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

• Published in: Journal of molecular modeling 2018-07, Vol.24 (7), p.152-9, Article 152
• Main Authors: Rufino, Virginia C., Resende, Stella M., Pliego, Josefredo R.
• Format: Article
• Language: English
• Subjects: Activation energy; Carbon; Catalysis; Characterization and Evaluation of Materials; Chemical reactions; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Free energy; Isomerization; Ketones; Molecular Medicine; Nitromethane; Original Paper; Piperidine; Polar environments; Reaction kinetics; Solvents; Theoretical and Computational Chemistry; Toluene; XIX - Brazilian Symposium of Theoretical Chemistry (SBQT2017)
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-018-3694-8

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 CH 2 NO 2 − ion and the enone is very favorable, with a free energy of activation of 21.1 kcal mol −1 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 −1 , 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 CH 3 NO 2 reactant to the CH 2 NO 2 H 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 −1 ), 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