Evaluation of the Cycloaddition Reaction Mechanism of Phenyl Azide with Ethyl 3-oxobutanoate and Ethyl 2-methyl-3-oxobutanoate by DFT Study

Abstract: This study investigates the cycloaddition reactions of ethyl 3-Oxobutanoate (EOB 1a) and ethyl 2-Methyl-3-Oxobutanoate (EMOB 1b) with phenyl azide (PA 2), addressing the knowledge gap in understanding their reaction mechanisms. Using density functional theory (DFT) at the B3LYP/6- 311G(d,p) level, we explored the reactions in the gas phase and in solvent, identifying two distinct stepwise pathways (I and II) for each system. The calculated energy barriers reveal that replacing the hydrogen atom in EOB with a methyl group in EMOB significantly alters the pathway preference and energy profiles, where pathway II for methyl-substituted systems and pathway I for hydrogensubstituted systems are the most preferred pathways. Additionally, the most favorable Pathway II in EMOB has a 4.7 kcal·mol⁻¹ lower barrier than Pathway I in EOB, highlighting the significant impact of methyl substitution. Reactivity indices confirm the electrophilic nature of PA and identify critical nucleophilic and electrophilic sites that govern these reactions. Moreover, the role of 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) in proton transfer is elucidated, emphasizing its importance in facilitating the reactions. These insights advance the field by providing a mechanistic basis for optimizing reaction conditions and developing efficient strategies for synthesizing nitrogen-containing heterocycles, particularly triazoles, which have applications in medicinal chemistry and drug discovery.