Boris Galabov

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.

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.

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.

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.

A model for parametric analysis of the intensities in the infrared spectra

A model for parametric analysis of IR intensities based on the use of molecular polar parameters related with vibrational distortions of separate bonds is described. The parameters represent derivatives of the total dipole moment with respect to coordinates describing the changes in the length and orientation of each bond in a molecule. The mathematical procedure is given using matrix representation. The analysis results in determination of bond polar vectors obtained from the intensities of stretching modes, and bond polar (3×3) matrices calculated from the intensities of deformation modes. The rotational contributions to the intensities in the case of polar molecules are explicitly considered. An example of application is presented in detail.

Electrophilic Aromatic Sulfonation with SO3: Concerted or Classic SEAr 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.

Molecular electrostatic potential as reactivity index in hydrogen bond formation: an HF/6-31+G(d) study of hydrogen-bonded (HCN)n clusters, n=2,3,4,5,6,7☆

Abstract Ab initio molecular-orbital calculations of (HCN) n clusters for n =2,3,4,5,6,7 were performed following the procedure of King and Weinhold [B.F. King, F. Weinhold, J. Chem. Phys. 103 (1995) 333]. Geometry optimisation and vibrational frequency calculations at the optimised geometry were carried out at HF/6-31+G(d) level of theory. The calculations confirm the known linear relations between the energy of hydrogen bond formation (Δ E ( n ) ) and: (1) the hydrogen bond length ( r N⋯H ( n −1) ); (2) the change of the neighbouring C–H bond length (Δ r C–H ( n ) ); and (3) its characteristic vibrational frequency shift (Δ ν C–H ( n ) ). An excellent linear dependence is found between the energy of hydrogen bond formation (Δ E ( n ) ) and the molecular electrostatic potential at the end nitrogen atom ( V N (n−1) ). A perfect linear relation also exists between Δ E ( n ) and the molecular electrostatic potential at the end hydrogen atom ( V H ( n −1) ). The results obtained confirm that the molecular electrostatic potential at atomic sites can be used as a reactivity index reflecting the ability of molecules to participate in hydrogen bonding.

Spectra and conformations of substituted thioureas

Abstract IR and 1H NMR spectroscopic data are used to analyse the conformations of the -NH-CS-NH- group in a series of di- and tri-substituted thioureas. In organic media (CCl4, C2Cl4, CHCl3, CH2Cl2) various conformational forms are detected resulting from the possibility of cis and trans arrangements of the -CS-NH- groups. The trans -CS-NH- form occurs when there is no steric hindrance whereas with bulkier aliphatic or aromatic substituents a proportion of cis structures is found. The results indicate that a complex equilibrium between several rotational isomers of the type cis-cis ⇄ cis-trans ⇄ trans-cis ⇄ trans-trans exists. For substituents of medium size (n-propyl, n-butyl, allyl) the spectroscopic data are consistent with a third type, the “out” conformation of the -CS-NH-group.

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.