Unravelling the Mechanism of Non–photoactivated [2+2] Cycloaddition Reactions: Relevance of Orbital Interactions and Zwitterionic Intermediates

Abstract

In this work, a thorough theoretical study of the [2+2] cycloaddition reaction between asymmetric substituted alkenes is presented. The simulations evidence a concerted asynchronous or stepwise mechanism, depending on the nature of the electron‐deficient alkene. We have found a direct relation between the interaction of the frontier‐orbitals (HOMO‐LUMO) and the distortion energy with the activation energy (whose values oscillate between ∼4 and ∼35 kcal/mol in the studied cases). We thus conclude that the interaction between the frontier‐orbitals govern the reaction, through changes in the distortion energy. We also show that the lifetime of the zwitterionic intermediate determine the relative stereochemistry of the products.

NMR and Computational Studies on the Reactions of Enamines with Nitroalkenes That May Pass through Cyclobutanes

“…For the analogous N -cyclohexenylpirrolidines, the steric inhibition of resonance was comparatively higher. As known 1,3,5 and mentioned in preceding sections, with large substituents on C2 of the pyrrolidine ring, aminocatalytic reactions do not work in practice—starting enamines are hardly formed, but these imaginary cases can also be computationally investigated, as we have done in Figure 23 (eq 6), to find a general explanation of the differences between cyclopentanone and cyclohexanone enamines.…”

“…Since all of the iminium ions are in equilibrium, by rotation around the C1–C2 single bond and through the enamines by deprotonation and protonation (general acid catalysis), it may appear that the protonation step is rather stereoselective. 3 At least in apolar solvents, all of the iminium species fall down to im + . In other words, the calculations suggest that the hydrolysis of the final enamines goes through this iminium ion.…”

“…The more recent works of the groups of Seebach, Hayashi, Blackmond, Pihko, and Papai are the exception. 3 Our eclectic view of their mechanistic proposals, for a large substituent at pyrrolidine C2, is shown in Figure 2. Whereas Seebach, Hayashi, and co-workers 3a proposed that nitrocyclobutanes are off-cycle intermediates and may be considered “resting states” of the catalyst, Burés et al 3c,3f indicated that the stereochemical outcome can be determined by these “downstream intermediates” (nitrocyclobutanes), which may either enhance or reduce the selectivity established in the initial steps.…”

“…Intermediates such as zwitterions zw , cyclobutanes cb (formal 2 + 2-cycloadducts), dihydrooxazine- N -oxides (2 + 4-cycloadducts, dh ), 4 and adduct enamines en (that is, the enamines of the final Michael products) have been proposed or detected. 3 Seebach et al. have characterized up to 17 cyclobutanes of the cb type, all from the JH catalyst or related diphenylprolinols.…”

A novel partitioning scheme for the application of the distortion/interaction - activation strain model to intramolecular reactions

“…Among all pericyclic reactions, the Diels-Alder [8][9][10][11][12][13][14][15] and the 1,3-dipolar cycloaddition [16][17][18][19][20] have been thoroughly studied, with an endless variety of alkenes and dienes/ dipoles. Other pericyclic reactions such as the Alder-ene [21] and the [2 + 2] cycloaddition [22] have been also investigated. Another strength of this model is its ability to be easily combined with previous reactivity models, like EDA [23] or FMO [5, 6, 9, 10, 14-17, 20, 22, 24], so a more complete analysis of the reaction profile can be provided.…”