No abstract

Primary-amine thioureas are preeminent organocatalysts used in challenging asymmetric Michael-type reactions, such as in the addition of nitromethane to enones. However, the complete reaction mechanism of this reaction has not yet been fully elucidated. Considering that the primary-amine group could act via both base and iminium ion catalysis, both mechanisms were investigated in this work using theoretical methods. The calculations have indicated that the base catalysis is kinetically unfeasible, with very high overall ΔG � . An imine-iminium ion catalysis is a viable route. This mechanism requires the participation of an acid as a cocatalyst (additive) in several steps, including the formation of the imine. The rate-determining step corresponds to the proton transfer from the nitromethane to the imine, forming the nitronate-iminium ion-pair intermediate. This complex reacts via nucleophilic attack of the nitronate ion to the electrophilic carbon of the iminium ion, forming a new CÀ C bond that determines the enantioselectivity of the reaction.

The reaction between primary amine and α,β‐unsaturated aldehydes and ketones can produce α,β‐unsaturated imines or aza‐Michael products. However, a theoretical reaction mechanism with the corresponding free energy profile compatible with experimental kinetics in aprotic apolar solvents has not been reported yet. In this work, we have used theoretical calculations to investigate the mechanism behind the 1,2‐addition and 1,4‐addition of benzylamine (BnNH2) to methyl vinyl ketone (MVK) in toluene solution. The calculation of the free energy profile was followed by a microkinetic analysis. According to our results, the experimentally observed formation of the aza‐Michael product is due to more favorable kinetics of the nucleophilic attack of the BnNH2 to the β‐carbon of s‐cis conformation of MVK. Furthermore, acetic acid can be present in MVK as a stabilizer. This contaminant catalyzes the transfer of protons for the formation of the aza‐Michael product and can also catalyze the imine formation. The present analysis indicates that catalysts for proton transfer are essential for the reaction to proceed in aprotic solvent and explain the use of carboxylic acids as an additive in aza‐Michael reactions. In the case of acetic acid, this species has a powerful catalytic effect, which explains why even a trace amount is enough for catalysis. A higher concentration of acetic acid could in principle favor the imine mechanism. However, a high concentration of acetic acid leads to the dimerization of this species, producing a low concentration of the free acid and limiting its ability to produce competitive kinetics for imine formation.

Theoretical modeling of the formation imines in aqueous medium from the reaction of amines with aldehydes is difficult due to formation of charged species, zwitterions, acid-base equilibria and a substantial solvent effect. In this work, a model reaction of methylamine with acetaldehyde was investigated involving neutral and ionic pathways, influence of the pH and different approaches for treating the solvent effect. We have found a mechanism able to explain the fast kinetics of this system, involving the zwitterion formation followed by its isomerization to the carbinolamine and an easy iminium ion formation via an ionic elimination mechanism.

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.