophilic attack.36 These examples show that ES(r) provides insight into a molecules local
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41 reactivity for nucleophilic processes, but that ES(r), like any computational chemistry approach,
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44 must be applied together with knowledge of potential reaction mechanisms and reaction
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46 conditions to be useful for predicting chemistry.
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49 The applicability of E(r) to the NAS class of reactions has recently been established by
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51 studying a series of congeneric compounds active in the SNAr reaction.25 In addition, the use of
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54 E(r) is motivated by a previous study of electrophilic aromatic substitution reactions,37 where the
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56 nucleophilic analogue to E(r) (i.e. the average local ionization energy [Ī(r)]38) was successfully
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employed for estimations of relative reaction rates and regioselectivity. By the use of ground-
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6 state reactivity descriptors such as E(r), the computational cost can be substantially reduced
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8 compared to e.g. elaborate transition-state calculations; this while maintaining good accuracy in
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the reactivity estimations.
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14 Computational Methods
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16 All DFT calculations have been performed within the Gaussian 09 program suite.39 The ground-
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18 state geometry optimizations were carried out at the B3LYP40,41/6-31G(d) level of theory, while
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20 the local electron attachment energy [E(r)] and the electrostatic potential [V(r)] were evaluated at
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23 the 0.004 a.u isodensity surface with the in-house program HS95 (T. Brinck), using the Kohn-
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25 Sham42 wave functions obtained from B3LYP/6-31+G(d,p) single-point calculations. For the
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iodine containing compounds we have employed the LACV3P*//LACVP* basis set
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30 combination.43 This is based on the LANL2-DZ basis set where the core electrons are treated
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32 with Los Alamos style effective core potentials.44 Gas phase calculations were compared to
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condensed phase by including solvation effects via the polarizable continuum model (PCM)
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37 using the integral equation formalism.45,46 The piperidine solvent was described by a dielectric
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39 constant of ε=5.9. For the mechanistic studies, including all transition-state (TS) calculations, we
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42 used the M06-2X47 exchange correlation functional in piperidine PCM and the 6-
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44 311+G(3df,2p)//6-31+G(d,p) basis set combination for all atoms but the iodine atoms, for which
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46 LACV3P*//LACVP* were used. The choice of the M06-2X functional is motivated by its
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49 excellent performance for main-group thermochemistry and kinetics.47 For comparison, the
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51 B3LYP functional was also tested in the mechanistic studies yielding similar trends and
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geometries as M06-2X while severely overestimating the TS barriers. Harmonic vibrational
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56 frequencies were calculated to verify the nature of all stationary points, i.e. zero (one) imaginary
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frequency for ground-state (TS) structures. The thermochemical analysis was carried out
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6 employing the harmonic oscillator, rigid rotor and ideal gas approximations, and assuming a
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8 standard state of 298.15 K and the experimental 10 M piperidine concentration. Gibbs free
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11 energy corrections ∆∆ → to the 10 M concentration from the program default of 0.041 M
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13 (i.e. 1bar) were added as:
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15 .
16 ∆∆ → = = −3.26 kcal ∙ mol
(1)

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19 The E(r) descriptor is defined as
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& ) &' (' "#$
22 !"#$ = ∑*+,-.
'
(2)
23 ("#$
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where εi is the eigenvalue of the i:th virtual orbital, ρi(r) represents its density at the position r,
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28 and ρ(r) is the total density of the occupied orbitals.25 Only virtual orbitals below the free
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electron limit are included in the summation. Equation 2 is motivated based on Janak's theorem48
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33 and the piecewise linear energy dependence upon electron addition to atomic and molecular
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35 systems.49 In our previous study,25 it was shown that E(r) can be divided into contributions from
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38 the electrostatic potential, the exchange-correlation energy and the kinetic energy densities of the
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40 contributing virtual orbitals. The last term explains the capacity of E(r) to predict strong
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42 intermolecular interactions that are not entirely electrostatic in character, but also has significant
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45 contributions from charge transfer and polarization. Equation 2 is valid for the generalized Kohn-
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47 Sham methods (GKS-DFT),50 which includes methods ranging from local DFT via hybrid-
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methods to pure Hartree-Fock (HF). However within the GKS-DFT class of methods the
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52 energies of the virtual orbitals vary rather strongly with the amount of HF exchange in the
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54 method, and it has been argued that methods where the LUMO energy is close to -EA (EA =
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57 electron affinity) should preferentially be used with eq 2.25 In our previous study we found that
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E(r) computed with standard hybrid functionals, such as B3LYP and PBE0,51 that typically
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6 includes 15-25 % HF exchange, have a high predictive power for interactions such as halogen
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8 bonding, nucleophilic attack of activated double bonds, and SNAr. Our tests further indicated that
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these methods provide a more balanced description of the virtual orbital energies, and better E(r)
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13 predictions of reactivity, than long range corrected methods such LC-BLYP52 and CAM-
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15 B3LYP.53
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18 In our previous article25 we also discuss the connection between using E(r) and FMO theory
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21 for analyzing electrophilicity. We demonstrate that the two approaches are basically equivalent
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23 for small organic molecules that have only one virtual orbital (the LUMO) of negative energy.
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25 On the other hand, for molecules of more complex electronic structure and with several low
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28 lying virtual orbitals, an FMO analysis based on a single orbital is generally inferior to a multi-
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30 orbital approach, such as E(r). As an example, an E(r) computation of pentafluoronitrobenzene
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included four virtual orbitals and was shown, in contrast to the LUMO density, to give a good
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35 representation of the stereoselectivity for SNAr.
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38 The electrostatic surface potential VS(r) was computed at the same isodensity surface as E(r)
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40 and is given by:
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01 (6# 7 89# 7
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/"#$ = ∑4 |3 #|
−5 |# 7 #|
(3)
44 1
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46 Here ZA is the charge of A:th nucleus, RA its spatial coordinate and r and r’ represents the
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coordinates of two electrons. The surface contour graphics were prepared in the UCSF Chimera
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For the statistical validations we have employed the coefficient of determination (R2), cross-
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6 validated R2 (i.e. Q2) and standard error (SE). Q2 was evaluated according to the leave-one-out
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8 procedure55 by:
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∑@ "= =>$?
: ; = 1 − ∑'AB
11 '
@ "= (4)
12 'AB ' =C$?
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14 where D* is the i:th value of y in the data series, DC is the mean value of y over the data series and
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17 D>*/* is the predicted value of y=y(F* ) based on a linear regression analysis of the data series with
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19 the i:th data point excluded from the regression.
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4 Results and Discussion
5 This work consists of, all together, six series of electrophilic arenes, with the range of
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8 electrophiles chosen so as to facilitate proper evaluation of the ES(r) descriptor: Its ability to
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10 estimate relative reactivity as well as its performance in regioselectivity predictions is examined
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by reducing the influence of other contributions to the compounds reactivities (e.g. steric or
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15 entropic effects) besides those reflected by the descriptor (i.e. charge-transfer/polarization and
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17 electrostatic interactions25). The experimental reaction rate constants and regioisomeric
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20 distributions that are used for comparison have previously been reported in the literature.10–12,14,56–
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22 Series 1-4 follow the SNAr mechanism while series 5 and 6 belong to the VNS family of
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reactions. For most of the compounds local maxima in the electrostatic potential, VS,max, could
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27 not be determined at the specific site of reaction. Hence, the local electrostatic potential, VS,loc, at
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29 the ES,min sites (local minima of ES(r) on the 0.004 a.u. isodensity surface, i.e. electrophilic sites)
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32 are used for comparison between the two descriptors. For series 1 the performance of the ES,min
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34 is, in addition, compared to estimated Gibbs free energy barriers obtained by TS calculations.
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SNAr
39 Among the four SNAr series the first (series 1) examines the relative reactivity of a number of
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brominated nitroarenes with the neutral piperidine as nucleophile and Br-/BrH as leaving group.
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44 As mentioned in the introduction, the putative two-step mechanism of SNAr has lately been
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46 questioned and found to be correct primarily in cases of reluctant leaving groups (as F-/HF) or
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49 highly stabilized intermediates.20,26–28 Given more favorable leaving groups like Cl-/HCl or Br-
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51 /BrH, as in the case of series 1, the reaction is expected to proceed via a concerted mechanism in
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the sense that no σ-adduct intermediate is formed. The compounds of series 2-4 reacts with
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56 anionic nucleophiles and have F-/FH as leaving group, were the latter presumably leads to the
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putative two-step mechanisms. Another significant difference between the series is that series 1
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6 consists of arenes with only one plausible SNAr site, in contrast to series 2-4 were multiple
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8 reaction sites are active.
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12 Series 1
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The 1-bromo-4-R-2-nitrobenzene compounds of series 1 (inset of Figure 2) are taken from a
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16 study by Berliner and Monack.56 A nitro group in ortho position to the leaving group activates
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18 the reaction site while the R substituent in the para position is varied. The activating effect in the
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21 SNAr reaction for the different substituents ranges from strongly activating (NO2) to strongly
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23 deactivating (H2N) relative to the H compound. Throughout the series the sterical variations at
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25 the reacting site are minimal since the site of reaction is situated at a distance far from the
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28 substituents. Piperidine acts as both nucleophile and solvent. Since piperidine is a neutral
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30 nucleophile, an additional deprotonating step is included in the mechanism compared to Figure 1
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(see Scheme 1).
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Figure 2. Logarithmized experimental rate constants relative to R=H plotted against ES,min values of series 1, R = H, F, Cl, Br, I,
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t-Bu, Me, OH, OMe, OEt, COOH, NH2, NMe2, NO2. Note that NO2 is not include in the correlations since it was reported to
53 react too fast under the reaction conditions for a rate constant to be determined.56 The ES,min values are obtained on the 0.004 a.u.
54 isodensity surface in gas phase (left) and in the piperidine solvent (right) represented by explicit solvent molecules and PCM. The
55 asterisk (*) marks the site of reaction.
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3 Table 1. Experimental rate constants and computed descriptor data at the site of reaction (i.e. position 1) for the compounds of
4 series 1. ES,min values for the ring positions 3 and 5 (ortho and para with respect to NO2) are included in the supporting
5 information.
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7 Gas phase Piperidine solvation
8
UVWXSYSZ b)
9 R= ln krela) GH,JKL b) MH,NOP c,d) GH,JKL b) GQ,RST MH,NOP c,d) ∆[\ c) ∆[\,UVWXSYSZ c)
10
11 H 0.00 -1.11 16.63 -0.76 -0.76 14.13 21.2 21.2
12 Me -1.93 -0.95 14.14 -0.66 -0.66 6.5 22.5 22.5
13
14 MeO -4.02 -0.81 12.12 -0.49 -0.49 3.64 25.6 25.6
15 Me2N -6.71 -0.59 3.12 -0.31 -0.31 -4.89 26.9 26.9
16 OH -7.45 -0.86 14.02 -0.5 -0.32 5.36 24.9 27.7
17
18 H 2N -8.99 -0.7 6.44 -0.37 -0.27 -1.52 26.2 27.4
19 Br 2.06 -1.26 20.92 -0.88 -0.88 15.26 19.6 19.6
20 Cl 1.72 -1.24 19.51 -0.88 -0.88 15.47 20.0 20.0
21
22 I 1.65 -1.25 20.24 -0.91 -0.91 22.59 20.1 20.1
23 F -1.35 -1.15 20.08 -0.72 -0.72 13.04 22.2 22.2
24 t-Bu -1.77 -0.95 13.21 -0.66 -0.66 5.82 22.0 22.0
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26 EtO -4.19 -0.78 11.34 -0.48 -0.48 2.93 24.8 24.8
27 COOH 0.92 -1.34 23.31 -1.01 -0.90 16.98 16.4 19.4
28 NO2 n.r. e)
-1.74 31.16 -1.14 -1.14 27.24 13.5 13.5
29 2 f)
30 R 0.827 0.730 0.869 0.978 0.790 0.792 0.960
31 Q2 f) 0.755 0.612 0.796 0.966 0.703 0.612 0.940
32 SE f) 1.611 2.014 1.403 0.588 1.775 1.767 0.773
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a)
34 Pseudo first-order reaction rates in min-1 from ref. 56 at 25°C relative to that of H. b) In eV, explicit=explicit solvent
35 molecules were used, c) in kcal mol-1, d) No VS,max could be found at the reactive site, e) the reaction was reported as
36 too fast to determine a reaction constant under the given conditions, f) compared to ln krel.
37 Br
38 NO2-
39
H+
40 N
41 H
42 R σH-adduct
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44
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46 Br-
47 Br Br NH+ N N
48 NO2- NO2 NO2 BrH NO2 NO2
49 +
50 H HN -HBr
51 NH+
R R R R R
52
53 σH-adduct
54 Scheme 1. Showing the concerted SNAr mechanism for the neutral piperidine nucleophile. Shown are also the reversible and
55 non-productive formation of σH-adducts at position ortho and meta with respect to the NO2 group.
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Owing to the good leaving group, Br-/BrH, a concerted reaction mechanism without a σ-adduct
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6 intermediate is anticipated for series 1. Consequently we expect a relatively early TS, structurally
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8 close to the ground-state geometries from which the ES,min values are obtained. The validity of
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this assumption was tested by a closer examination of the mechanism for the whole series of R
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13 substituents. Ormazábal-Toledo et al. have recently investigated the SNAr reaction of similar
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15 reactants: including e.g. the reaction of 1-Bromo-2,4-dinitrobenzene (i.e. R=NO2) with the
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18 morpholine nucleophile59 as well as the reaction of mono-, di-, and tri-nitro-Fluoro-benzenes
19
20 with piperidine.60 They report a step-wise mechanism that passes over a zwitterionic σ-adduct
21
22 intermediate, which is formed in an initial rate-determining step. This step is assumed to be
23
24
25 followed by deprotonation and expulsion of the halide leaving group (alternatively by expulsion
26
27 of the halide followed by deprotonation) via a two-step process. The formation of the σ-adduct
28
29
intermediate can be explained by the activation of two nitro groups in the case of 1-Bromo-2,4-
30
31
32 dinitrobenzene as well as by the poor F-/HF leaving group of 1-Fluoro-2,4-dinitrobenzene. The
33
34 aforementioned calculations were moreover performed in gas phase. Upon reoptimization in the
35
36
37 piperidine solvent, we were not able to identify intermediate σ-adducts for any of the R
38
39 substituents considered. This also includes the 1-Bromo-2,4-dinitrobenzene (i.e. R=NO2).
40
41 Instead the first TS leads directly to the expulsion of the Br- leaving group and the formation of
42
43
44 the protonated product in a concerted mechanism. Upon expulsion, the Br- coordinates to the
45
46 amine proton originating from piperidine. HBr may leave from this state via a NO2-mediated and
47
48 non-rate-limiting proton transfer from the amine to the Br anion, as demonstrated for the H, NO2
49
50
51 (activated) and NH2 (deactivated) substituents in Figure 3. Alternatively a solvent molecule
52
53 could facilitate the deprotonation. The absence of a σ-adduct intermediate in condensed phase is
54
55
56
compatible with the experimental evidence that the reaction of 1-X-2,4-dinitrobenzene with
57
58
59
60
13
1
2
3
secondary amines results in one intermediate for X=Cl, Br, and I, while X=F leads to two
4
5
6 intermediates.61 Compared to gas-phase, the lack of σ-adduct intermediates can be rationalized
7
8 by a stabilization of the Br anion in the solvent. Scheme 1 summarizes the concerted SNAr
9
10
11
mechanism for the case of a neutral piperidine nucleophile. It also includes the possible
12
13 formation of reversible σH-adducts at the hydrogen substituted ortho (position 3) and para
14
15 (position 5) ring sites with respect to the nitro group. These sites are also activated but due to the
16
17
18 reaction conditions the formation of the σH-adducts is unproductive. Instead these sites are
19
20 potentially active in e.g. the VNS reaction given a suitable nucleophile. ES,min values for addition
21
22 to these sites are included in the supporting information.
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46 Figure 3. Displays the Gibbs free energy reaction profile for the SNAr reaction with the piperidine nucleophile for compounds H,
NO2 and NH2 of series 1. The inset shows the rate-determining TS structure for R=H (distances in Å). The ∆G values are shown
47
at 298.15 K assuming the experimentally specified56 piperidine concentration of 10 M and a 0.04 M HBr concentration (i.e. 50%
48 conversion). TSPT represents the TS of a NO2-mediated proton transfer from the amine towards the coordinated Br anion. The
49 reaction profile of NH2 was obtained with an explicit piperidne solvent molecule coordinated to the NH2 group.
50
51
52
53
54 The identification of a concerted mechanism (i.e. lack of an intermediate σ-adduct) with an
55
56 early rate-determining TS should facilitate the use of ground-state reactivity descriptors for this
57
58
59
60
14
1
2
3
reaction series. Accordingly, a good correlation between ES,min values at the reaction site
4
5
6 obtained in gas-phase for the set of electrophiles and logarithmized relative experimental
7
8 reaction constants (ln krel) was found, with a R2-value of 0.827 and a standard error of 1.611
9
10
11
(Table 1). Compared to other methods, the ES,min performs overall better than VS,loc (R2=0.730 in
12
13 gas-phase) and much better than the LUMO energies (R2=0.618). It should also be pointed out
14
15 that the there are no maxima in the surface electrostatic potential VS(r) on the sites of reaction for
16
17
18 this series. Hence V(r) is unfit to identify local reactivity in this series. In addition, as can be seen
19
20 in Figure 3, the relative energetics of the intermediate structures (I) cannot be used as a reactivity
21
22 indicator since the σ-adduct energies does not reflect the ordering of the TS barriers for the
23
24
25 various R substituents. To illustrate the ease of comparing the reactivity for the different
26
27 reactants by ES(r), Figure 4 shows the descriptor value mapped on the 0.004 a.u. molecular
28
29
isodensity surfaces for the Me and Br compounds.
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
Figure 4. ES(r) mapped on the 0.004 a.u. isodensity surfaces of a) Me and b) Br from series 1. Coloring: Red < -1.4 eV < yellow
45 < -0.9 eV < green. The asterisk (*) marks the site of reaction via the SNAr mechansim.
46
47
48
49
50 Despite the relatively good correlations found, some obvious anomalies can be recognized in
51
52 the plot of ES,min against ln krel (Figure 2). The NH2, OH, COOH, and possibly F, compounds
53
54
55 appear to belong to a separate trend. Without these entries the gas phase correlation increases to
56
57 R2=0.998 and within the divergent group the correlation is R2=0.984. These discrepancies could
58
59
60
15
1
2
3
have several explanations including, besides the possibility of experimental errors, a more
4
5
6 complex mechanism than outlined above, as well as pronounced solvent effects, to mention a
7
8 few examples.
9
10
11 In order to further evaluate the validity of the proposed mechanism we compare calculated
12
13
Gibbs free energy activation barriers ∆G† (obtained with piperidine PCM solvation) for the first
14
15
16 TS with the experimental reaction rates. Somewhat surprisingly, the TS barriers turn out to give
17
18 weaker correlations than the ES,min (note: ES,min obtained in gas phase) with a R2 of 0.792, despite
19
20
21
that the TS calculations, in contrast to ES(r), are performed with implicit consideration of solvent
22
23 effects. This R2-value corresponds to TS energies obtained with the M06-2X functional, the
24
25 corresponding R2-value for B3LYP barriers is 0.751. Again the largest deviations in the
26
27
28 correlation are seen for NH2, OH, and COOH. The correlation without these entries improves
29
30 significantly to R2=0.968. The divergent groups span from activating to deactivating, which
31
32 suggests that a mechanistic change to step-wise for these compounds is not a likely explanation
33
34
35 for the deviations. Moreover, even if the mechanism would be step-wise, the first TS, as
36
37 identified here, is expected to be rate-limiting for the studied compounds due to the good leaving
38
39
groups and because the reactions were run under an excess of base (piperidine) to deprotonate
40
41
42 the product. Hence the TS structures obtained here should be valid. A better rationalization can
43
44 be found by invoking solvent effects, as discussed below. First it should be noted that the ∆G†
45
46
47
and ES,min values, both in piperidine, show a close mutual relationship (R2=0.954), suggesting
48
49 that ES,min may well be used in lieu of TS calculations for these reactions. The latter is of course
50
51 attractive since it allows for a considerable reduction of computational time.
52
53
54 By including solvation effects and reevaluating the ES,min values, we find that the correlations
55
56
57
improve significantly; accounting for piperidine solvation implicitly via PCM yields a R2 value
58
59
60
16
1
2
3
of 0.869 (R2=0.790 for VS,loc). The effect of solvation highlights the stabilizing role of the solvent
4
5
6 for the hydrogen bond donating substituents OH, NH2 and COOH. After inclusion of PCM
7
8 solvation, the ES,min values of these compounds are shifted considerably towards lower predicted
9
10
11
reactivities, as is ES,min of F. Piperidine has a rather low dielectric constant of ε=5.9. However,
12
13 owing to the amine group the piperidine solvent is able to form directional interactions that
14
15 effectively would yield an amplified local dielectric response compared to the solvent’s average
16
17
18 response. Hence, in order to fully capture the effects of the piperidine solvent, its ability to form
19
20 H-bonds with the solute has to be modeled explicitly. The OH, NH2 and COOH compounds are
21
22 expected to form the strongest H-bonds amongst series 1. Adding explicit H-accepting piperidine
23
24
25 solvent molecules in proximity to the aforementioned substituent R groups (and still also
26
27 applying the PCM solvation) the obtained correlation is excellent, R2=0.977. (Note, furthermore,
28
29
that inclusion of explicit solvent molecules for the non-hydrogen bonding compounds of series 1,
30
31
32 e.g. I or Cl, does not significantly alter their corresponding descriptor values.) Apparently, the
33
34 inclusion of solvent effects is very important for modeling the reactivity within this particular
35
36
37 series of compounds. This explains the anomalies from the gas phase correlations and also the
38
39 failure to describe the reaction by TS calculations in implicit solvation. Using explicit solvation
40
41 in the TS calculations, the correlation is increased to R2=0.960. The above is consistent with
42
43
44 previous reports regarding the importance of utilizing explicit solvent molecules in the modeling
45
46 of SNAr reactions.62
47
48
49
50 Series 2-4
51 Over the next three series it is shown that besides being able to rank compound reactivity, the
52
53
54 ES(r) descriptor is also well-suited for regioselectivity predictions. We find that ES(r) can
55
56 successfully rank the various reactive sites for multiply fluorinated arenes, i.e. for cases where
57
58
59
60
17
1
2
3
two or more SNAr active sites are present in the same compound. Compared to series 1, the
4
5
6 sterical variations of the studied reaction sites are, however, large for the compounds of series 2-
7
8 4. Combined with the later TSs owing to the F-/HF leaving group, we thus expect weaker overall
9
10
11
reactivity correlations for these compounds compared to series 1. The series 2-4 (Figure 5) have
12
13 recently been investigated in a theoretical study by Liljenberg et al.,63 with the exception of the
14
15 augmented series 2’ that has been added in the present work. In the study by Liljenberg et al.,
16
17
18 very good correlations were found between ln k of experimentally determined reaction
19
20 constants10–12,58 and the relative energies of the σ-adduct intermediate (referred to as the Nα-
21
22 value) at different sites. However, the procedure to determine the Nα-values is computationally
23
24
25 demanding compared to evaluation of ES(r). Given e.g. an arene with three active sites, this
26
27 compound would demand five geometry optimizations (one for each of the three possible
28
29
30
intermediate σ-adducts as well as one each for the two reactants), whereas merely one
31
32 optimization is sufficient for the E(r) descriptor. The performance of ES,min on the compounds of
33
34 the non-augmented series 2 was reported recently, showing promising initial results.25
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
18
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Figure 5. Schematic representation of the compounds of series 2-4.
27
28
29
30
31 Most striking for the three series 2 (including 2’), 3 and 4 is that ES(r) is capable of correctly
32
33 predicting the most active fluorine SNAr site and, where applicable, rank the second and third
34
35
36 most active site with only two exception (compound 2o’ and 3g, where the difference in ES,min
37
38 between the sites are within only 0.1 eV), see Table 2-4. As is illustrated by Figure 6, the most
39
40
41
reactive sites can readily be determined from a map of E(r) on a molecular isodensity surface,
42
43 i.e. ES(r).
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
19
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Figure 6. ES(r) mapped on the 0.004 a.u. isodensity surface of compound 4e. Coloring: Red < -1.4 eV < yellow < -1.1 eV <
17
green. The experimental SNAr activity ordered as 4 > 2 > 3.58 ES,min ranks position 4 (ES,min= -1.52eV) as the most reactive
18 followed by position 2 (-1.42eV) and lastly position 3 (-1.39eV).
19
20
21
22
23 As mentioned above, because of the F-/FH leaving group, the SNAr reactions of series 2-4 are
24
25 expected to proceed via the two step addition-elimination mechanism, were the first step is
26
27
28 usually rate-determining.2,3 Hence late transition states are anticipated for series 2-4 (since
29
30 formation of the σ-adduct intermediate is endergonic), and thus the transition state geometry
31
32 should be significantly shifted from the ground-state structure. Consequently the relatively weak
33
34
35 correlations between ES,min and ln k for all series (see Figure 7 and Table 2-4) are not very
36
37 surprising. However, it is noteworthy that for series 3 and 4 the discrepant entries are those with
38
39
the reactive sites immediately adjacent to substituent groups other than fluorine. Groups like
40
41
42 trifluoromethyl, cyanide and multiple chlorines are likely to create a dissimilar sterical
43
44 environment than fluorine. These groups may also participate in the reactions via other through-
45
46
47
space (not reflected by the ES,min) rather than through-bond (accounted for in ES,min) interactions
48
49 and will thus affect reactivity to a different degree. This is a clear difference compared to series
50
51 1, where the variations of the neighboring environment of the reactive sites were minimal over
52
53
54 the series of compounds. By removing the affected entries from the trends in Figure 7 the
55
56 correlations are increased from 0.66 and 0.68 to 0.96 and 0.95 for series 3 and 4 respectively.
57
58
59
60
20
1
2
3
(Performing the same kind of exclusion on series 2 will not alter the correlation). The observed
4
5
6 changes for series 3 and 4 addresses the inherent inability of E(r) to account for e.g. steric
7
8 effects. If such effects are not corrected for by for instance a linear combination with Taft
9
10
11
constants, as used in the Hammett-Taft relations,6–8 E(r) can only be used efficiently for
12
13 comparison between compounds (and sites) with similar sterical surroundings. Nonetheless,
14
15 when the contribution from neighboring groups are kept constant the ES,min values are capable of
16
17
18 accurately reproducing reactivity trends for the series 2-4. Note, in addition, that the inclusion of
19
20 solvent effects by means of PCM does not alter the correlations to any significant degree for
21
22 these series.
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
21
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
-1 -1
52 Figure 7. Logarithmized experimental reaction rate constants (k in mol s ) plotted against ES,min values at the site of reaction
53 for the series 2-4 (including 2’). The outliers marked by full-black squares include the entries with dissimilar neighboring
54 environments at the site of reaction. All reaction rates have been corrected for statistical factors where applicable.
55
56
57
58
59
60
22
1
2
3
In comparison, ES,min values are performing as good as or better than the VS,loc for estimations
4
5
6 of reactivity trends, except for series 2 (including 2’) where VS,loc gives a correlation with
7
8 R2=0.908 compared to R2=0.828 for ES,min. However, although VS(r) shows a better correlation
9
10
11
than ES(r) for this series, we must again point out that a significant drawback of VS(r) is the fact
12
13 that local maxima cannot be identified at the sites of reaction. This is in stark contrast to ES(r)’s
14
15 ability to locate reaction sites at each ring carbon, displayed e.g. in Figure 6. With respect to
16
17
18 LUMO energies, ES,min performs much better for the series 2-4 (LUMO’s R2-values for series 2
19
20 including 2’, 3, and 4 are 0.396, 0.333 and 0.588 respectively). Compared to the Nα-values
21
22 determined by Liljenberg et al.,63 the ES(r) descriptor is, however, incapable of reaching the
23
24
25 same level of correlation. This may to some extent be attributed to the expected potential energy
26
27 surface of the reaction with a late rate-determining TS. Since the intermediate σ-adduct, from
28
29
30
which the Nα-values are determined, has a geometry that is structurally closer to the TS
31
32 geometry than the ground-state structure on which ES(r) is computed, the better performance of
33
34 Nα-values compared to ES(r) is sensible. In contrast, the Nα-values cannot be used for
35
36
37 compounds like those in series 1 where the mechanism is concerted and no intermediate σ-
38
39 adduct exists. Whereas Nα-values better describe reactions with late TS, ES(r) performs best for
40
41 reactions with early TS. Hence ES(r) and Nα can in many aspects be seen as complementary
42
43
44 descriptors.
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
23
1
2
3 Table 2. Experimental reaction data and descriptor values for series 2 (including 2’).
4
5 Posi- Site pre-
6 tion ln k a,b)
Es,min c)
Vs,loc d)
dictione)
7
2a 2 -13.38 -1.51 38.82 correct
8
9 2b 6 -12.04 -1.5 36.01 correct
10 2c eq. -9.89 -1.82 44.27 n.a.
11
2d 4 -7.29 -2.27 42.75 correct
12
13 2e 4 -6.26 -2.11 41.76 correct
14 2f 4 -3.68 -2.57 48.30 correct
15
2g(4) 4 -2.94 -2.26 46.98 correct
16
17 2g(6) 6 -3.63 -2.2 45.80 correct
18 2h(2) 2 0.27 -2.41 50.13 correct
19
2h(4) 4 1.22 -2.73 50.67 correct
20
21 2i 4 0.30 -2.37 48.76 correct
22 2j’(2) 2 -15.42 -1.11 31.35 correct
23
2j’(4) 4 -14.17 -1.20 31.86 correct
24
25 2k’ 2 -5.35 -1.98 41.29 correct
26 2l’(4) 4 -10.72 -1.78 37.98 correct
27
2l’(6) 6 -12.05 -1.25 34.93 correct
28
29 2m’ 4 -10.44 -1.89 37.59 correct
30 2n’ 4 -7.25 -2.16 41.85 correct
31
2o’(2) 2 -10.10 -1.48 38.01 incorrect
32
33 2o’(6) 5 -12.23 -1.58 38.39 incorrect
34 2p’ eq. -8.95 -1.54 38.20 n.a.
35
2q’ 4 -7.34 -2.05 41.12 correct
36
37 2r’ eq. 6.52 -2.73 56.75 n.a.
38
39 R2 f) 0.828 0.908
2 f)
40 Q 0.786 0.894
41 SE f) 2.373 1.730
42 a)
43 All reaction rates have been corrected for statistical factors where applicable, b) rate constants in mol-1s-1, c) eV, d)
44 kcal mol-1, e) only SNAr sites included, f) versus ln k.
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
24
1
2
3 Table 3. Experimental reaction data and descriptor values for series 3.
4
5 Posi- Site pre-
6 tion ln k a,b)
Es,min c)
Vs,loc d)
dictione)
7
3a 4 -11.42 -1.68 34.26 correct
8
9 3b eq. -11.31 -1.93 41.38 n.a.
10 3c 4 -9.9 -1.85 36.63 correct
11
3d eq. -9.49 -2.34 47.63 n.a.
12
13 3e 4 -9.04 -2.12 42.81 correct
14 3f 4 -8.29 -2.18 43.06 correct
15
3g 4 -6.61 -2.37 53.53 incorrectf)
16
17 R2 g) 0.659 0.648
18 (0.960)h) (0.935)h)
19
20 0.289 0.371
Q2 g)
21 (0.897) h)
(0.761)h)
22
23 SE g) 1.081 1.098
24 (0.415) (0.528)h) h)
25 a)
All reaction rates have been corrected for statistical factors where applicable, b) rate constants in mol-1s-1, c) eV, d)
26 kcal mol-1, e) only SNAr sites included, f) the correct site has a Es,min of 0.05eV higher, g) versus ln k, h)obtained after
27 exclusion of sites with sterical discrepancies.
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
25
1
2
3 Table 4. Experimental reaction data and descriptor values for series 4.
4
5 Posi- Site pre-
6 tion ln k a,b)
Es,min c)
Vs,loc d)
dictione)
7
4a eq. -19.81 -0.83 25.23 n.a.
8
9 4b 2 -14.73 -1.12 25.78 correct
10 4c 1 -13.63 -1.09 26.44 correct
11
4d(3) 3 -13.12 -1.17 30.09 correct
12
13 4d(1) 1 -9.2 -1.49 31.23 correct
14 4e(2) 2 -8.8 -1.42 33.73 correct
15
4e(3) 3 -9.85 -1.39 32.51 correct
16
17 4e(4) 4 -5.98 -1.52 33.43 correct
18 4f eq. -9.49 -1.48 34.24 n.a.
19
4g one -5.71 -1.26 30.81 n.a.
20
4h site
eq. -5.34 -1.33 31.7 n.a.
21
22 4i 4 -5.24 -1.45 33.79 correct
23
4j eq. -4.99 -1.4 32.6 n.a.
24
25 R2 f) 0.685 0.667
26 (0.944)g) (0.786)g)
27
28 Q2 f) 0.584 0.520
g)
29 (0.901) (0.593)g)
30 SEf) 2.658 2.731
31
32 (1.044) (2.041)g) g)
a)
33 All reaction rates have been corrected for statistical factors where applicable, b) rate constants in mol-1s-1, c) eV, d)
34 kcal mol-1, e) only SNAr sites included, f) versus ln k, g) obtained after exclusion of sites with sterical discrepancies.
35
36 VNS
37
38 The lowest ES,min on the arenes of series 1-4 does typically not correspond to a SNAr active site.
39
40 Instead the lowest ES,min is in most cases found at a ring carbon attached to hydrogen (see e.g.
41
42
43 Figure 1). This indicates that hydrogen substituted carbons are more electron deficient (i.e. more
44
45 electrophilic) than e.g. halide substituted carbons, consistent with experimental findings.4 As
46
47
pointed out in the introduction, nucleophilic attack at the hydrogen-substituted carbons does not
48
49
50 lead to a product unless special nucleophiles are used. This is why the SNAr type of reaction is
51
52 often the prevalent reaction. Under beneficial condition, the carbons with H substituents can,
53
54
55
however, react in the VNS type of reactions. In the series 5 and 6, the reactivity at hydrogen-
56
57 substituted carbon sites is explored by employing the ES(r) descriptor on two series of VNS
58
59
60
26
1
2
3
active arenes. Both of the VNS series follow the general mechanism presented in the lower route
4
5
6 of the scheme in Figure 1, with the α-halocarbanion of chloromethyl phenyl sulfone as
7
8 nucleophile and HCl as leaving group.14,57
9
10
11
12 Series 5
13
14
In series 5 (inset of Figure 9) each compound has two possible, non-equivalent, sites for the VNS
15
16 reaction (three sites for the H compound): The para positions with respect to the activating nitro
17
18 group are blocked by the various substituents, thus leaving only the ortho and, in theory, meta
19
20
21 positions free to react (for H the para position will also react). Experimentally it is found that the
22
23 ortho positions are the preferred reaction sites, while the meta positions are non-active.57 In the
24
25 case of the H substituent the para site is also active in VNS. Interestingly both experiments and
26
27
28 computations have, however, identified an ortho directing effect of the nitro group thus yielding
29
30 the ortho product in some excess over para.35,64 The TS structures of the ortho and para addition
31
32
to H are shown in Figure 8. These demonstrate that the neighboring nitro group interacts with the
33
34
35 nucleophile upon ortho but not para addition, thus allowing for a stabilizing effect of NO2 on the
36
37 ortho TS. Over series 5 the sterical and neighboring group variations are negligible, owing to the
38
39
40
relatively large distance between the active ortho site and the para substituents.
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56 Figure 8. Displays the ortho and para TS structure for VNS addition of the chloromethyl phenyl sulfone carbanion nucleophile to
57 the H compound of series 5 optimized in gas phase at the M06-2X/6-31+(d,p) level of theory. The 0.004 a.u. isodensity contours
58
59
60
27
1
2
3 are included to demonstrate the interaction (ortho) and lack of interaction (para) of the nitro group with the nucleophile in the TS.
4 Distances are given in Å.
5
6
7
8
9 The good correlation (R2=0.909) between ES,min and ln krel (Figure 9 and Table 5) demonstrates
10
11 that ES,min can well be used for predictions of relative reactivity also in VNS reactions. While the
12
13 LUMO energies has a weak correlation (R2=0.737), the prediction from VS,loc is of similar
14
15
16 accuracy (R2=0.910) as ES,min in this case, suggesting electrostatics to be important for the
17
18 formation of the σH-adduct. Note again that no local maxima in VS(r) could be located at the
19
20
active sites. We also note that the inclusion of solvation effects does not alter the trends
21
22
23 significantly.
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42 Figure 9. Correlation trend between experimental data and ES,min values at the site of reaction for series 5 (inset), R=H, OMe, F,
43 Cl, Br, I, CF3, OPh, SMe, SPh, CN, i-Pr, t-Bu, COOiPr.
44
45
46
47
48
In the original study of the compounds of series 5, the kinetic data was compared to the
49
50 Hammett σm constants (see Figure 1 in ref. 57) of the R group. In that comparison, the compounds
51
52 cCOOC2H5 and SPh were excluded and the R2-correlation between the σm constant and
53
54
55 experimental data (ln krel) was determined to 0.89.57 By excluding the mentioned compounds in
56
57 the ES(r) evaluation the corresponding correlation is 0.91. Obviously ES,min has the potential to
58
59
60
28
1
2
3
be used as a substitute for Hammett constants. This would be especially useful for cases where
4
5
6 Hammett constants are not available, for instance for previously undocumented or short-lived
7
8 compounds. We have also found that ES,min and the Hammett constants are complementary to
9
10
11
some degree. This is exemplified by the fact that by forming a multi-linear regression, ln
12
13 krel(predicted) = 6.261σm – 6.826ES,min – 9.422, a R2-value of 0.955 is obtained for the correlation
14
15 with the experimental ln krel for the VNS reaction.
16
17
18 Table 5. Reactivity data and descriptor values for series 5 at the ortho position with respect to the NO2 substituent.
19
20
21 R= ln krela) ES,minb,c) VS,locc,d,e)
22 Br 4.98 -1.71 17.85
23
Cl 4.83 -1.71 18.12
24
25 COOiPr 2.71 -1.4 14.78
26 H 0.00 -1.4 12.64
27 OMe -0.12 -1.4 11.69
28
29 SMe 2.4 -1.43 12.32
30 CF3 6.46 -1.81 21.14
31 CN 6.96 -1.9 24.44
32
i-Pr -1.24 -1.3 10.28
33
34 OPh 0.99 -1.39 11.49
35 t-Bu -1.02 -1.27 9.84
36 F 3.91 -1.72 17.99
37
I 3.78 -1.67 18.01
38
39 cC3O2H5 -0.08 -1.32 11.02
40 SPh 2.48 -1.58 16.9
41
42 R2 f) 0.909 0.910
43 Q 2 f)
0.885 0.876
44
SE f) 0.835 0.829
45 a)
46 Relative to R=H, reaction rates from ref. 57, b) eV, c) obtained in gas-phase, d) kcal mol-1, e) no VS,max could be
47 established at the reactive sites, h) versus ln krel.
48
49
50
51 Series 6
52
53 It has been demonstrated that a variety of compounds can be studied with ES(r). In series 6 it is
54
55
shown that the reactivity probe is not only useful for comparisons of reactions within well-
56
57
58
59
60
29
1
2
3
defined families of compounds, but also for rather dissimilar molecules reacting via the same
4
5
6 mechanism. The compounds of series 6 (Figure 10) were studied experimentally by Seeliger et
7
8 al,14 and contains nine N-hetero nitroarenes of different ring sizes with varied numbers and
9
10
11 positions of the nitrogen heteroatoms. As for series 5, a clear ortho directing effect of the nitro
12
13 group has been reported for series 6.14
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33 Figure 10. Schematic representation of the compounds of series 6.
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54 Figure 11. Experimental rate constants plotted against ES,min values for series 6.
55
56
57
58
59
60
30
1
2
3
Despite the vast mix of compounds included in series 6, ES,min values are able to nicely
4
5
6 reproduce the experientially determined reactivity trends. The correlation between ln krel and
7
8 ES,min has a R2-value of 0.941 and a standard error of only 0.98. This correlation is much stronger
9
10
11
than that of the LUMO energies (R2=0.590) and the local VS,loc (0.573), see Table 6. In Figure 11
12
13 the ln krel of the compounds is plotted against ES,min and only slight variations from the estimated
14
15 reaction trend is observed; one can identify compounds 6f, 6h and 6i as minor outliers, possibly
16
17
18 also including entry 6c(2). The three former compounds can be considered to react at sterically
19
20 more hindered sites (due to the methyl group of the adjacent nitrogen) than the rest of series 6. It
21
22 is moreover clear from e.g. Figure 8 that the chloromethyl phenyl sulfone carbanion nucleophile
23
24
25 addition not only gives rise to interactions at the site of reaction but also interacts with
26
27 neighboring groups. For series 6, neighboring methyl and nitro groups as well as the N-
28
29
heteroatom of the ring may form interactions with the nucleophile during the course of reaction.
30
31
32 This may explain why the expected reactivities (based on the ES,min values) slightly deviates from
33
34 the experimental values. However, these deviations may well fall within the range of
35
36
37 experimental errors and the inherent errors of the applied DFT method.
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
31
1
2
3 Table 6. Reaction rates and descriptor values for the series 6 compounds.
4
5
6
Position ln krela) ES,min b) VS,locc,d)
7
8 6a 2 8.70 -1.72 21.38
9
4 11.18 -2.18 23.77
10
11 6b 4 11.37 -2.31 28.06
12 6c 2 5.80 -1.64 16.46
13 6 6.51 -1.49 16.75
14
15 6d 6 9.74 -1.95 19.23
16 6e 3 0.00 -0.73 2.26
17 6f 2 1.61 -1.08 11.70
18
6g 2 2.20 -1.08 11.30
19
20 4 2.20 -0.96 22.30
21 6h 5 6.31 -1.40 18.28
22 6i 5 4.53 -1.55 22.66
23
24 R2 e) 0.941 0.573
25 2 e)
Q 0.924 0.429
26
27 SE e) 0.983 2.640
a)
28 from ref. 14, b) eV, c) kcal mol-1, d) no VS,max could be found at the site of reaction, e) versus ln krel.
29
30
31
32
33 Conclusion
34 It is herein established that the DFT based surface local electron attachment energy [ES(r)]
35
36
37 descriptor is a useful tool for reactivity predictions for the nucleophilic aromatic substitution
38
39 reactions of SNAr and VNS. Experimental reactivity trends have been reproduced with good to
40
41 excellent correlations for six series of congeneric compounds, including reactions with different
42
43
44 solvents, temperatures, nucleophiles and leaving groups. Remarkably, such diverse sets of
45
46 compounds as those of e.g. series 2 and 6, including homo- and heteroaromatic species of
47
48
49
different ring sizes, can be accurately described by ES(r). It has, furthermore, been demonstrated
50
51 that ES(r) is an efficient tool for estimation of regioselectivities, as long as the variations in the
52
53 neighboring environment are small.
54
55
56
57
58
59
60
32
1
2
3
In the present study it is shown that the ES(r) readily outperforms LUMO for electrophilicity
4
5
6 estimations. ES(r) is also found to be overall more reliable than the electrostatic surface potential,
7
8 VS(r), this since ES(r) in general gives stronger correlations but also because ES(r) is able to
9
10
11
locate the reactive sites, whereas VS(r) fails in the majority of the considered cases. For the case
12
13 of concerted SNAr reactions, the ES(r) descriptor has, furthermore, been found to be a valid
14
15 substitute to elaborate transition state calculations and hence offers an inexpensive alternative.
16
17
18 Considering the descriptors low computational cost and its accuracy, it is anticipated to find uses
19
20 in large reactivity screenings, in e.g. drug discovery or toxicological studies, but also for general
21
22 studies of various types of electron accepting chemical reactions and interactions.
23
24
25
26 Acknowledgment
27
28 J.H.S. gratefully acknowledge funding from the Excellence award of the School of Chemical
29
30 Science and Engineering at KTH Royal Institute of Technology.
31
32
33 Supporting Information. Coordinates of optimized structures and corresponding energies, as
34
35 well as ES,min values of ring position 3 and 5 of the series 1 compounds.
36
37
38
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Nucleophilic Aromatic Substitution Reactions Described by The Local Electron Attachment Energy

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