High regioselectivity in the amination reaction of isoquinolinequinone derivatives using conceptual DFT and NCI analysis.

DFT-derived reactivity descriptors and Non-Covalent interaction (NCI) analysis were performed to rationalize the regioselectivity in the amination reaction of some isoquinolinequinone derivatives. Statistical analysis was performed to assess robustness of atomic charges to the basis set. Various electronic population schemes including Mulliken population analysis (MPA), electrostatic method (ChelpG), Hirshfeld population analysis (HPA) and Natural population analysis (NPA) have been considered. The results revealed that NPA was the most efficient for this purpose. NCI study using the reduced density gradient (RDG) was performed for revealing weak interactions. Domains defined by isosurfaces of RDG have been integrated to quantitatively study the strength of weak interactions and their stabilities have also been examined. Steric hindrance caused by coordination of ethanol with the neighboring carbonyl prevents the nucleophilic attack on C-6 and therefore leads to preferential C-7 substitution. The quantitative study of NCI clearly demonstrates that the hydrogen bond of carbonyl (2) is more stabilizing. Consequently, the high polarity of hydrogen bond on this carbonyl may explain the high electrophilicity of C-5 compared to C-8. Our work proved that the difference in local reactivity, as well as the steric hindrance are the key elements explaining the high regioselectivity exhibited by the amination reaction.