Mechanistic Insights into the Mode of Action of Bifunctional Pyrrolidine-Squaramide-Derived Organocatalysts.

The catalytic modes of action of three squaramide-derived bifunctional organocatalysts have been investigated using DFT methods. The [5+2] cycloaddition between oxidopyrylium ylides and enals was used as the model reaction. Two primary modes were possible for the different catalysts studied. The preference for one mode over the other was due to the possibility of additional favorable π-π interactions between the hydrogen-bond activated pyrylium ylide and an electron-deficient aromatic ring bonded to the squaramide NH group. The model can be extended to other reactions catalyzed by the same catalysts, such as formal [2+2] cycloadditions between nitroalkenes and α,ß-unsaturated aldehydes. The computational results were in excellent concurrence with the available experimental reports on the observed total enantioselectivity and differences in diastereoselectivity depending on the substrate and the reaction.

Revealing Stepwise Mechanisms in Dipolar Cycloaddition Reactions: Computational Study of the Reaction between Nitrones and Isocyanates.

The mechanism of cycloaddition reactions of nitrones with isocyanates has been studied using density functional theory (DFT) methods at the M06-2X/cc-pVTZ level of theory. The exploration of the potential energy surfaces associated with two reactive channels leading to 1,2,4-oxadiazolidin-5-ones and 1,4,2-dioxazolidines revealed that the cycloaddition reaction takes place through a concerted mechanism in gas phase and in apolar solvents but a stepwise mechanism in polar solvents. In stepwise mechanisms, the first step of the reaction is a rare case in which the nitrone oxygen acts as a nucleophile by attacking the central carbon atom of the isocyanate (interacting with the π-system of the C═O bond) to give an intermediate. The corresponding transition structure is stabilized by an attractive electrostatic interaction favored in a polar medium. The second step of the reaction is the rate-limiting one in which the formation of 1,2,4-oxadiazolidin-5-ones or 1,4,2-dioxazolidines is decided. Calculations indicate that formation of 1,2,4-oxadiazolidin-5-ones is favored both kinetically and thermodynamically independently of the solvent, in agreement with experimental observations. Noncovalent interactions (NCI) and topological analysis of the gradient field of electron localization function (ELF) bonding confirmed the observed interactions.

Understanding bond formation in polar one-step reactions. Topological analyses of the reaction between nitrones and lithium ynolates.

The mechanism of the reaction between nitrones and lithium ynolates has been studied using DFT methods at the M06-2X/cc-pVTZ/PCM=THF level. After the formation of a starting complex an without energy barrier, in which the lithium atom is coordinated to both nitrone and ynolate, the reaction takes place in one single kinetic step through a single transition structure. However, the formation of C-C and C-O bonds takes place sequentially through a typical two-stage, one-step process. A combined study of noncovalent interactions (NCIs) and electron localization function (ELFs) of selected points along the intrinsic reaction coordinate (IRC) of the reaction confirmed that, in the transition structure, only the C-C bond is being formed to some extent, whereas an electrostatic interaction is present between carbon and oxygen atoms previous to the formation of the C-O bond. Indeed, the formation of the second C-O bond only begins when the first C-C bond is completely formed without formation of any intermediate. Once the C-C bond is formed and before the C-O bond formation starts the RMS gradient norm dips, approaching but not reaching 0, giving rise to a hidden intermediate.

DFT investigation of the mechanism of E/Z isomerization of nitrones.

The hitherto unknown mechanism of E/Z isomerization of nitrones, with important implications in 1,3-dipolar cycloaddition chemistry, has been investigated using density functional theory calculations. Unimolecular and bimolecular processes have also been considered. Both concerted and stepwise mechanisms involving either zwitterionic or diradical species have been studied. The unimolecular torsional mechanism and isomerization through intermediate oxaziridines present energy barriers too high to justify the observed experimental results. Several bimolecular processes involving an initial dimerization are possible. Among them, the concerted process can be discarded in terms of energy barrier. Zwitterionic intermediates are too high in energy to be considered. From the two possible diradical approaches consisting of either C-O or C-C coupling, the latter is the most favored. Thus, the mechanism of E/Z isomerization of nitrones proceeds via a diradical bimolecular process involving an initial dimerization through a C-C coupling followed by a dedimerization, with energy barriers for the rate-limiting step of 29.9 kcal/mol for C-methyl nitrones and 25.8 kcal/mol for C-(methoxycarbonyl) nitrones. These values are in very good agreement with the experimental data previously measured through kinetic experiments.

[2n2π + 2n2π] cycloadditions: an alternative to forbidden [4π + 4π] processes. The case of nitrone dimerization.

A theoretical study based on (U)M06-2X/cc-pVTZ calculations has been used to investigate the [3 + 3] thermal dimerization of nitrones to 1,4,2,5-dioxadiazinanes in both the gas phase and in dichloromethane solution. Calculations suggest that dimerization of nitrones takes place through a concerted mechanism involving a formal disallowed [4π + 4π] cycloaddition with a free energy barrier of 30.8 kcal mol(-1). The corresponding diradical and zwitterionic stepwise mechanisms have also been studied, but the located transition structures are kinetically disfavoured. An alternative mechanism through a five-membered ring intermediate formed by a classical [3 + 2] dipolar cycloaddition can also be discarded. The five-membered ring intermediate is unstable to cycloreversion and its isomerization to the final dioxadiazinane involves a high free energy barrier (68.6 kcal mol(-1)). Calculations also show that the dimerization process is slower in dichloromethane than in the gas phase owing to the larger polarity of nitrones and that inclusion of diffuse functions at the studied level does not modify the observed results. The apparently disfavoured [3 + 3] dimerization of nitrones can actually be explained as a bispseudopericyclic [2n2π + 2n2π] process in which the favourable FO interactions between the nitrone oxygen and the C=N π* bypass the WH-forbidden process.

A Friedel-Crafts alkylation mechanism using an aminoindanol-derived thiourea catalyst.

Computational calculations based on experimental results shed light on the mechanistic proposal for a Friedel-Crafts alkylation reaction between indole and nitroalkenes, catalysed by a chiral aminoindanol-derived thiourea. In our hypothesis both substrates are simultaneously coordinated to the catalyst in a bifunctional mode. This study elucidates the crucial role played by the hydroxyl group of the catalyst in the success of the reaction. The OH group seems to be involved in the preferential attack of the indole over the nitroalkene, affording the major enantiomer and stabilizing the resulting transition state by a concomitant coordination with the nitroolefin. The results obtained with other catalysts from the same family, and other indoles, are reported and discussed. Theoretical calculations are in agreement with the experimental outcomes and with our previously developed mechanism, displaying the pivotal role played by hydrogen bond interactions.

Racemic hemiacetals as oxygen-centered pronucleophiles triggering cascade 1,4-addition/Michael reaction through dynamic kinetic resolution under iminium catalysis. Development and mechanistic insights.

2-Hydroxydihydropyran-5-ones behave as excellent polyfunctional reagents able to react with enals through oxa-Michael/Michael process cascade under the combination of iminium and enamine catalysis. These racemic hemiacetalic compounds are used as unconventional O-pronucleophiles in the initial oxa-Michael reaction, also leading to the formation of a single stereoisomer under a dynamic kinetic resolution (DKR) process. Importantly, by using ß-aryl or ß-alkyl substituted α,ß-unsaturated substrates as initial Michael acceptors either kinetically or thermodynamically controlled diastereoisomers were formed with high stereoselection through the careful selection of the reaction conditions. Finally, a complete experimental and computational study confirmed the initially proposed DKR process during the catalytic oxa-Michael/Michael cascade reaction and also explained the kinetic/thermodynamic pathway operating in each case.