W. Langenaeker

Quantum-chemical study of the Fukui function as a reactivity index1: Part 2. Electrophilic substitution on mono-substituted benzenes

Abstract The Fukui function f−, and the condensed form fc−, are studied as reactivity indices for electrophilic substitution reactions on substituted benzenes. The systems studied are PhX with X = O−, NH2, OH, F, CN, NO2, CHO, NH3+, and CHCH2. The results were obtained from SCF and density calculations using the 3-21G basis. A comparison between the Fukui function and experimental data, the molecular electrostatic potential (MEP), the HOMO-density and the Laplacian of the electronic charge distribution was made. The comparison between the Fukui function and the MEP indicated that these two properties might be complementary to each other. The Fukui function seems to describe the soft-soft interactions, whereas the MEP describes the hard-hard interactions. The HOMO-density was found to be a poor approximation to the Fukui function f−, even when taking the (HOMO-1)-density into account. A comparison of the Laplacian of the electronic charge distribution and the Fukui function showed that the relation between these two properties is not as obvious as expected.

Quantum-chemical study of the Fukui function as a reactivity index : probing the acidity of bridging hydroxyls in zeolite-type model systems

Abstract The Fukui function, ƒ+, was studied for a series of compounds which proved to be adequate model structures for zeolite systems containing bridging hydroxyls. The structures were derived from the basic structure H3SiOAlH3 in which the hydrogen atoms on Si and Al are gradually replaced by fluorine atoms, thus mimicking changes in the average framework electronegativity upon variation of the Si/Al ratio. A basis-set study of the condensed Fukui function for a series of small molecules (H2CO, NH3 and H2O) indicated that, at least for the larger systems, the 3–21G basis may be expected to yield an optimal quality/cost ratio. Calculations on NH3 show that highly diffuse functions should not be introduced in the evaluation of ƒ+ in order to cope with the anionic metastability problem. The condensed Fukui function, ƒH+ , correlates well with the experimentally observed increase in acidity upon increasing framework electronegativity. Moreover, the function is found to be a more sensitive probe for the acidity of the OH group than is the previously calculated isolated molecule OH group properties, including the dipole-moment derivative. The trends in ƒ+H are duplicated in the contour plots of ƒ+ in the OH region indicating that the “probing” capacity of ƒ+ is not lost by the highly approximate integration performed when condensing ƒ+ via a Mulliken population analysis. A study of ƒ+ along the OH bond axis reveals that its sensitivity, being more difficult to extract than that of the condensed function, is of comparable magnitude to that of ƒH+.

The electronegativity equalization method II: Applicability of different atomic charge schemes

The amenability of different schemes for the calculation of atomic charges in the electronegativity equalization method (EEM) is investigated. To that end, a large training set of molecules was composed, comprising H, C, N, O, and F, covering a wide range of medicinal chemistry. Geometries are calculated at the B3LYP/6-31G* level. Atomic charges are calculated using five different methods, belonging to different types of population analysis. Effective electronegativities and hardness values are calibrated from the different quantum chemically calculated atomic charges. The resulting quality of EEM charges is investigated for the different types of atomic charge calculation methods. EEM-derived Mulliken and NPA charges are in good agreement with the ab initio values, electrostatic potential derived, and Hirshfeld charges show no good agreement.

Acidity of alkyl substituted alcohols: Are alkyl groups electron-donating or electron-withdrawing?

Abstract Two important functional group properties, the group electronegativity and hardness, are calculated for a number of alkyl groups. The results indicate that alkyl groups become less electronegative and hard with increasing group size. The calculated properties are used in a study of the inversion of the alkyl alcohol acidity scale when going from aqueous solution to the gas phase. Finally, the Sanderson electronegativity equalization principle using functional group properties is shown to be a valuable tool in describing the charge distribution of these molecular systems.

On the use of density functional theory based descriptors for the interpretation of the influence of alkyl substitution on the basicity of amines

Abstract The influence of alkyl substitution on the gas phase basicity of amines was studied using density functional based reactivity descriptors, together with two more traditional quantum chemical properties. Softness related local properties such as the Fukui function f − k and local softness s − k are found to be inadequate for predicting the reactivity order of the alkyl amines studied in this work. As a first approximation to local hardness, the Mulliken population on the nitrogen atom q N and the minimum of the molecular electrostatic potential (MEP) near the nitrogen were calculated. Both were found to correlate inversely with the amine basicity order, a result consistent with the literature. As the polarizability of the alkyl substituent is often cited as a factor determining alkyl amine basicity, the corresponding group property (group softness) and the group electronegativity were combined in a dual correlation, providing a successful interpretation of the basicity order. The group softness or polarizability was found to be the more important factor in determining the basicity of the alkyl amines.

Quantum-chemical study of the Fukui function as a reactivity index: Part 3. Nucleophilic addition to α,β-unsaturated compounds1

Abstract The intramolecular reactivity sequence for a nucleophilic attack on a series of α,β-unsaturated compounds (acrolein, acrylonitrile, methylacrylate and methyl methacrylate) was investigated by means of the Fukui function f + ( r ) and its condensed counterpart f c + . A comparison was made with the molecular electrostatic potential (MEP) and the LUMO-density. The results of the Fukui function correlate well with experimental data. In this case, the LUMO-density was found to be a relatively good approximation to the Fukui function. The intermolecular reactivity sequence for the same systems was examined by the non-condensed local softness s + ( r ) and the condensed local softness s c + . These results were compared with the MEP and the Laplacian of the charge density. The comparison turns out to be especially favourable for the condensed local softness.

A NON-EMPIRICAL ELECTRONEGATIVITY EQUALIZATION SCHEME. THEORY AND APPLICATIONS USING ISOLATED ATOM PROPERTIES

Abstract The electronegativity equalization principle, originally formulated by Sanderson and proven quantum mechanically by Parr et al., within the framework of density functional theory, is studied numerically. A first order expression for the electronegativity x of an atom A in a molecule is derived, based on the change, upon molecule formation, of the number of electrons N A and the external potential v A ( r ) of this atom with respect to the isolated atom case. The relative importance of the two corrections to the isolated atom electronegativity is discussed. Furthermore, the expression was identified with other density functional theory based electronegativity equalization formalisms and was applied to small molecular systems: the resulting charge distributions and molecular electronegativities showed a fair correlation with other estimations for these quantities. The importance of second order terms is also discussed, together with an extension, permitting the use of functional group electronegativities and hardnesses.

THE USE OF DENSITY FUNCTIONAL THEORY-BASED REACTIVITY DESCRIPTORS IN MOLECULAR SIMILARITY CALCULATIONS

Abstract Molecular similarity is studied via density functional theory-based similarity indices using a numerical integration method. Complementary to the existing similarity indices, we introduce a reactivity-related similarity index based on the local softness. After a study of some test systems, a series of peptide isosteres is studied in view of their importance in pharmacology. The whole of the present work illustrates the importance of the study of molecular similarity based on both shape and reactivity.

Reactivity of 2-t-butyl-4,5-didehydropyrimidine and electronic structure of the parent hetaryne

Abstract 2-t-Butyl-4,5-didehydropyrimidine, generated by oxidation of 3-amino-5-t-butyl-3H-v-triazolo[4,5-d] pyrimidine, was allowed to react with a variety of reagents. Trapping experiments with furan and two tetracyclones gave the expected adducts in low to moderate yields. On treatment with anthracene and 1,3-cyclohexadiene, complex mixtures were obtained from which the adducts could not be isolated. Cycloaddition of phenyl azide to the intermediate yielded 3-phenyl-5-t-butyl-3H-v-triazolo[4,5-d]pyrimidine as the major product together with the unexpected 2-t-butyl-9H-pyrimido[4,5-b]indole in lesser amount. The structure of these two compounds was established by comparison with authentic specimens whose synthesis is described. Cycloaddition also occurred with 2,3,5-tri-O-benzoyl-β-D-ribofuranosyl azide to give an 8-azanucleoside in low yield. Oxidation of the precursor in ethanol gave solely 4-ethoxy-2-t-butylpyrimidine. Oxidation in the presence of iodine, in dichloromethane or benzene, afforded products arising from attack on the solvent, i.e. 4-chloro-5-iodo-2-t-butylpyrimidine and 5-iodo-4-phenyl-2-t-butylpyrimidine respectively. In addition, 5-iodo-2-t-butyl-4(3H)-pyrimidinone was obtained in both cases. Mechanisms for these reactions are proposed. The electronic structure of 4,5-didehydropyrimidine has been calculated by an ab initio 3-21G quantum chemical method. Both the Molecular Electrostatic Potential and the Fukui function give a very reasonable account of the strong orientation effects observed in the additions to 2-t-butyl-4,5-didehydropyrimidine.

Electron correlation effects on Fukui functions

The effect of electron correlation on the Fukui function f− (r) is studied for three closed shell molecules of the ambident nucleophile type using the Configuration Interaction with Single and Double excitations (CISD) method. These effects are shown to be of relatively small importance, thereby stressing the reliability of Hartree-Fock type calculations.