Ï-Hydrogen Bonding Probes the Reactivity of Aromatic Compounds

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A: Spectroscopy, Molecular Structure, and Quantum Chemistry

#-Hydrogen Bonding Probes the Reactivity of Aromatic Compounds: Nitration of Substituted Benzenes Boris Galabov, Gergana Koleva, Boriana Hadjieva, and Henry F. Schaefer J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.8b12508 • Publication Date (Web): 09 Jan 2019 Downloaded from http://pubs.acs.org on January 10, 2019

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The Journal of Physical Chemistry

π-Hydrogen Bonding Probes the Reactivity of Aromatic Compounds: Nitration of Substituted Benzenes Boris Galabov,*† Gergana Koleva,† Boriana Hadjieva,† Henry F. Schaefer III*‡ †Department ‡Center

of Chemistry and Pharmacy, University of Sofia, Sofia 1164, Bulgaria

for Computational Quantum Chemistry, University of Georgia, Athens, GA 30602 E-mail: [email protected], [email protected]

Abstract The shifts of phenol O-H stretching vibration frequencies [Δν(OH)exp] upon π-hydrogen bonding with aromatic compounds is proposed as a spectroscopic probe of the reactivity of aromatic substrates towards electrophiles. A single infrared spectrum reflecting the Δν(OH)exp shift for an aromatic species in a reference solvent (CCl4 in this study) provides a good estimate of reactivity. The methodology is applied in rationalizing reactivity trends for the BF3 catalyzed nitration by methylnitrate in nitromethane of 20 aromatic reactants, including benzene, 11 methylbenzenes, several monoalkyl benzenes, the four halobenzenes, and anisole. Literature kinetic data1 are employed in the analysis. Very good correlations between relative rates of nitration and Δν(OH)exp are obtained. The approach is best applied to reactions, where the initial interactions between the reactants controls the rates. A new theoretical quantity, the shifts (with respect to benzene) of the molecular electrostatic potential at 1.5 Å over the centroid of the aromatic ring [ΔV(1.5)] is defined and shown to provide a good description of substituent effects on properties of the aromatic species. B3LYP density functional and MP2 ab initio methods combined with the 6-311++G(3df,2pd) basis set are employed in evaluating the ΔV(1.5) values. Introduction In the present communication we present a straightforward spectroscopic approach for predicting the overall reactivity of aromatic compounds towards electrophilic reactants. The hypothesis employed relates the reactivity in electrophilic aromatic substitution (EAS) reactions with the electron density over the aromatic ring as assessed by the shifts of phenol O-H stretching vibration frequency [Δν(OH)exp] upon π-hydrogen bonding. Δν(OH)exp is accepted as an experimental measure of reactivity. It is expected that electron richer rings facilitate the interaction between the aromatic species and the electrophile. As a test case, we examine the rates of the electrophilic nitration of benzene, 11 methylbenzenes, several monoalkyl benzenes, the four halobenzenes, and anisole by methyl nitrate in nitromethane, catalyzed by BF3. The relative rates of these reactions have been reported by Olah and Lin.1 Quantifying the reactivity of aromatic compounds has been of paramount interest in organic chemistry. Over 80 years ago Hammett introduced the first quantitative concept of reactivity in the field by defining the substituent σ constants.2 The scales of σ constants and associated various further developments315

still find extensive application in chemical studies in rationalizing kinetic results, resolving the mechanisms of

organic reactions as well as in QSPR/QSAR investigations.16-18 The basic idea of connecting quantitatively 1 ACS Paragon Plus Environment

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structural variations with properties is in the core of many contemporary fields in chemical science, such as the development of new drugs in medicine as well as molecules and materials for specific applications.19-33 Electronic structure theory has opened new horizons in quantifying chemical reactivity. Transition state theory and molecular dynamics simulations have provided tools for examining the mechanisms of organic reactions.5 Various approaches have also been proposed to quantify reactivity in terms of theoretical parameters. The frontier orbital methodology of Fukui represented the first significant breakthrough in the field.34,35 Subsequent developments in the framework of density functional theory employing the energies of frontier orbitals resulted in the introduction of a number of theoretical quantities describing reactivity, such as hardness, softness, electronic chemical potential as well as electrophilicity and nucleophilicity indexes.36-38 Atomic charges and associated properties,39 bond orders,39 molecular electrostatic potential (MEP) maps,40 minima and maxima at isoelectron density surfaces of MEP,21,22,40 electrostatic potentials at nuclei,27,41 and average local ionization energies42,43 also find wide application. The quantum theoretical parameters have offered efficient, though not always successful, approaches in predicting chemical reactivity. A recent review of Liljenberg and Brinck39 provides an extensive survey and valuable insights into the applicability of theoretically derived molecular parameters in quantifying the reactivity of aromatic systems. Many textbooks still rationalize aromatic reactivity and positional selectivity in terms of the partial charges at atomic sites of the aromatic substrate.44-46 This methodology has been verified in recent studies by applications to some EAS reactions employing Hirshfeld atomic charges and electrostatic potentials at nuclei as reactivity parameters.41,47 Such an approach has good physical grounds for reactions, in which the first stage, the initial interaction of the electrophilic reactant with the aromatic substrate, defines reactivity. Many studies have, however, shown that the second stage of EAS reactions, the formation of a σ-complex (Wheland intermediate), is rate-determining.44-46 It can be argued, nonetheless, that even in such cases, the substitution is favored by higher electron densities at the respective ring sites. In the present communication we present a simple and efficient spectroscopic approach for quantifying reactivity. The proposed methodology requires essentially the recording of a single infrared spectrum of the aromatic reactant in a reference solvent, reflecting the π-hydrogen bonding with a convenient proton-donating molecule. In our investigation we applied phenol as the proton donor and CCl4 as solvent. Supporting theoretical computations were conducted to verify the origin of the good correlation between the O-H stretching frequency shifts and kinetic parameters for the nitration of a series of benzene derivatives. The kinetic data employed provide comparative (with respect to benzene) rates of catalyzed by BF3 nitration of 20 aromatic derivatives by methyl nitrate in nitromethane solvent.1 The aromatic reactants include benzene, a series of eleven methylbenzenes, several other monoalkyl derivatives, the four halobenzenes, and anisole. Olah and Lin discussed that the overall rates for the investigated nitrations depends on the initial interaction between the reactants.1 These kinetic results represent, therefore, a suitable basis to test the validity of the proposed in the present research methodology. 2 ACS Paragon Plus Environment

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Methods Infrared spectra Most infrared spectroscopic data for the O-H frequency shifts upon π-hydrogen bonding between the aromatic substrates and the phenol proton donor were taken from the studies of Yoshida and Seguin et al.48-50 We recorded the IR spectra of π-hydrogen-bonded complex with phenol for 1,2,3,4-tetramethylbenzene and 1,2,3,5-tetramethylbenzene, which were not available in the above references. We also verified the accuracy of measurement in the literature sources by recording the spectra of complexes with phenol of several other derivatives - benzene, 1,2,3-trimethylbenzene, 1,3,5-trimethylbenzene, pentamethylbenzene, and anisole - by using a newer generation FTIR spectrometer, which employs a laser controlled frequency recording. The infrared spectra were measured for solutions in CCl4, containing 0.01 mol/l of phenol and 0.3 mol/l of the aromatic derivatives. The spectra were recorded at ambient temperature (25 °C ± 1 °C) in a 1 cm quartz cell as the average of 100 scans at resolution 1 cm−1. The spectra obtained are given in the Supporting Information (SI). The spectrum of pure monomer phenol recorded under the same conditions is also provided in SI. Existing equilibrium between π-hydrogen bonded and non-bonded O-H group in the solutions results in the appearance of two bands in the region of O-H stretching vibrations. The assignment of these bands to free and participating in π-hydrogen bonding species has been made in earlier studies.48-50 Theoretical computations All structures of monomeric benzene derivatives were fully optimized using the B3LYP hybrid functional51-53 and MP2 ab initio level,54 combined with the 6-311++G(3df,2pd)55 basis set. As an illustration, we also conducted theoretical computations on the π-hydrogen bonded complex between benzene and phenol (Figure 1). To account for the effect of the dispersion contributions to the energy of the complex, we applied the ωB97X-D density functional,56 combined with the same basis set. Harmonic vibrational frequencies were evaluated to ensure that each optimized structure is a true minimum on the potential energy surfaces. The influence of nitromethane and tetrachloromethane solvents was assessed by applying the Integral Equation Formalism of Polarizable Continuum Model (IEFPCM) method.57 The computations employed the Gaussian09 program package.58 The B3LYP/6-311++G(3df,2pd) level of theory has provided accurate predictions of O-H stretching frequency shifts (ΔνOH) upon π-hydrogen bonding.59,60 As already emphasized, ΔνOH is a key experimental property, considered in the present study. Besides, the B3LYP method predicts analogous structure for complexes between substituted phenols and aromatic compounds as obtained by alternative density functional theory methods: B97-D, PBE0, and ωB97X-D. 59,60 Medvedev et al.61 showed that a number of earlier proposed density functionals, including B3LYP, provide more reliable predictions of electron density distribution in molecules, compared to some recently defined density functionals. The charge density distribution is another important molecular property for our research. To characterize the electric charge 3 ACS Paragon Plus Environment


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effects on reactivities we employed the molecular electrostatic potentials (MESP) values at 1.5 Å over the centroid of the aromatic ring [V(1.5)] and their variations [ΔV(1.5)] upon substitution. The molecular electrostatic potential (MEP) at a point r is defined according to the expression:40

V (r )   A

ZA  (r )  dr  RA  r r  r

(1)

In Eqn. 1, RA is the position vector of nucleus Y, ZA is the charge of nuclei A, ρ(r) is the electron density function, and r’ – an integration variable. Molecular electrostatic potential maps onto a surface of constant electron density for the aromatic reactants are also employed in rationalizing reactivity trends. Results and Discussion The basic hypothesis in the present research considers the expected link between the shifts in the phenol O-H stretching frequency upon π-hydrogen bonding with arene derivatives and the electron densities over the aromatic ring. The reactivity of aromatic molecules is usually associated with the variations of electron densities at the ring sites.44-46 Our recent investigations59,60 have shown that the shifts of O-H stretching frequencies upon π-hydrogen bonding may be correlated with the electron densities associated with the arene π-electron system. Stoyanov and Read62 have emphasized the relationship between basicities of organic compounds and N-H stretching frequency shifts upon π-hydrogen bonding. Rzepa63 has discussed the possibilities for deriving information on the regiospecificity in electrophilic aromatic substitution, that can be obtained from three-dimensional structural searches on hydrogen bonding to the aromatic ring by using the Cambridge crystal structure database. Earlier theoretical computations64-67 have also revealed that the minimum energy conformers of the resulting hydrogen-bonded complexes between phenols and arenes possess a T-shaped structure. Figure 1 illustrates the structure the complex between benzene and phenol. Our theoretical studies revealed also that two types of π-hydrogen bonds are simultaneously formed: a red-shifting O-H···π and a blue-shifting C-H···π bonds.59,60 The C-H bond at ortho position to the phenol hydroxyl group is involved in the complex (Figure 1).

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Figure 1. Different views of the π-hydrogen-bonded complex between benzene and phenol at wB97X-D/6311++G(3df,2pd). Table 1 presents the relative rates (with respect to benzene) of the BF3 catalyzed nitration of benzene and 19 substituted derivatives (methylbenzenes, monoalkylbenzenes, halobenzenes, and anisole) with methyl nitrate in nitromethane as reported by Olah and Lin.1 These kinetic data are juxtaposed to the observed shifts of the phenol O-H stretching bands [Δν(OH)exp] upon π-complex formation with the respective aromatic species. The spectroscopic results are given in the last column of Table 1. Following a detailed analysis of the kinetic results, Olah and Lin concluded that the rates of the aromatic nitration reactions investigated are governed by an early transition state associated with the initial interaction between the reactants.1 Scheme 1 shows the proposed reaction path1 for the reaction investigated. As already emphasized, the kinetic data of Olah and Lin1 form an ideal platform to test the validity of the proposed methodology for aromatic reactivity assessment. It was gratifying to establish that the plot between the relative rates of nitration (log krel) and ∆ν(OH) yielded in a good correlation (r = 0.966) between the two sets of quantities. The obtained plot is illustrated in Figure 2. This result clearly demonstrated the applicability of O-H frequency shifts upon π-hydrogen bonding as an experimental measure of reactivity for the aromatic species in the EAS reactions considered.

Scheme 1. Schematic representation for CH3ONO2−BF3 arene nitration (adapted from Ref. 1, Copyright 1974, ACS).



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Table 1. Relative overall rate constantsa (log krel) for the nitration of benzene, alkylbenzenes, halobenzenes, and anisoleb and shifts of phenol ν(OH) stretching frequencies (in cm-1) upon π-hydrogen bonding in CCl4 solvent.c Species

log krel

Benzene 0.00 Toluene 1.41 Ethylbenzene 1.36 Isopropylbenzene 1.32 tert-Butylbenzene 1.29 1,2-Dimethylbenzene 2.28 1,3-Dimethylbenzene 2.46 1,4-Dimethylbenzene 2.47 1,2,3-Trimethylbenzene 2.96 1,2,4-Trimethylbenzene 3.03 1,3,5-Trimethylbenzene 2.98 1,2,3,4-Tetramethylbenzene 3.33 1,2,3,5-Tetramethylbenzene 3.27 1,2,4,5-Tetramethylbenzene 3.34 Pentamethylbenzene 3.41 Fluorobenzene -0.92 Chlorobenzene -1.52 Bromobenzene -1.52 Iodobenzene -1.00 Anisole 2.27 r (linear) r (2nd order polynomial) aRelative rates with respect to benzene (k benzene = 1). bFrom Ref. [1]. For details on the reaction conditions see the text and the cited references. cRefs. [48-50] and present study. dPresent study.

∆ν(OH)exp [cm−1] 48 58 59 55 60 68 69 71d 75d 78 77d 87d 88d 85 93d 38 33 37 38 60d 0.966 0.991

Olah and Lin discussed that steric influences associated with the different size of the alkyl substituents may affect reactivity.1 The measured rates also reflect multiple simultaneous monosubstitutions at different ring sites for some of the arene derivatives investigated. The overall rates depend, therefore, on a number of factors. These effects may contribute to deviations from fully linear relationship between reaction rates and ∆ν(OH) shifts (Figure 2A). This is well-manifested in Figure 2B, which illustrates a second order polynomial dependence between ∆ν(OH) and log krel with a correlation coefficient r = 0.991. Overall, the obtained good correlations between relative rates and ∆ν(OH), shows that reactivity is largely dominated by the electron densities over the aromatic ring as reflected in the measured ∆ν(OH) shifts.


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Figure 2. Plots [linear (A) and 2nd order polynomial (B)] of relative rate constants (log krel) for the nitration of benzene, alkylbenzenes, halobenzenes, and anisole vs. shifts of phenol ν(OH) stretching frequencies. To gain further insights into the intramolecular effects influencing reactivity, we conducted theoretical computations illustrating the variation of electrostatic potentials in the aromatic systems studied. As a suitable molecular parameters to illustrate the electrostatic field over the ring we adopted the shift with respect to the value in benzene of the molecular electrostatic potentials at 1.5 Å over the centroid of the aromatic ring, ∆V(1.5). ∆V(1.5) values are expected to characterize, at least qualitatively, the variations of electron densities over the aromatic cycle upon substitution. The definition of this quantity resembles the NICSs (Nucleusindependent chemical shifts) aromaticity index.68 Because of the inverse relationship to distance (Eq. 1), at 1.5 Å over the ring centroid the molecular electrostatic potential is less dependent on the positive nuclear charges of the substituents, while still strongly influenced by the variation of the π-electron density. Tables S2-S5 present the shifts of MESP values at the ring centroid and at 0.5, 1.0, 1.5, and 2.0 Å over the centroid for the series of substituted benzenes investigated. The evaluated ∆V(1.5) values for the series of benzene derivatives investigated are presented in Table 2.



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Table 2. Computed shifts of molecular electrostatic potentials (in a.u., relative to benzene) at 1.5 Å over the centroid of the aromatic ring, and shifts of phenol ν(OH) stretching frequencies (in cm-1) upon π-hydrogen bonding in CCl4 solvent. Species

∆ν(OH)exp

a

Benzene 48 Toluene 58 Ethylbenzene 59 Isopropylbenzene 55 tert-Butylbenzene 60 1,2-Dimethylbenzene 68 1,3-Dimethylbenzene 69 1,4-Dimethylbenzene 71b 1,2,3-Trimethylbenzene 75b 1,2,4-Trimethylbenzene 78 1,3,5-Trimethylbenzene 77b 1,2,3,4-Tetramethylbenzene 87b 1,2,3,5-Tetramethylbenzene 88b 1,2,4,5-Tetramethylbenzene 85 Pentamethylbenzene 93b Fluorobenzene 38 Chlorobenzene 33 Bromobenzene 37 Anisole 60b r (linear) r (2nd order polynomial) aFrom Refs. [48-50] and present study. bPresent study.

∆V(1.5) B3LYP/6-311++G(3df,2pd) gas phase CH3NO2 CCl4 0.0000 0.0000 0.0000 -0.0027 -0.0029 -0.0028 -0.0032 -0.0033 -0.0032 -0.0024 -0.0030 -0.0026 -0.0027 -0.0033 -0.0029 -0.0045 -0.0048 -0.0046 -0.0048 -0.0051 -0.0048 -0.0047 -0.0050 -0.0048 -0.0067 -0.0073 -0.0069 -0.0066 -0.0072 -0.0068 -0.0069 -0.0075 -0.0072 -0.0087 -0.0095 -0.0090 -0.0090 -0.0098 -0.0092 -0.0084 -0.0091 -0.0086 -0.0108 -0.0117 -0.0111 0.0110 0.0114 0.0112 0.0123 0.0134 0.0128 0.0129 0.0140 0.0134 -0.0013 -0.0020 -0.0016 0.936 0.935 0.935 0.990 0.990 0.990

MP2/6-311++G(3df,2pd) gas phase 0.0000 -0.0029 -0.0034 -0.0027 -0.0031 -0.0048 -0.0052 -0.0050 -0.0071 -0.0074 -0.0076 -0.0094 -0.0098 -0.0090 -0.0116 0.0124 0.0132 0.0142 -0.0002 0.935 0.986

Figure 3. Second order polynomial dependence of the phenol O-H stretching frequency shifts [∆ν(OH)] upon πhydrogen bonding with benzene, alkylbenzenes, halobenzenes, and anisole vs. molecular electrostatic potentials (in a.u., relative to benzene) ∆V(1.5) at B3LYP/6-311++G(3df,2pd) in the gas-phase.


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Figure 4. Molecular electrostatic potential (MEP) maps at the electron isodensity surfaces (at 0.0004 au) for selected monomer methylbenzenes in the gas-phase at B3LYP/6-311+G(3df,2pd). Negative and positive MESP areas are represented in red and blue colors respectively. An important correlation emerges from the data obtained. The plot between the shifts of phenol ν(OH) stretching frequencies [∆ν(OH)exp] and ∆Vring center values (illustrated in Figure 3) reveals a satisfactory second order polynomial dependence (r = 0.990) between these quantities. The correlation coefficient characterizing this relationship does not change significantly with computations for isolated molecules (gas phase) and for modeled nitromethane and tetrachloromethane solutions. MP2/6-311++G(3df,2pd) computations yielded in analogous correlation between ∆ν(OH)exp and ∆V(1.5). Table 2 shows clearly that increase of the alkyl substitution in the ring results in more negative ∆V(1.5) values. These shifts are consistent with the hyperconjugative effect of the alkyl groups adding electron densities to the ring. On the contrary, the halogen and methoxy group substitution leads to positive ∆V(1.5) values, thus clearly illustrating their electron withdrawing properties. We may, therefore, conclude that the newly defined ∆V(1.5) theoretical parameter characterizes well the variations of electric charge distribution induced by the substituents. Further insights provide the comparisons of the electrostatic potential maps at 0.0004 au electron isodensity surfaces. Figure 4 illustrates how the molecular electrostatic potentials change with increasing the methyl substitution in the ring. The deeper red color (more negative electrostatic potential) may be linked to the increased electron densities over the ring, resulting from the methyl hyperconjugation effects.



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Figure 5. Second order polynomial plot of the relative rates of nitration of benzene, alkylbenzenes, halobenzenes, and anisole vs. ∆V(1.5) at B3LYP/6-311++G(3df,2pd) in nitromethane solvent. The relationship between relative rates of nitration (log krel) and ∆V(1.5) also results in satisfactory linear correlation coefficient (r = 0.969, Figure 5). If we, however, correlate ∆V(1.5) with the relative nitration rates for the derivatives with identical positions for monosubstitution (Table 3), we arrive at a much better correlation (r = 0.998). The low number of points does not guarantee statistical significance for this dependence. As discussed, the parallel reactions taking place for some derivatives (e. g. ortho, meta, and para substitutions in the monosubstituted derivatives), lead to certain dispersion of the overall reaction rates. The results presented in Table 3 reveal an improved correlation, when this factor is not present. Table 3. Relative rate constantsa (log krel) for the nitration of alkylbenzenes with identical position for substitution and computed values of molecular electrostatic potentials at 1.5 Å over the ring centroid (in a.u., relative to benzene) at MP2/6-311++G(3df,2pd). Species

log krel

∆V(1.5)

Benzene 0.00 0.0000 1,4-Dimethylbenzene 2.47 -0.0050 1,3,5-Trimethylbenzene 2.98 -0.0076 1,2,3,4-Tetramethylbenzene 3.33 -0.0094 1,2,3,5-Tetramethylbenzene 3.27 -0.0098 1,2,4,5-Tetramethylbenzene 3.34 -0.0090 Pentamethylbenzene 3.41 -0.0116 nd r (2 order polynomial) 0.998 aFrom Ref. [1]. For details on the reaction conditions see the text and the cited reference. The proposed methodology only reflects the overall reactivity of the aromatic species. The positional selectivity cannot be assessed. The mechanism of the particular electrophilic aromatic substitution reaction is also of importance in applying Δν(OH)exp shifts for assessing reactivity. The present approach is best applied to reactions, in which the initial interaction between the aromatic molecule and electrophile governs the reactivity. As mentioned, in cases where the rate is controlled by the formation of the σ-complex 10 ACS Paragon Plus Environment

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intermediate,5,44-46 we may expect a more complicated picture of intramolecular factors influencing reaction rates. Summary An efficient spectroscopic methodology for assessment of aromatic reactivity is presented. The shifts of phenol O-H stretching frequency shifts upon π-hydrogen bonding with the aromatic reactant is proposed as a measure of reactivity. A single infrared spectrum of the formed complex in a reference solvent may be employed in characterizing reactivity. The approach provides a plausible quantitative assessment of reactivity for the BF3 catalyzed nitration by methyl nitrate in nitromethane solution of 18 aromatic reactants, including benzene, 11 methylbenzenes, and several monoalkyl- and halobenzene derivatives. The procedure best applies to reactions where the initial interaction between the reactants controls the rate. A newly defined theoretical quantity, the shift with respect to a reference value (for benzene) of the electrostatic potential at 1.5 Å over the aromatic ring centroid [∆V(1.5)], is shown to correlate well with both experimental Δν(OH) IR frequency shifts and relative rates of nitration. Acknowledgements Financial support from the National Science Fund (Bulgaria), Grant DN 09/4, EU Grant „Materials Networking“, and U.S. National Science Foundation, Grant CHE - 1661604, is gratefully acknowledged. Supporting Information. IR spectra of π-hydrogen-bonded complexes, shifts of MESP values at the ring centroid and at several distances over the centroid for the series of substituted benzenes investigated, Cartesian coordinates and energies of all optimized structures are given in the Supporting Information. References (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)

Olah, G. A.; Lin, H. C. Aromatic Substitution. XXXV. Boron Trifluoride Catalyzed Nitration of Benzene, Alkylbenzenes, and Halobenzenes with Methyl Nitrate in Nitromethane Solution. J. Am. Chem. Soc. 1974, 96, 2892–2898. Hammett, L. P. Physical Organic Chemistry, 2nd ed.; McGraw-Hill: New York; St. Louis; San Francisco, 1970. Jaffé, H. H. A Reëxamination of the Hammett Equation. Chem. Rev. 1953, 53, 191–261. Correlation Analysis in Chemistry: Recent Advances; Chapman, N., Ed.; Springer US, 1978. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry: Part A: Structure and Mechanisms, 5th ed.; Springer US, 2007. Hansch, C.; Leo, A.; Taft, R. W. A Survey of Hammett Substituent Constants and Resonance and Field Parameters. Chem. Rev. 1991, 91, 165–195. Exner, O.; Krygowski, T. M. The Nitro Group as Substituent. Chem. Soc. Rev. 1996, 25, 71–75. Shorter, J. Compilation and Critical Evaluation of Structure-Reactivity Parameters and Equations - Part I: Values of σm, and σp Based on the Ionization of Substituted Benzoic Acids in Water at 25 C. Pure and Applied Chemistry 1994, 66, 2451–2468. Charton, M. Electrical Effect Substituent Constants for Correlation Analysis. In Progress in Physical Organic Chemistry; John Wiley & Sons, Ltd, 2007; pp 119–251. Wiberg, K. B. Substituent Effects on the Acidity of Weak Acids. 1. Bicyclo[2.2.2]Octane-1-Carboxylic Acids and Bicyclo[1.1.1]Pentane-1-Carboxylic Acids. J. Org. Chem. 2002, 67, 1613–1617. 11 ACS Paragon Plus Environment


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