Unravelling the Mysteries of the [3+2] Cycloaddition Reactions

Abstract

After Huisgen's and Firestone's mechanistic proposals made in the 1960s based on experiments, several theories were proposed during the last century to explain [3+2] cycloaddition (32CA) reactions, most of them still prevailing today. Recent molecular electron density theory (MEDT) studies of 32CA reactions involving representative three‐atom components have allowed characterising at least four different electronic structures, which experience a dissimilar chemical reactivity. In this review, the four simplest reactivity models are presented, providing a modern rationalisation of 32CA reactions based on MEDT.

A molecular electron density theory study of the participation of tetrazines in aza-Diels–Alder reactions

“…26 On the other hand, Houk's DIM, 19,20 based on the Energy Decomposition Analysis (EDA) scheme proposed by Morokuma in 1981, 27,28 has no quantum physical meaning within DFT, since in DFT the energy of a system is a functional of the electron density and the external potential, 23 and consequently, the energy of the constrained separated geometries conforming the TS has no relationship with the energy of the actual TS as each of them loses the external potential created by the other fragment. 29,30 In 2016, Domingo proposed the Molecular Electron Density Theory 31 (MEDT) for the study of the reactivity in Organic Chemistry, in which changes in the electron density, but not MO interactions, as the Frontier Molecular Orbital (FMO) theory proposes, 32 are responsible for the feasibility of an organic reaction. A thorough study of experimental Diels-Alder reactions allowed establishing a linear relationship between activation energies and the polar character of the reactions, measured through the GEDT 33 taking place at the TSs, making it possible to establish the polar Diels-Alder (P-DA) mechanism, in which the activation energies depend mainly on the nucleophilic/electrophilic behaviours of the reagents.…”

Unveiling the Different Chemical Reactivity of Diphenyl Nitrilimine and Phenyl Nitrile Oxide in [3+2] Cycloaddition Reactions with (R)-Carvone through the Molecular Electron Density Theory

“…Note that this polarisation is larger at phenyl NO 4a as a consequence of the more electronegative character of the oxygen atom that the nitrogen one (see Figure 1). It is interesting to remark that the charge distribution of phenyl NO 4a, which is classified as a zwitterionic TAC, is not a consequence of the set of resonance Lewis structures, as proposed [27], but of the different nature of the three nuclei of this TAC [21].…”

“…In order to characterise the electronic structure of diphenyl-NI 2a and phenyl NO 4a and, thus, to establish their reactivity in 32CA reactions [21], a topological analysis of the ELF [25] of these TACs was first performed; the electronic structure of (R)-carvone 1 is also analysed. ELF localisation domains, ELF basin attractor positions together with the valence basin populations, as well as the proposed ELF-based Lewis-like structures together with the natural atomic charges, are shown in Figure 1.…”

“…The distances between the interacting C1 and Cx and N3 and Cy centres at the gas phase TSs are 2.213 (C1−C4) and 2.642 (N3−C5) Å at TS-1-NI, 2.221 (N3−C4) and 2.380 (C1−C5) Å at TS-2-NI,2.263 (C1−C8) and 2.621 (N3−C9) Å at TS-3-NI, and 2.304 (N3−C8) and 2.331 (C1−C9) Å at TS-4-NI. Some appealing conclusions can be drawn from these geometrical parameters: i) the more favourable regioisomeric TSs,TS-1-NI and TS-3-NI, are more asynchronous than TS-2-NI and TS-4-NI; ii) the most favourable TS-1-NI is associated with a two-centre interaction between the most nucleophilic centre of diphenyl NI 1, the carbenoid C1 carbon, and the most electrophilic centre of carvone 3, the β-conjugated C4 carbon (see Section S1 in Supplementary Material); iii) the C−C and C−N distances associated to the formation of the corresponding single bonds, > 2.2 Å , indicating that formation of these single bonds has not started yet at any of the four TSs [21]; and iv) a comparison of the geometrical parameters obtained at the B3LYP/6-31G(d) level, in the gas phase and in DCM, and those obtained at the B3LYP/6-311G(d,p) level in DCM, shows that there are no significant differences (see Figure 2). Finally, in order to evaluate the polar nature of the 32CA reaction of diphenyl NI 2a with (R)-carvone 1, the global electron density transfer (GEDT) [34] at the more favourable regioisomeric TSs was analysed.…”

An MEDT study of the mechanism and selectivities of the [3+2] cycloaddition reaction of tomentosin with benzonitrile oxide

“…Finally, in order to evaluate the polar nature of the 32CA reaction of tomentosin 4 and benzonitrile oxide 5, the GEDT at the more favorable Some appealing conclusions can be drawn from this ELF topological analysis: (a) the relatively high activation energy of the nonpolar 32CA reaction between tomentosin 4 and benzonitrile oxide 5, 13.2 kcalÁmol −1 from S1 (Table S1), can mainly be related to the rupture of the C1 N2 triple bond of the nitrile oxide framework, which leads to the formation of nonbonding electron density at the N2 nitrogen and the C1 carbon. Due to the nonpolar character of the reaction, these bonding changes are not favorable [49] ; (b) this finding allows relating the reaction to a nonpolar zw-type 32CA reaction [19] ; (c) formation of the first C1 C4 single bond takes place at a C C distance of ca. (Table S1) of the structures at which formation of the two single bonds occurs, that is, S3 and S5, the bond formation can be considered highly asynchronous despite the nonpolar nature of the reaction.…”