ORIGINAL PAPER Free energy profile and microkinetic modeling of base-catalyzed conjugate addition reaction of nitroalkanes to α,β-unsaturated ketones in polar and apolar solvents Virginia C. Rufino 1 & Stella M. Resende 1 & Josefredo R. Pliego Jr 1 Received: 2 February 2018 /Accepted: 23 May 2018 /Published online: 7 June 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract 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 theo- retical 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. Keywords Michael addition . Bifunctional thiourea . Organocatalysis . Base catalysis, theoretical calculations . Microkinetic modeling Introduction One of the main important reactions of carbon-carbon bond formation involves nitroalkanes and α,β-unsaturated ke- tones, named Michael addition reaction or 1,4-conjugated addition (Scheme 1). These reactions usually require the formation of carbanions as reactive species, via deproton- ation of nitroalkanes, and are base-catalyzed. Bases like hydroxide, alkoxides, potassium fluoride, amines, and het- erogeneous bases have been used as catalysts [1–7]. Because of the importance of Michael reactions in organ- ic synthesis, efforts have been made to develop efficient asymmetric versions. In 2003, Takemoto and co-workers reported a seminal study of a bifunctional thiourea catalyst able to catalyze nitro-Michael reactions [8]. Following this finding, several catalysts based on bifunctional thioureas have been proposed [9–16]. These catalysts have a thiourea moiety able to interact with the substrate via hydrogen bonding [17–19], and an amine group, which can work like a base [20, 21] or via iminium activation [22]. In addition, these catalysts have a chiral scaffold, which induces enantioselectivity [12]. Scheme 2 presents a general struc- ture of the thiourea bifunctional catalyst. Theoretical calculations are playing an increased role in the understanding of catalyzed reactions [23–26]. In the case of bifunctional thioureas, theoretical studies on the mechanism are focused on the enantioselectivity and This paper belongs to Topical Collection XIX - Brazilian Symposium of Theoretical Chemistry (SBQT2017) Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00894-018-3694-8) contains supplementary material, which is available to authorized users. * Josefredo R. Pliego, Jr pliego@ufsj.edu.br 1 Departamento de Ciências Naturais, Universidade Federal de São João del-Rei, São João del-Rei, MG 36301-160, Brazil Journal of Molecular Modeling (2018) 24: 152 https://doi.org/10.1007/s00894-018-3694-8