Theoretical study of the pyridyl-cholestane formation pathway using DFT: A stepwise mechanistic approach

The reaction mechanism of the formation of pyridyl-cholestane derivative 4 from a multi-component reaction involving cholestane-6-one, aromatic aldehyde, malononitrile, and ammonium acetate in presence of magnesium oxide nanoparticles (MgO NPs) as catalyst, was studied successfully by using DFT calculations. The mechanism involved condensation, cyclization, and aromatization steps which were investigated successfully theoretically. The theoretical calculations of physicochemical parameters, including Gibbs free energy, frontier molecular orbitals (FMOs), dipole moments, and hardness, of all the intermediates and transition states molecules. The study revealed the formation of key intermediates and transition states, with detailed analysis of their stability and electronic structures. The reaction pathway begins with the formation of enamine I and α,β-unsaturated nitrile II, followed by Michael addition to produce intermediate B. The cyclization of A to intermediate B, which has the highest activation energy barrier was identified as slowest and the rate-determining step. The following steps, including cyclization (B to C) and proton transfer (C to D), exhibit progressively lower activation barriers and enhanced stability. Theoretical analysis indicates that the reaction is thermodynamically favorable, as the product is more stable than the initial reactants. This study highlights the mechanistic insights contributing to the understanding of multi-component reactions in organic synthesis involved effectiveness of MgO NPs as a heterogeneous catalyst in enabling the efficient synthesis of pyridyl-cholestane derivative 4.