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By: Vanishree Shankar Naik, Nayela Javeed, and Ganga Periyasamy.
1Student, Department of Chemistry, Bangalore University, Bangalore, Karnataka, India.
2Assistant Professor, Department of Chemistry, Bangalore University, Bangalore, Karnataka, India.
Abstract
Oxazoles constitute an important class of heterocycles with widespread applications in medicinal chemistry and materials science, yet the mechanistic features governing their formation via cationic cycloaddition reactions remain incompletely understood. In this work, we present a comprehensive density functional theory (DFT) investigation into the reaction between the propadienyl cation and oxoamides as a model system for oxazole ring formation. Using the CAM-B3LYP/6–31+G(d,p) level of theory, we systematically compare gas-phase reactivity with implicit (PCM) and explicit solvation effects in water, acetonitrile, and dichloromethane. Our results reveal that in the gas phase, the reaction preferentially proceeds through a stepwise ionic mechanism, while a concerted [3+2] cycloaddition pathway is energetically inaccessible without geometric constraints. Inclusion of implicit solvation fundamentally alters the reaction landscape, stabilizing polarized transition states and enabling a viable concerted pathway with solvent-dependent activation barriers. Explicit solvation further lowers the activation energies, particularly in polar solvents, through specific hydrogen-bonding and dipole–dipole interactions that stabilize charge development along the reaction coordinate. Quantitative comparison shows that explicit solvation reduces concerted activation barriers by up to 4 kcal mol⁻¹ relative to implicit models and significantly stabilizes ionic intermediates in stepwise pathways. This study demonstrates that solvent effects are decisive in controlling both the feasibility and mechanism of propadienyl-cation-mediated oxazole formation. The insights gained highlight the importance of incorporating explicit solvation for accurately modeling highly polarized cycloaddition reactions and provide a rational basis for solvent-controlled, regioselective synthesis of oxazole derivatives. These findings offer guidance for experimental design, catalyst selection, and modeling of heterocycle synthesis.
Citation:
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