In this work we report on the progress that has been made towards gaining an understanding of the molecular mechanism of 1,3-dipolar cycloadditions using the bonding evolution theory (BET). A detailed analysis of the flow of electron density along the reaction pathway of the formal 1,3-dipolar cycloaddition reaction between cyclic nitrones (pyrroline-1-oxide and 2,3,4,5 tetrahydropyridine-1-oxide) and ethyl acrylate, as a case study, allowed the nature of the molecular mechanisms to be characterized.The present study provides a deep insight into the reaction mechanism, based on the electron density rearrangements given by the structural stability domains, and their connection with the bond breaking/forming processes along the reaction pathway.Electron pushing formalism is a powerful tool to describe chemical reactivity. Here, we show how the Lewis structures can be recovered and how curly arrows describe electron density transfers in chemical reaction mechanisms based on the BET results. The reaction mechanism is described by four consecutive events taking place as the reaction progresses: 1) the population of the initial N−C double bond is transferred to the N and C atoms; 2) the population of the initial double C-C bond is transferred to the C atoms.Along the ortho pathway the next steps are: 3) the C−C bond-forming, and 4) the O-C 2 bond-forming process. The order of 3) and 4) is inverted in the meta channel. Based on the sequence of the structural stability domains along the intrinsic reaction coordinate, a new synchronicity index is proposed, allowing us to classify and quantify the (a)synchronicity of the 1,3-DC reactions and, therefore, the nature of the reaction mechanism.3

The [3 + 2] cycloaddition (32CA) reactions of three nitrile oxides (NOs) (R‐CNO; R = Ph, CO2Me, and Br) with methyl acrylate (MA) have been theoretically studied within the molecular electron density theory. Topological analysis of the electron localization function of these NOs permits to establish that they will participate in zw‐type 32CA reactions. Analysis of the conceptual DFT indices indicates that these zw‐type 32CA reactions will have a low polar character as a consequence of the relatively low electrophilic character of MA and the low nucleophilic character of NOs, in agreement with the global electron density transfer computed at the corresponding TSs. The activation enthalpies associated with these 32CA reactions range from 8.2 to 12.7 kcal·mol−1. The presence of the bromide atom provokes the larger acceleration. While the 32CA reaction involving the CO2Me substituted NO is highly ortho regioselective, the other two reactions are poorly ortho regioselective. A bonding evolution theory study of the more favorable ortho regiosiomeric channel associated with the 32CA reaction involving the Br substituted NO indicates that this reaction is associated to a nonconcerted two‐stage one‐step mechanism, in which the activation energy is mainly related to the initial rupture of the CN triple bond of the NO.

The intramolecular [3+2] cycloaddition (IM32CA) reactions of cyclic nitrones Z‐7 and E‐7 have been studied within the Molecular Electron Density Theory at the MPWB1K/6‐311G(d) computational level. For these IM32CA reactions, which take place through a one–step mechanism, two regioisomeric reaction paths associated with the formation of the 6,6,5‐ring fused and 6,5,5‐ring bridged isoxazolidines have been considered. Analysis of the relative Gibbs free energies indicates that under thermodynamic control, these IM32CA reactions are completely regioselective, stereoselective and stereospecific, cyclic nitrones Z‐7 and E‐7 yielding the fused isoxazolidines 8 and 9, respectively, as the only product, in complete agreement with the experimental outcomes. The low electrophilic character of nitrones Z‐7 and E‐7 together with the strain caused by the chain along these intramolecular processes are responsible for the high activation energies found in these IM32CA reactions. An ELF topological analysis of the asynchronous TSs associated with the IM32CA reaction of cyclic nitrone Z‐7 indicates that along the more favourable fused reaction path, the IM32CA reaction begins with the formation of the C−O single bond involving the most nucleophilic and electrophilic centers of the molecule.

In the present work, the electron density flows involved throughout the progress of the four reaction pathways associated with the intramolecular [3 + 2] cycloaddition of cyclic nitrones Z-1 and E-1 are analyzed using the bonding evolution theory. The present study highlights the nonconcerted nature of the processes, which can be described as taking place in several stages. The first stage consists in the depopulation of the initial C N and C C double bonds to render the N lone pair and the corresponding C N and C C single bonds, and these electronic flows initiate the reactions. The C C and C O sigma bond formations take place later on, once the transition states have been overcome. Along the bridged pathways, the C C bond formation process precedes the O C bond formation event, although, along the fused paths, the O C bond formation process occurs first and the formation of the C C bond is the last electronic flow to take place. Finally, curly arrow representations accounting for the timing of the electron flows are obtained from the bonding evolution theory results. K E Y W O R D S bonding evolution theory, curly arrows, cyclic nitrones, intramolecular [3 + 2]cycloaddition

The nitration reaction of nitrobenzene with nitronium ion yielding ortho‐, meta‐ and para‐dinitrobenzenes has been studied within the Molecular Electron Density Theory, using DFT computational methods at the B3LYP/6‐311G(d,p) level. This electrophilic aromatic substitution (EAS) reaction takes place through a two‐step mechanism involving the formation of a tetrahedric cation intermediate. The electrophilic attack of nitronium ion on nitrobenzene is the rate‐determining step of this EAS reaction, and consequently, responsible for the composition of the reaction mixture. The subsequent proton abstraction from the cation intermediate is barrierless. From the computed activation Gibbs free energies, a relationship 11.0 (ortho) : 87.3 (meta) : 1.7 (para) of the dinitrobenzenes is estimated, in clear agreement with the experimental outcome. The similar nucleophilic activation of the ortho and meta carbons of nitrobenzene makes it possible to question the hypothesis for the orientation in EAS reactions involving nucleophilically deactivated benzenes based on the relative stability of the tetrahedric cation intermediates.