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.

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.

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.

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.

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.

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.

Conformation of some biologically active aromatic ureas.

Experimental IR spectroscopic data for the N-H stretching mode frequencies for several types of tri-substituted ureas containing benzyl and/or phenyl substituents as well as theoretical results from B3LYP/6-31G(d,p) computations on selected compounds provide sufficient evidence to determine the conformational state of these molecules. Two types of N-H bands may be found the spectra: (a) A type band due to a classical trans conformation (trans I) of the CONH structure; (b) B type band arising from an alternative trans form (trans II), in which the N-H band is involved in a hydrogen bond like interaction with the aromatic ring at the neighbouring nitrogen atom (benzyl or phenyl substituents). The N-H band of trans ICONH structure is observed at frequencies higher than 3460 cm-1, the actual position depending on weather the non-substituted N-H group is linked to aryl or alkyl substituents. The N-H band of the trans II rotameric structure is observed at 3430-3420 cm-1.

Theory supplemented by experiment. Electronic effects on the rotational stability of the amide group in p-substituted acetanilides.

The electronic effect of polar substituents on the barrier of internal rotation around the amide carbon-nitrogen bond in a series of 10 p-substituted acetanilides is studied by applying density functional theory at the B3LYP/6-31G(d,p) level. The theoretical results are supplemented by experimental data on the amide C=O and N-H stretching mode frequency shifts. It is shown that computations at the theoretical level employed provide a valuable approach in studying the factors determining the conformational stability of the studied series of compounds. It is found that an excellent linear dependence between the barriers of rotation and frequency shifts exists. It is concluded that the variations of the amide C=O stretching mode frequency can be used for quantitative characterization of the amide group conformational flexibility in the studied series of acetanilides.