1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 z Organic & Supramolecular Chemistry Experimental and Theoretical MEDT Study of the Thermal [3 + 2] Cycloaddition Reactions of Aryl Azides with Alkyne Derivatives Hicham Ben El Ayouchia,* [a] Bahsis Lahoucine, [a] Hafid Anane, [a] Mar Rı ´os-Gutie´rrez,* [b] Luis R. Domingo, [b] and Salah-Eddine Stiriba [a, c] The reactivity and regioselectivity of the [3 + 2] cycloaddition (32CA) reactions of a series of 4-substituted-aryl azides/alkynes in toluene have been explored experimentally. These 32CA reactions have been also studied within the Molecular Electron Density Theory (MEDT) using Density Functional Theory (DFT) calculations at the B3LYP/6-31G(d) computational level. The computed activation energies, in gas phase and in toluene, show that the 1,5-regioisomeric channels are slightly favoured kinetically as found experimentally. The topological analysis of the electron localisation function (ELF) of some relevant points of the regioisomeric reaction paths shows that while the formation of the 1,4-diaryl triazoles takes place via a low asynchronous CN bond formation process, the formation of the favoured 1,5-diaryl triazoles takes place via a two-stage one- step mechanism, as the result of the attack of the most nucleophilic center of the aryl alkyne on the most electrocyclic center of aryl azide. Introduction The [3 + 2] cycloaddition (32CA) reactions of azides, acting as the three-atom-component (TAC), with C-C triple bonds is a classical organic reaction recognised and established by Huisgen in 1965, [1] in which five-membered 1,2,3-triazolic compounds are prepared as a mixture of two 1,4- and 1,5- regioisomers. [2] Current understanding of the underlying principles in reactions such as 32CA reactions has grown from a fruitful interplay between theory and experiment. A recent experimen- tal study of the 32CA reaction between aryl azides and alkynes in order to synthesise 1,2,3-triazolic compounds prompted us to perform a theoretical study using DFT methods to depict the mechanism of these reactions. [3] Very recently, Domingo proposed a new reactivity theory in Organic Chemistry named the Molecular Electron Density Theory (MEDT), [4] which establishes that the feasibility for the changes in the electron density along a reaction path is responsible for the reactivity in Organic Chemistry. Within MEDT, besides a deep exploration and characterisation of the stationary points associated with the reaction paths of the studied reaction, quantum chemical tools based on the analysis of the electron density, such as the Conceptual Density Functional Theory (CDFT) reactivity indices, [5,6] the electron localisation function (ELF) [7] and the non-covalent interactions (NCI), [8] are used to study the molecular reactivity in organic reactions rigorously. Unlike 1,3-dienes participating in Diels-Alder reactions, [9] the electronic structure of TACs participating in 32CA reactions strongly depends on the type and hybridisation of the atoms present in the TAC. Thus, depending on their electronic structure, TACs have recently been classified as pseudodiradical, pseudoradical, carbenoid and zwitterionic TACs (see Scheme 2). [10,11] Recent MEDT studies devoted to the understanding of the reactivity of the TACs participating in 32CA reactions with ethylene revealed a very good correlation between their electronic structure and reactivity and, thus, 32CA reactions have been classified into pseudodiradical-type (pdr-type), pseu- doradical-type (pmr-type), carbenoid-type (cb-type) and zwitter- ionic-type (zw-type) reactions, depending on the electronic structure of the TAC (see Scheme 2). [11] The activation energy of these 32CA reactions increases in the following order: pdr-type [a] Dr. H. B. El Ayouchia, B. Lahoucine, Prof. H. Anane, Prof. S.-E. Stiriba Laboratoire de Chimie Analytique et MolØculaire - LCAM, FacultØ Poly- disciplinaire de Safi, UniversitØ Cadi Ayyad, Safi 46030, Morocco. E-mail: belayou@gmail.com [b] M. Ríos-GutiØrrez, Prof. L. R. Domingo Departamento de Química Orgµnica, Universidad de Valencia, Dr. Moliner 50, 46100 Burjassot, Valencia, Spain. E-mail: rios@utopia.uv.es [c] Prof. S.-E. Stiriba Instituto de Ciencia Molecular/ICMol, Universidad de Valencia, C/Ca- tedrµtico JosØ Beltrµn N8 2, 46980 Paterna, Valencia, Spain. Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.201702588 Scheme 1. 32CA reaction between azides and alkynes. Full Papers DOI: 10.1002/slct.201702588 1215 ChemistrySelect 2018, 3, 1215 – 1223 # 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim