Correlation of AM1-Calculated Molecular Descriptors with Experimental pKa Values of Imine Compounds

Abstract

The ionisation properties of the imines depend on the electronic distribution around the nitrogen of the imine and the presence of electron-donating, electron-withdrawing and hydrogen-bonding groups in the vicinity. We examined the correlations between semi-empirical AM1 molecular descriptors and experimental pKa values for a coded series of 14 imine compounds. Geometry optimisations and descriptor calculations were performed in ChemOffice using the AM1 method. The variables extracted included Mulliken atomic charges, selected bond lengths and bond angles, highest occupied and lowest unoccupied molecular orbital energies (HOMO and LUMO), chemical potential (μ), chemical hardness (η), electrophilicity index (ω), steric energy (S.E.), and van der Waals energy. The calculated variables were correlated with the experimental pKa values by bivariate statistical analysis in SPSS. The best correlation reported was for the combined N8-charge and hydroxyl-group model (R2 = 0.969), followed by stretching plus hydroxyl-group descriptors (R2 = 0.966), and the lowest reported value was for van der Waals energy plus N3 charge (R2 = 0.769). These results suggest that the local electronic environment around N8 and the presence or geometry of an O-H group are the most influential descriptors in the current dataset. However, before publication, the compound identities, experimental pKa values, software version, and full statistical output must be provided, and the R/R² notation reported must be checked. The results thus support AM1 descriptors as preliminary screening variables rather than a fully validated predictive model.