Mini-Review on Structure-Reactivity Relationship for Aromatic Molecules: Recent Advances.

Recent advances in quantifying nucleophilic reactivities in chemical reactions and intermolecular interactions of aromatic molecules are reviewed. This survey covers experimental (IR frequency shifts induced by hydrogen bonding) and theoretical (modeling of potential energy surfaces, atomic charges, molecular electrostatic potential) approaches in characterizing chemical reactivity. Recent advances in software developments assisting the evaluation of the reactive sites for electrophilic aromatic substitution are briefly discussed.

π-Hydrogen Bonding Probes the Reactivity of Aromatic Compounds: Nitration of Substituted Benzenes.

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 toward 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 data 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 [Δ V(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 Δ V(1.5) values.

Atomic Charges in Describing Properties of Aromatic Molecules.

The performance of four frequently employed population analysis methods is assessed by comparisons with experimentally derived properties of monosubstituted benzene derivatives. The analysis is based on the expected dependence between site reactivities and electron densities at the respective ring carbon atoms. The correspondence between charges obtained from Mulliken, NPA, Hirshfeld, and QTAIM approaches and the σ0m and σ0p aromatic substituent constants is examined. The series of molecules investigated includes benzene and 18 monosubstituted derivatives. The atomic charges are derived using the B3LYP, ωB97X-D density functional, and MP2 MO methods combined with the 6-311++G(3df,2pd) basis set. A quantitative correspondence between Hirshfeld charges and σ0 constants is established. Application of Møller-Plesset second-order perturbation theory (MP2) wave functions appears to be essential in obtaining a more realistic electron density distribution. NPA and QTAIM charges provide in most cases a satisfactory description of the substituent effects. The net transfer of charges between substituents and the aromatic ring is assessed.

Nucleophilic Influences and Origin of the SN 2 Allylic Effect.

The potential energy surfaces for the SN 2 reactions of allyl and propyl chlorides with 21 anionic and neutral nucleophiles was studied by using ωB97X-D/6-311++G(3df,2pd) computations. The "allylic effect" on SN 2 barriers was observed for all reactions, and compared with propyl substrates, the energy barriers differed by -0.2 to -4.5 kcal mol-1 in the gas phase. Strong correlations of the SN 2 net activation barriers with cation affinities, proton affinities, and electrostatic potentials at nuclei demonstrated the powerful influence of electrostatic interactions on these reactions. For the reactions of anionic (but not neutral) nucleophiles with allyl chloride, some of the incoming negative charge (0.2-18 %) migrated into the carbon chains, which would provide secondary stabilization of the SN 2 transition states. Activation strain analysis provided additional insight into the allylic effect by showing that the energy of geometric distortion for the reactants to reach the SN 2 transition state was smaller for each allylic reaction than for its propyl analogue. In many cases, the interaction energies between the substrate and nucleophile in this analysis were more favorable for propyl chloride reactions, but this compensation did not overcome the predominant strain energy effect.

Hyperconjugative effects in π-hydrogen bonding: Theory and experiment.

Density functional theory computations with the B3LYP/6-311++G(2df,2p) method and IR spectroscopy are employed in investigating the properties of twenty π-hydrogen bonded complexes between substituted phenols and hexamethylbenzene. All complexes possess T-shaped structures. The methyl hyperconjugative effects on interactions energies and OH stretching frequencies are estimated via comparisons with previously reported theoretical and experimental results for analogous phenol complexes with benzene. The theoretical computations provide excellent quantitative predictions of the OH stretching frequency shifts (ΔνOH ) resulting from the hydrogen bonding. The ΔνOH shifts in the hexamethylbenzene complexes are approximately twice as large as the corresponding shifts for the benzene complexes. Hirshfeld charges, electrostatic potential at nuclei values, and molecular electrostatic potential maps are employed in gaining insights into the mechanisms of methyl hyperconjugative effects on complex formation. © 2017 Wiley Periodicals, Inc.

Electrophilic Aromatic Substitution: New Insights into an Old Class of Reactions.

The classic SEAr mechanism of electrophilic aromatic substitution (EAS) reactions described in textbooks, monographs, and reviews comprises the obligatory formation of arenium ion intermediates (σ complexes) in a two-stage process. Our findings from several studies of EAS reactions challenge the generality of this mechanistic paradigm. This Account focuses on recent computational and experimental results for three types of EAS reactions: halogenation with molecular chlorine and bromine, nitration by mixed acid (mixture of nitric and sulfuric acids), and sulfonation with SO3. Our combined computational and experimental investigation of the chlorination of anisole with molecular chlorine in CCl4 found that addition-elimination pathways compete with the direct substitution processes. Detailed NMR investigation of the course of experimental anisole chlorination at varying temperatures revealed the formation of addition byproducts. Moreover, in the absence of Lewis acid catalysis, the direct halogenation processes do not involve arenium ion intermediates but instead proceed via concerted single transition states. We also obtained analogous results for the chlorination and bromination of several arenes in nonpolar solvents. We explored by theoretical computations and experimental spectroscopic studies the classic reaction of benzene nitration by mixed acid. The structure of the first intermediate in this process has been a subject of contradicting views. We have reported clear experimental UV/vis spectroscopic evidence for the formation of the first intermediate in this reaction. Our broader theoretical modeling of the process considers the effects of the medium as a bulk solvent but also the specific interactions of a H2SO4 solvent molecule with intermediates and transition states along the reaction path. In harmony with the obtained spectroscopic data, our computational results reveal that the structure of the initial π complex precludes the possibility of electronic charge transfer from the benzene π system to the nitronium unit. In contrast to usual interpretations, our computational results provide compelling evidence that in nonpolar, noncomplexing media and in the absence of catalysts, the mechanism of aromatic sulfonation with sulfur trioxide is concerted and does not involve the conventional σ-complex (Wheland) intermediates. Stable under such conditions, (SO3)2 dimers react with benzene much more readily than monomeric sulfur trioxide. In polar (complexing) media, the reaction follows the classic two-stage SEAr mechanism. Still, the rate-controlling transition state involves two SO3 molecules. The reactivity and regioselectivity in EAS reactions that follow the classic mechanistic scheme are quantified using a theoretically evaluated quantity, the electrophile affinity (Eα), which measures the stabilization energy associated with the formation of arenium ions. Examples of applications are provided.

An Experimentally Established Key Intermediate in Benzene Nitration with Mixed Acid.

Experimental evidence is reported for the first intermediate in the classic SEAr reaction of benzene nitration with mixed acid. The UV/Vis spectroscopic investigation of the reaction showed an intense absorption at 320 nm (appearing as a band shoulder) arising from a reaction intermediate. Our theoretical modeling shows that the interaction between the two principal reactants with solvent (H2SO4) molecules significantly affects the structure of the initial complex. In this complex, a larger distance between the aromatic ring and nitronium ion precludes the possibility for electronic charge transfer from the benzene π-system to the electrophile. The computational modeling of the potential energy surface reveals that the reaction favors a stepwise mechanism with intermediate formation of π- and σ-(arenium ion) complexes.

Experimental measurement and theory of substituent effects in π-hydrogen bonding: complexes of substituted phenols with benzene.

IR spectroscopic experiments and theoretical DFT computations reveal the effects of aromatic substituents on π-hydrogen bonding between monosubstituted phenol derivatives and benzene. Simultaneous formation of two π-hydrogen bonds (red-shifting O-H···π and blue-shifting ortho-C-H···π) contribute to the stability of these complexes. The interaction of the acidic phenol O-H proton-donating group with the benzene π-system dominates the complex formation. The experimental shifts of O-H stretching frequencies for the different phenol complexes vary in the range 45-74 cm(-1). Strong effects on hydrogen-bonding energies and frequency shifts of electron-withdrawing aromatic substituents and very weak influence of electron-donating groups have been established. Experimental quantities and theoretical parameters are employed in rationalizing the properties of these complexes. The acidities of the proton-donating phenols describe quantitatively the hydrogen-bonding process. The results obtained provide clear evidence that, when the structural variations are in the proton-donating species, the substituent effects on π-hydrogen bonding follow classic mechanisms, comprising both resonance and direct through-space influences. The performance of three alternative DFT functionals (B3LYP, B97-D, and PBE0 combined with the 6-311++G(2df,2p) basis set) in predicting the O-H frequency shifts upon complexation is examined. For comparison, O-H frequency shifts for several complexes were also determined at MP2/6-31++G(d,p).

Arenium ions are not obligatory intermediates in electrophilic aromatic substitution.

Our computational and experimental investigation of the reaction of anisole with Cl2 in nonpolar CCl4 solution challenges two fundamental tenets of the traditional SEAr (arenium ion) mechanism of aromatic electrophilic substitution. Instead of this direct substitution process, the alternative addition-elimination (AE) pathway is favored energetically. This AE mechanism rationalizes the preferred ortho and para substitution orientation of anisole easily. Moreover, neither the SEAr nor the AE mechanisms involve the formation of a σ-complex (Wheland-type) intermediate in the rate-controlling stage. Contrary to the conventional interpretations, the substitution (SEAr) mechanism proceeds concertedly via a single transition state. Experimental NMR investigations of the anisole chlorination reaction course at various temperatures reveal the formation of tetrachloro addition by-products and thus support the computed addition-elimination mechanism of anisole chlorination in nonpolar media. The important autocatalytic effect of the HCl reaction product was confirmed by spectroscopic (UV-visible) investigations and by HCl-augmented computational modeling.

Do π-conjugative effects facilitate SN2 reactions?

Rigorous quantum chemical investigations of the SN2 identity exchange reactions of methyl, ethyl, propyl, allyl, benzyl, propargyl, and acetonitrile halides (X = F(-), Cl(-)) refute the traditional view that the acceleration of SN2 reactions for substrates with a multiple bond at Cß (carbon adjacent to the reacting Cα center) is primarily due to π-conjugation in the SN2 transition state (TS). Instead, substrate-nucleophile electrostatic interactions dictate SN2 reaction rate trends. Regardless of the presence or absence of a Cß multiple bond in the SN2 reactant in a series of analogues, attractive Cß(δ(+))···X(δ(-)) interactions in the SN2 TS lower net activation barriers (E(b)) and enhance reaction rates, whereas repulsive Cß(δ(-))···X(δ(-)) interactions increase E(b) barriers and retard SN2 rates. Block-localized wave function (BLW) computations confirm that π-conjugation lowers the net activation barriers of SN2 allyl (1t, coplanar), benzyl, propargyl, and acetonitrile halide identity exchange reactions, but does so to nearly the same extent. Therefore, such orbital interactions cannot account for the large range of E(b) values in these systems.

Aminolysis of phenyl N-phenylcarbamate via an isocyanate intermediate: theory and experiment.

A comprehensive examination of the mechanism of the uncatalyzed and base-catalyzed aminolysis of phenyl N-phenylcarbamate by theoretical quantum mechanical methods at M06-2X/6-311+G(2d,2p) and B3LYP-D3/6-31G(d,p) levels, combined with an IR spectroscopic study of the reaction, was carried out. Three alternative reaction channels were theoretically characterized: concerted, stepwise via a tetrahedral intermediate, and stepwise involving an isocyanate intermediate. In contrast to dominating views, the theoretical results revealed that the reaction pathway through the isocyanate intermediate (E1cB) is energetically favored. These conclusions were supported by an IR spectroscopic investigation of the interactions of phenyl N-phenylcarbamate with several amines possessing varying basicities and nucleophilicities: n-butylamine, diethylamine, triethylamine, N-methylpyrrolidine, and trimethylamine. The reactivity of substituted phenyl N-phenylcarbamates in the aminolysis reaction was rationalized using theoretical and experimental reactivity indexes: electrostatic potential at nuclei (EPN), Hirshfeld and NBO atomic charges, and Hammett constants. The obtained quantitative relationships between these property descriptors and experimental kinetic constants reported in the literature emphasize the usefulness of theoretical parameters (EPN, atomic charges) in characterizing chemical reactivity.

Does the molecular electrostatic potential reflect the effects of substituents in aromatic systems?

A detailed analysis of the molecular electrostatic potential (MEP) at selected positions in molecular space was performed for a series of substituted benzene derivatives. We show that appropriately selected MEP values can quantitatively reflect the regiospecific effects of substituents on the aromatic ring. Theoretically evaluated electrostatic potentials in close proximity to the ring carbon atoms reflect well both through-space and resonance effects and excellent correlation is established between the MEP values and substituent constants. The best descriptor of the local properties at different ring positions is the electrostatic potential at nuclei (EPN).

Electrophilic aromatic sulfonation with SO3: concerted or classic S(E)Ar mechanism?

The electrophilic sulfonation of several arenes with SO(3) was examined by electronic structure computations at the M06-2X/6-311+G(2d,2p) and SCS-MP2/6-311+G(2d,2p) levels of theory. In contrast to the usual interpretations, the results provide clear evidence that in nonpolar media and in the absence of catalysts the mechanism of aromatic sulfonation with a single SO(3) is concerted and does not involve the conventionally depicted 1:1 σ complex (Wheland) intermediate. Moreover, the computed activation energy for the 1:1 process is unrealistically high; barriers for alternative 2:1 mechanisms involving attack by two SO(3) molecules are 12-20 kcal/mol lower! A direct 2:1 sulfonation mechanism, involving a single essential transition state, but no Wheland type intermediate, is preferred generally at MP2 as well as at M06-2X in isolation (gas phase) or in noncomplexing solvents (such as CCl(4) or CFCl(3)). However, in polar, higher dielectric SO(3)-complexing media, M06-2X favors an S(E)Ar mechanism for the 2:1 reaction involving a Wheland-type arene-(SO(3))(2) dimer intermediate. The reaction is slower in complexing solvents, since the association energy, e.g., with nitromethane, must be overcome. But, in accord with the experimental kinetics (second-order in SO(3)), attack by two sulfur trioxide molecules is still favored energetically over reaction with a single SO(3) in CH(3)NO(2). The theoretical results also reproduce the experimental reactivity and regioselectivity trends for benzene, toluene, and naphthalene sulfonation accurately.

Electrophile affinity: quantifying reactivity for the bromination of arenes.

Electrophile affinity (Ealpha), a recently proposed theoretical construct based on computed energies of arenium ion formation, rationalizes the substrate reactivity and regioselectivity of S(E)Ar bromination of three sets of available experimental arene data where closely related conditions had been employed uniformly. The Ealpha parameters (computed at B3LYP/6-311+G(2d,2p)) correlated very well (r = 0.987) with the partial rate factors (log f) for 18 regiospecific brominations of benzene and various methyl benzenes. Analysis of the bromination reactivities of 32 mono- and polysubstituted benzenes including various polar groups gave similar results (r = 0.982). The electrophile affinity treatment also accounted satisfactorily (r = 0.957) for bromination reactivities of polybenzenoid hydrocarbons. Conversely, comparisons with NBO-based charges and the electrostatic potential at nuclei (EPN) were not generally successful. The uniform effectiveness of Ealpha treatments for the cases analyzed with regard both to relative substrate reactivity (e.g., benzene vs toluene) and to regiospecificity (e.g., the positional reactivity of toluene) supports the "limiting case" conventional interpretation of the electrophilic aromatic substitution mechanism as being governed by the energy of sigma-complex formation. Although other mechanisms are possible under different conditions, the computed energies of arene-dibromine pi-complex formation for the polysubstituted benzene set examined correlated poorly with experimental reactivity data (r = 0.714) and only varied from 1.8 (for benzene) to 3.5 kcal/mol, in contrast to the 10(12) range in reactivity measured experimentally.

Electrophile affinity: a reactivity measure for aromatic substitution.

The reactivity and regioselectivity of the electrophilic chlorination, nitration, and alkylation of benzene derivatives were rationalized by comparing literature data for the partial rate factors (ln f) for these S(E)Ar processes with theoretical reactivity parameters. The Electrophile Affinity (Ealpha), a new quantity, is introduced to characterize reactivity and positional selectivity. Ealpha is evaluated theoretically by the energy change associated with formation of an arenium ion by attachment of a model electrophile to the aromatic ring. The dependence between Ealpha and ln f values for chlorination for 11 substitutions of benzene and methyl benzenes had a high correlation coefficient (r = 0.992). Quite satisfactory correlations between Ealpha values and partial rate factors also were obtained for the nitration of substituted benzenes (r = 0.971 for 12 processes) and benzylation of benzene and halobenzenes (r = 0.973 for 13 processes). These results provide clear evidence for the usefulness of the electrophile affinity in quantifying reactivity and regiochemistry. Satisfactory relationships (r >0.97) also were found between EPN (electrostatic potential at nuclei) values, which reflect the variations of electron density at the different arene ring positions, and the experimental partial rate factors (ln f) for the chlorination and nitration reactions, but not for the benzylation. This disaccord is attributed to strong steric influences on the reaction rates for substitutions involving the bulky benzyl moiety.

Origin of the SN2 benzylic effect.

The S N2 identity exchange reactions of the fluoride ion with benzyl fluoride and 10 para-substituted derivatives (RC6H 4CH 2F, R = CH3, OH, OCH 3, NH2, F, Cl, CCH, CN, COF, and NO2) have been investigated by both rigorous ab initio methods and carefully calibrated density functional theory. Groundbreaking focal-point computations were executed for the C6H5CH 2F + F (-) and C 6H 5CH2Cl + Cl (-) SN2 reactions at the highest possible levels of electronic structure theory, employing complete basis set (CBS) extrapolations of aug-cc-pV XZ (X = 2-5) Hartree-Fock and MP2 energies, and including higher-order electron correlation via CCSD/aug-cc-pVQZ and CCSD(T)/aug-cc-pVTZ coupled cluster wave functions. Strong linear dependences are found between the computed electrostatic potential at the reaction-center carbon atom and the effective SN2 activation energies within the series of para-substituted benzyl fluorides. An activation strain energy decomposition indicates that the SN2 reactivity of these benzylic compounds is governed by the intrinsic electrostatic interaction between the reacting fragments. The delocalization of nucleophilic charge into the aromatic ring in the SN2 transition states is quite limited and should not be considered the origin of benzylic acceleration of SN2 reactions. Our rigorous focal-point computations validate the benzylic effect by establishing SN2 barriers for (F (-), Cl (-)) identity exchange in (C6H5CH2F, C6H 5CH2Cl) that are lower than those of (CH3F, CH3Cl) by (3.8, 1.6) kcal mol (-1), in order.

Predicting reactivities of organic molecules. Theoretical and experimental studies on the aminolysis of phenyl acetates.

The quality of reactivity predictions coming from alternative theoretical approaches as well as experimental reactivity constants is examined in the case of the ester aminolysis process. The aminolysis of a series of para-substituted phenyl acetates is studied. The barrier heights for the rate-determining stage of the aminolysis of 16 phenyl acetate derivatives were predicted by employing density functional theory at the B3LYP/6-31+G(d,p) level. Experimental kinetic studies were carried out for the n-butylaminolysis of seven p-substituted phenyl acetates in acetonitrile. The results show that the electrostatic potential at the carbon atom of the carbonyl reaction center provides an excellent description of reactivities with regard to both theoretical barrier heights and experimental rate constants. The performance of other reactivity indices, Mulliken and NBO atomic charges, electrophilicity index, and Hammett constants, is also assessed.

Conformations of allyl amine: theory vs experiment.

The relative stabilities of the five conformers of allyl amine, a medium-size aliphatic molecule, were estimated by applying ab initio quantum mechanical methods at several levels of theory. The second-order Møller-Plesset perturbation method (MP2), quadratic configuration interaction including single and double excitations (QCISD), coupled-cluster with single and double excitations (CCSD) and CCSD plus perturbative triple excitations [CCSD(T)] were applied. The Dunning correlation consistent basis sets (through aug-cc-pVQZ and cc-pV5Z) were employed. The MP2 energies relative to the energy of the cis-trans conformer reported here appear to approach the basis set limit. The predicted allyl amine conformer energies approaching the Hartree-Fock basis set limit are 158 cm-1 (cis-gauche), -5 cm-1 (gauche-trans), and -146 cm-1 (gauche-gauche). The same three relative energies near the MP2 basis set limit are 135, 103, and 50 cm-1, respectively. The analogous energies deduced from experiment are 173 +/- 12, 92 +/- 8, and 122 +/- 5 cm-1. The theoretical results obtained in the present study suggest that satisfactory predictions of the conformer energetics of allyl amine may be achieved only by theoretical methods that incorporate consideration of correlation effects in conjunction with large basis sets. Evaluation of the zero-point vibrational energy corrections is critical, due to the very small classical energy differences between the five conformers of allyl amine. Agreement between theory and experiment for the gauche-gauche conformational energy remains problematical.