[3+2] Cycloaddition Reaction of C‐Phenyl‐N‐methyl Nitrone to Acyclic‐Olefin‐Bearing Electron‐Donating Substituent: A Molecular Electron Density Theory Study

Abstract

The [3+2] cycloaddition (32CA) reactions of C‐phenyl‐N‐methyl nitrone to acyclic olefins bearing electron donating and weak electron withdrawing groups lead to complete ortho regioselectivity. The experimentally observed ortho selectivity can be rationalized from the activation energies of the located transition states at DFT/MPW1PW91/6‐311G(d,p) level of theory. The reaction of this nitrone to ethyl vinyl ether is predicted to be non‐polar by global electron density transfer (GEDT) calculations. Bonding evolution theory (BET) study led to topological characterization of the reaction pathway into different phases and indicated initial rupture of the olefinic double bond followed by the formation of pseudoradical centres and earlier formation of C−C bond. Quantum theory of atoms in molecules (QTAIM) study of electron density was performed for (3,–1) critical points at the region near the forming C−C and C−O bonds and was found to be in complete agreement with the Electron localization function (ELF) topological analysis. Electrostatic potential surface study for the transition states indicated greater mutual penetration distances of C−C forming bond compared to the C−O forming bond.

Unveiling the Unexpected Reactivity of Electrophilic Diazoalkanes in [3+2] Cycloaddition Reactions within Molecular Electron Density Theory

“…This computational level has been recently used in the study of 32CA reactions. [27,28,[30][31][32] Frequency calculations were performed at the located stationary points to ensure that the TSs have one and only one imaginary frequency and all positive frequencies exist for the local minimum. The intrinsic reaction coordinate [51] (IRC) calculations using González-Schlegel integration method [52,53] verified the minimum energy reaction pathway connecting the reactants and the products.…”

“…The underlying theory adopted for explaining 32CA reactions was based on the Frontier Molecular Orbital [24] (FMO) concept since last 50 years, until in 2016, Domingo proposed the Molecular Electron Density Theory [25,26] (MEDT) to recognize the decisive role of the changes in electron density on the molecular reactivity. The MEDT concept, which rejects any analysis based on molecular orbitals, has allowed explaining the experimental outcome of 32CA reactions, for example, the strain promotion [27,28], selectivities [29,30], substituent effects [31][32][33], catalysis [34,35] etc.…”

Understanding the Reactivity of Trimethylsilyldiazoalkanes Participating in [3+2] Cycloaddition Reactions towards Diethylfumarate with a Molecular Electron Density Theory Perspective

“…Interestingly, the reactivity of these TACs in 32CA reactions has put forward a useful classification of the 32CA reactions into zwitterionic type (zw-type), carbenoid type (cb-type), pseudo(mono)radical type (pmr-type), and pseudodiradical type (pdr-type), reactions, with progressive decrease in the activation energies along the series. The zw-type reactions are associated with high energy barrier, which is demanding to overcome through sufficient nucleophilic-electrophilic activations [17,18], while the pdr-type 32CA reactions show low activation energies and can be performed very easily. This classification has allowed characterizing the simplest diazoalkane as a pseudoradical TAC participating in pmr-type 32CA reactions (see Figure 1) [19] Herein, an MEDT study for 32CA reactions of silyldiazoalkanes 1-3 with DFM 4 (Scheme 4), experimentally reported by Bassindale and Brook,[13] is carried out in order to understand how the presence of silicon on these silyldiazoalkanes changes the structure and reactivity of these TACs, and thus, explain the experimental outcomes.…”

Understanding the regio-and diastereoselective synthesis of a potent antinociceptive isoxazolidine from C-(pyridin-3-yl)-N-phenylnitrone in the light of molecular electron density theory

“…Topological analysis of the ELF and visualization of ELF localisation domains has been employed in several MEDT studies [4][5][6] to analyse the reactivity of three--atom components [4][5][6] (TACs) participating in 32CAs. This has allowed the classification of TACs into pseudodiradical (pdr-) 15 type, pseudo(mono)radical 16 (pmr-) type, carbenoid (cb-) 15 type and zwitter-ionic (zw-) 5,6,17 type. Monosynaptic V(A) basin integrating at a population of less than 1e is associated with pseudoradical center, while that integrating at a population of 2e in neutral molecules is associated with carbenoid centre.…”