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For Abstract see ChemInform Abstract in Full Text.

The applicability of the electronegativity equalization method (EEM) is investigated for the fast calculation of atomic charges in organic chemistry, with an emphasis on medicinal chemistry. A large training set of molecules was composed, comprising H, C, N, O, and F, covering a wide range of medicinal chemistry. Geometries and atomic charges are calculated at the B3LYP/6-31G* level, and from the calculated charges, effective electronegativity and hardness values are calibrated in a weighted least-squares fashion. The optimized parameter set is compared to other theoretical as well as experimental values and origins of the differences discussed. An approach toward extension of EEM to include new atoms is introduced. The quality of the EEM charges is assessed by comparison with B3LYP/6-31G* charges calculated for a set of medicinal molecules, not contained in the training set. The EEM approach is found to be a very powerful way to obtain ab initio quality charges without the computational cost of the ab initio approach.

In the Hirshfeld partitioning of the electron density, the molecular electron density is decomposed in atomic contributions, proportional to the weight of the isolated atom density in the promolecule density, constructed by superimposing the isolated atom electron densities placed on the positions the atoms have in the molecule. A maximal conservation of the information of the isolated atoms in the atoms-in-molecules is thereby secured. Atomic charges, atomic dipole moments, and Fukui functions resulting from the Hirshfeld partitioning of the electron density are computed for a large series of molecules. In a representative set of organic and hypervalent molecules, they are compared with other commonly used population analysis methods. The expected bond polarities are recovered, but the charges are much smaller compared to other methods. Condensed Fukui functions for a large number of molecules, undergoing an electrophilic or a nucleophilic attack, are computed and compared with the HOMO and LUMO densities, integrated over the Hirshfeld atoms in molecules.

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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.

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The reactions of hydrogen isocyanide (HN⋮C) with various simple alkynes (HC⋮C−X, with X = H, CH3, NH2, F), formally [2 + 1] cycloadditions, have been studied by density functional theory (DFT) with the hybrid exchange correlation B3LYP functional and a 6-311G(d,p) basis set, as well as by MO theory with CCSD(T) calculations. For each reaction, the intrinsic reaction coordinate (IRC) pathway has been constructed. It is shown that each [2 + 1] cycloaddition is nonconcerted but proceeds in two steps:  rate-determining addition of HN⋮C to a carbon atom of HC⋮CX, giving rise to a zwitterion intermediate, followed by a ring closure of the latter, yielding finally cyclopropenimine. In all cases, HN⋮C behaves as an electrophile. The activation energies corresponding to both possible initial attacks of HN⋮C are distinguishable, introducing thus a site selectivity and an asynchronism of bond formation in the initial step, for which a rationalization using DFT-based reactivity descriptors and the local HSAB principle has been proposed. Except for HC⋮C−F, initial attack on the unsubstituted alkyne carbon is preferred. The hardness and polarizability profiles along the IRC reaction paths of the supersystem have also been constructed. In some cases, there are no clear-cut extrema; in other cases, there is a minimum in the hardness profile and a maximum in the polarizability profile, but these extrema do not coincide with the energy maximum and are rather shifted toward the side having the closest value, following apparently a generalized Hammond postulate. While the higher hardness−lower polarizability criterion seems to hold true, there is no obvious relationship between hardness and energy. The activation energy (E act) vs hardness difference relationship recently derived by Gázquez turns out to be successful in the interpretation of the calculated E act sequences.