Nucleophilic Aromatic Substitution Reactions Described by the Local Electron Attachment Energy.

A local multiorbital electrophilicity descriptor, the local electron attachment energy [E(r)], is used to study the nucleophilic aromatic substitution reactions of SNAr and VNS (vicarious nucleophilic substitution). E(r) considers all virtual orbitals below the free electron limit and is determined on the molecular isodensity contour of 0.004 atomic units. Good (R2 = 0.83) to excellent (R2 = 0.98) correlations are found between descriptor values and experimental reactivity data for six series of electron deficient arenes. These include homo- and heteroarenes, rings of five to six atoms, and a variety of fluorine, bromine, and hydride leaving groups. The solvent, temperature, and nucleophile are in addition varied across the series. The surface E(r) [ES(r)] is shown to provide reactivity predictions better than those of transition-state calculations for a concerted SNAr reaction with a bromine nucleofug, gives correlations substantially stronger than those of LUMO energies, and is overall more reliable than the molecular electrostatic potential. With the use of ES(r), one can identify the various electrophilic sites within a molecule and correctly predict isomeric distributions. Since the calculations of ES(r) are computationally inexpensive, the descriptor offers fast but accurate reactivity predictions for the important nucleophilic aromatic substitution class of reactions. Applications in, e.g., drug discovery, synthesis, and toxicology studies are envisaged.

Local Electron Attachment Energy and Its Use for Predicting Nucleophilic Reactions and Halogen Bonding.

A new local property, the local electron attachment energy [E(r)], is introduced and is demonstrated to be a useful guide to predict intermolecular interactions and chemical reactivity. The E(r) is analogous to the average local ionization energy but indicates susceptibility toward interactions with nucleophiles rather than electrophiles. The functional form E(r) is motivated based on Janak's theorem and the piecewise linear energy dependence of electron addition to atomic and molecular systems. Within the generalized Kohn-Sham method (GKS-DFT), only the virtual orbitals with negative eigenvalues contribute to E(r). In the present study, E(r) has been computed from orbitals obtained from GKS-DFT computations with a hybrid exchange-correlation functional. It is shown that E(r) computed on a molecular isodensity surface, ES(r), reflects the regioselectivity and relative reactivity for nucleophilic aromatic substitution, nucleophilic addition to activated double bonds, and formation of halogen bonds. Good to excellent correlations between experimental or theoretical measures of interaction strengths and minima in ES(r) (ES,min) are demonstrated.