Sonia Ilieva

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.

The electrostatic potential at atomic sites as a reactivity index in the hydrogen bond formation

The paper reviews results from computational studies by molecular orbital and density functional theories on several series of hydrogen bonded complexes. These studies aim at quantifying the reactivity of molecules for the complexation process. Excellent linear relationships are found between the electrostatic potential values at the sites of the electron donor and electron accepting atoms and the energy of hydrogen bond formation ðDEÞ: The series studied are: (a) complexes of R– CHO and R– CN molecules with hydrogen fluoride; (b) complexes of mono-substituted acetylene derivatives with ammonia; (c) (HCN)n hydrogen bonded cluster for n ¼ 2 ‐ 7: All 22 studied complexes of carbonyl and nitrile compounds with hydrogen fluoride fall in the same dependence between the energy of hydrogen bond formation and the electrostatic potential at the atomic site of the carbonyl oxygen and nitrile nitrogen atoms, with linear regression correlation coefficient r ¼ 0:979: In the case of complexes of mono-substituted acetylene and diacetylene derivatives with NH3, the correlation coefficient for the dependence between the electrostatic potential at the acidic hydrogen atom and DE equals 0.996. For the series of hydrogen bonded (HCN)n clusters, the correlation coefficient for the relationship between the electrostatic potential at the end nitrogen atom and DE is r ¼ 0:9996: Similarly, the analogous relationship with the electrostatic potential at the end hydrogen atom has a regression coefficient equal to 0.9994. The dependencies found are theoretically substantiated by applying the Morokuma energy decomposition scheme. The results show that the molecular electrostatic potential at atomic sites can be successfully used to predict the ability of molecules to form hydrogen bonds. q 2003 Elsevier Science B.V. All rights reserved.

Conformational isomerism in methyl cyanoacetate: A combined matrix-isolation infrared spectroscopy and molecular orbital study

Study of the conformational isomerism of methyl cyanoacetate (NCCH2COOCH3, MCA) aided for the first time by matrix-isolation infrared spectroscopy is reported. The conformational isomerization processes in MCA in the temperature range from 10 to 70 K were studied in detail in argon and xenon matrixes. During annealing of the matrixes direct interconversion of the gauche into the syn conformer has been registered. A similar, but more pronounced, gauche → syn interconversion effect was observed in a series of experiments in which matrixes were deposited at increased substrate temperature. The experiment is supported by theoretical predictions undertaken at different levels of approximation (MP2 and DFT/B3LYP). It is shown that, for the single molecule in vacuum, the syn conformer (C–C–CO dihedral angle equal to 0°) corresponds to the conformational ground state, with the doubly degenerated by symmetry gauche conformer (C–C–CO dihedral angle equal to ± 139.9°) being only slightly less stable than the most stable form (MP2/6-31G** ΔE(gauche → syn) = 0.174 kJ mol−1). In the matrixes, the energy gap between the syn and gauche conformers increases, with ΔE(gauche → syn) estimated to be about 1.4 kJ mol−1 in xenon. The predicted energy barriers for conformer interconversion were found to be significantly low: the MP2/6-31G** calculated ΔE(syn → gauche) energy barrier is ca. 3.65 kJ mol−1, while the calculated energy barrier separating the two symmetrically equivalent gauche conformers stays only 0.196 kJ mol−1 above the energy of these forms. In the matrixes, ΔE(syn → gauche) energy barrier increases to at least 17–18 kJ mol−1, while the ΔE(gauche → gauche) energy barrier is, with all probability, still lower than in the gaseous phase. The matrix isolation spectroscopic data indicate that interconversion between the gauche conformers occurs even in the low temperature matrixes.

Structure–reactivity relationships for aromatic molecules: electrostatic potentials at nuclei and electrophile affinity indices

Recent advances have been achieved in the quantitative description of the reactivity of aromatic compounds in terms of simple parameters derived from theoretical computations. The first part of this review surveys the use of electrostatic potentials at nuclei (EPN) in characterizing the reactivity of substituted aromatic compounds when the reaction center is situated outside the aromatic ring. The application of EPN for several typical reactions of substituted aromatic systems is described in detail. The performance of alternative reactivity descriptors, such as theoretical atomic charges, the Parr electrophilicity index, and the experimental Hammett constants, is considered as well. The second part of this review discusses the recently proposed electrophile affinity construct for quantifying reactivity and regiospecificity for the most typical reaction of arenes: electrophilic aromatic substitution. The characterization of reactivity of aromatic molecules in terms of proton affinities and arene nucleophilicity indices is surveyed briefly.

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).

Ab initio molecular orbital and infrared spectroscopic study of the conformation of secondary amides: derivatives of formanilide, acetanilide and benzylamides

Abstract Ab initio molecular orbital calculations at HF/4-31G level and infrared spectroscopic data for the frequencies are applied to analyse the grouping in a series model aromatic secondary amides: formanilide; acetanilide; o -methylacetanilide; 2,6-dimethylformanilide, 2,6-dimethylacetanilide; N -benzylacetamide and N -benzylformamide. The theoretical and experimental data obtained show that the conformational state of the molecules studied is determined by the fine balance of several intramolecular factors: resonance effect between the amide group and the aromatic ring, steric interaction between various substituents around the –NH–CO– grouping in the aromatic ring, conjugation between the carbonyl bond and the nitrogen lone pair as well as direct field influences inside the amide group.

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.

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).

Electrostatic potential at nuclei as a reactivity index in hydrogen bond formation. Complexes of ammonia with C–H, N–H and O–H proton donor molecules

Abstract In this study the use of molecular electrostatic potential at atomic sites as a reactivity descriptor for the process of hydrogen bonding is evaluated for a series of complexes involving different types of proton donor molecules and ammonia as a model proton acceptor. The compounds studied were: C 2 H 4 , CH 3 CCH, CH 2 CH–CCH, HCN, CH 3 NH 2 , (CH 3 ) 2 NH, HNC, C 6 H 5 NH 2 , cytosine, HCONHCH3, CH 3 OH, C 2 H 5 OH, C 3 H 7 OH, C 6 H 5 OH, HCOOH and H 3 CCOOH. Geometry optimisation and vibrational frequency calculations at the optimised geometry were performed for isolated monomers and hydrogen-bonded systems. Density functional theory computations at the B3LYP/6-31G(d,p) were employed. Linear dependence between the molecular electrostatic potential at the hydrogen atom in the isolated monomers and the energy of hydrogen bond formation is found. The results show that the electrostatic potential at atomic sites can be used as a reactivity descriptor for the ability different types of proton donor molecules to form hydrogen bonds.

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 Cβ (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 Cβ multiple bond in the SN2 reactant in a series of analogues, attractive Cβ(δ(+))···X(δ(-)) interactions in the SN2 TS lower net activation barriers (E(b)) and enhance reaction rates, whereas repulsive Cβ(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.