Synthesis, exploring the structural, non covalent interaction effects, biological assessment, molecular docking and quantum chemical properties of functionalized new N-nitrosopiperidin-4-one: An experimental and theoretical study

Abstract

The synthesis of 3-benzyl-1-nitroso-2,6-di-p-tolylpiperidin-4-one 2 has been carried via the nitrosation of 3-benzyl-2,6-di-p-tolylpiperidin-4-one 1 with sodium nitrite and dilute hydrochloric acid at room temperature. This work deals with the synthesis, characterization (1H and 13C NMR, 1H–1H-COSY, 1H–13C-COSY, and X-ray diffraction analysis), and stereochemical characterization of functionalized N-nitrosopiperidin-4-one. The molecular level behaviors of the compounds were determined by computational chemistry methods. It is to be noted that at room temperature, 3-benzyl-2,6-di-p-tolylpiperidin-4-one 1 preferentially exists in chair conformation with all substituents in equatorial orientation, whereas its nitroso derivative, 3-benzyl-1-nitroso-2,6-di-p-tolylpiperidin-4-one 2, exists in syn and anti isomers. The observed coupling constant data for 2 suggests that the syn isomer is an equilibrium mixture of two boat forms B1 and B2, and that the predominant conformer of the anti-isomer is boat form B1. Conformational analysis carried out through DFT calculation using Gaussian 09 program supported that B1 is the more stable conformer of compound 2 with minimum energy for both syn and anti isomers. Good correlations were obtained between the predicted boat conformation B1 from theoretical study (DFT calculation) and the corresponding experimental (1H NMR spectrum) ones. This was complemented by single-crystal X-ray analysis, which revealed that compound 2 exists as the anti-isomer with the piperidine ring adopting the B1 boat structure. Here, the phenyl group at C(2) and the benzyl group at C(3) are in axial orientation, and the phenyl group at C(6) are in equatorial orientation. Hirshfeld surface analysis of the molecule showed H⋯H (59.0 %), C⋯H/H⋯C (22.9 %), O⋯H/H⋯O (14.3 %), N⋯H/H⋯N (2.4 %), and O⋯O (0.5 %) interactions. Energy framework analysis revealed that among the components of the framework energies, electrostatic repulsion (Erep) is dominant. Finally, the molecular docking and dynamics simulation studies of the title ligand with 6LVM protein have shown better binding affinity, and stability. Further, ADME prediction of the compound 2 has exhibited excellent drug-likeness.