Free energy profile and microkinetic modeling of base-catalyzed conjugate addition reaction of nitroalkanes to α,β-unsaturated ketones in polar and apolar solvents.

Michael reactions involving nitroalkanes and enones are important carbon-carbon bond formation reactions. These reactions are base-catalyzed, and during the past 15 years, the asymmetric version using bifunctional amino-thiourea organocatalyst has been developed. In this work, the reaction of nitromethane and 4-phenyl-3-buten-2-one, catalyzed by the methoxide ion and piperidine as bases, was investigated by theoretical calculations. We obtained the theoretical free energy profile and did a microkinetic analysis of the catalytic cycle. The direct reaction of the CHNO ion and the enone is very favorable, with a free energy of activation of 21.1 kcal mol in methanol solvent. However, the generated MS2 product works like an inhibitor of the catalysis, and the effective barrier in the catalytic cycle becomes 25.5 kcal mol, leading to slow kinetics at room temperature. In the case of the reaction in apolar solvent (toluene), we found a pathway involving isomerization from the CHNO reactant to the CHNOH species, and the latter makes a nucleophilic attack on the enone. Piperidine works like a bifunctional catalyst. In this case, the barrier is very high (32.5 kcal mol), indicating the importance of the polar environment to accelerate the reaction in the catalytic cycle. Graphical abstract Base-catalyzed conjugate addition reaction of nitroalkanes to α,β-unsaturated ketones.