This report demonstrates the successful application of electrostatic surface potential distribution analysis for evaluating the relative catalytic activity of a series of azolium-based halogen bond donors. A strong correlation (R² > 0.97) was observed between the positive electrostatic potential of the σ-hole on the halogen atom and the Gibbs free energy of activation of the model reactions (i.e., halogen abstraction and carbonyl activation). The predictive ability of the applied approach was confirmed experimentally. It was also determined that the catalytic activity of azolium-based halogen bond donors was generally governed by the structure of the azolium cycle, whereas the substituents on the heterocycle had a limited impact on the activity. Ultimately, this study highlighted four of the most promising azolium halogen bond donors, which are expected to exhibit high catalytic activity.

The combination of experimental data and results of DFT calculations indicates that the catalytic activity of chalconium and halonium salts serving as σ-hole donating organocatalysts cannot be clearly estimated via analysis of the electrostatic potential on the catalysts' σ-holes and values of the catalyst⋯TS intermolecular interactions, such as polarization effects, charge transfer, or covalency of bonding. Moreover, the real catalytic effect might not correlate well with the values of Gibbs free energy of activation of the reactions, because solvation effects and other competitive binding processes play at least an equal or even more important role in the catalysis. It was shown in the present work that the solvation can either lead to the increase of equilibrium concentration of reactive catalyst⋯electrophile associates, thus accelerating the reaction, or brings favorable generation of catalyst⋯nucleophile species resulting in the suppression of the catalytic activity of the organocatalyst.

The developed one-pot protocol to 5-amino-1,2,4-triazoles or 5-amino-1,2,4-oxadiazoles includes an interplay between aminonitrones R¹C(NH₂)N⁺(Me)O⁻ (R¹ = Alk, Ar, Het), isocyanides R²NC (R² = Alk, Ar), Br₂, and hydrazines (for the triazoles) or hydroxylamine (for the oxadiazoles). This formally four-component reaction, involving aminonitrones, isocyanides, bromine, and N-nucleophiles, proceeds very rapidly under mild conditions (10 min, 20–25 °C), and is insensitive to moisture and air (in undried CHCl₃–MeOH, in air) and it gives the heterocyclic systems in good yields (up to 86%; 26 examples). The reaction scope includes aromatic-, heteroaromatic-, and aliphatic aminonitrones and also aliphatic- and aromatic isocyanides. Results of DFT calculations (M06-2X/6-311+G(d,p) level of theory) indicate that the O-nucleophilic center of bifunctional aminonitrones is more reactive than the N center; it first reacts with in situ generated R²NCBr₂ to grant 2-methyl-1,2,4-oxadiazolium salts, which are then converted to the target heterocyclic systems upon treatment with hydrazines or hydroxylamine. The nature and strength of the intramolecular hydrogen bonds N–H⋯N and O–H⋯N, which significantly contribute to the total energies of different transition states and products of the nucleophilic substitution, were studied theoretically using the topological analysis of the electron density distribution within the framework of Bader's theory (QTAIM method). Several new 5-amino-3-aryl-1,2,4-triazoles and -1,2,4-oxadiazoles exhibit high antibacterial activity against multidrug-resistant bacteria strains such as Staphylococcus aureus and Klebsiella pneumoniae (MIC = 8 mg L⁻¹).

The Schiff condensation between 4-methylbenzaldehyde and 2-aminopyridine, catalyzed by chloronium, bromonium, and iodonium triflates, as well as sulfonium, selenonium, and telluronium triflates, was investigated. ¹H NMR monitoring revealed that the catalytic activity increased significantly with heavier σ-hole-bearing heteroatoms. DFT calculations showed that the maximum electrostatic potential at the σ-hole was a more reliable predictor of the catalytic activity of these organoelement species. In contrast, the equilibrium concentrations of the activated form of the electrophile and the electrophile-to-onium cation charge transfer values did not accurately reflect the catalytic activity of the onium salts.