molecules Article A Theoretical Study of the Relationship between the Electrophilicity ! Index and Hammett Constant σp in [3+2] Cycloaddition Reactions of Aryl Azide/Alkyne Derivatives Hicham Ben El Ayouchia 1, Hafid Anane 1, Moulay Lahcen El Idrissi Moubtassim 1, Luis R. Domingo 2, Miguel Julve 3 and Salah-Eddine Stiriba 1,3,* 1 Laboratoire de Chimie Analytique et Moléculaire, Faculté Polydisciplinaire de Safi, Université Cadi Ayyad, Safi 46010, Morocco; [email protected] (H.B.E.A.); ananehafi[email protected] (H.A.); [email protected] (M.L.E.I.M.) 2 Departamento de Química Orgánica, Universidad de Valencia, Avda. Dr. Moliner 50, Burjassot 46100, Valencia, Spain; [email protected] 3 Instituto de Ciencia Molecular/ICMol, Universidad de Valencia, C/Catedrático José Beltrán No. 2, Paterna 46980, Valencia, Spain; [email protected] * Correspondence: [email protected]; Tel.: +34-96-354-4445; Fax: +34-96-354-7223 Academic Editor: James W. Gauld Received: 14 August 2016; Accepted: 21 October 2016; Published: 27 October 2016 Abstract: The relationship between the electrophilicity ! index and the Hammett constant σp has been studied for the [2+3] cycloaddition reactions of a series of para-substituted phenyl azides towards para-substituted phenyl alkynes. The electrophilicity ! index—a reactivity density functional theory (DFT) descriptor evaluated at the ground state of the molecules—shows a good linear relationship with the Hammett substituent constants σp. The theoretical scale of reactivity correctly explains the electrophilic activation/deactivation effects promoted by electron-withdrawing and electron-releasing substituents in both azide and alkyne components. Keywords: [2+3] cycloaddition reactions; arylazides; arylalkynes; substituent effects; electrophilicity index; Hammett constants 1. Introduction The [3+2] cycloaddition (32CA) reaction between azides, acting as the three-atom-component (TAC) and carbon–carbon triple bonds is a classical organic reaction initially established by Huisgen, in which five-membered 1,2,3-triazolic compounds are prepared as a mixture of 1,4 and 1,5-regioisomers. Since then, triazoles have played central roles in coordination chemistry as nitrogen-containing heterocyclic ligands, in bioconjugation issues, and in peptide-based drug design by mimicking peptide and disulfide bonds, leading to secondary structural components of peptides [1–3]. The interest in triazoles has recently attracted great attention, since the introduction of copper(I)-catalyzed 32CA reactions between azides and alkynes (CuCAA) [4]. The CuCAA reaction is classified as a click chemical process that takes place in a regioselective manner, giving only the 1,4-disubstituted triazole isomer [5]. A large number of mechanistic investigations were established describing the mechanistic pathways of these 32CA reactions (Scheme1)[6,7]. Unlike 1,3-dienes participating in Diels–Alder reactions [8], the electronic structure of TACs participating in 32CA reactions strongly depends on the type and hybridization of the atoms present in the TAC. Thus, depending on their electronic structure, TACs have recently been classified as pseudodiradical, carbenoid, and zwitterionic TACs (see Scheme2)[ 9,10]. It should be noted that only Molecules 2016, 21, 1434; doi:10.3390/molecules21111434 www.mdpi.com/journal/molecules Molecules 2016, 21, 1434 2 of 9 Molecules 2016, 21, 1434 2 of 8 Molecules 2016, 21, 1434 2 of 8 1,2-zwitterionic TACs such as nitrone or azides have the electronic structure of a 1,3-dipole as Huisgen proposed1,2-zwitterionic [[6].6]. TACs such as nitrone or azides have the electronic structure of a 1,3-dipole as Huisgen proposed [6]. R1 H R 1 R1 N H R1 N R [3+2] cycloaddition + 1 N [3+2] cycloaddition N R1 N N N N + R2 NNN N N NNN N N R2 R2 R2 R2 1,4-triazoleR2 1,5-triazole 1,4-triazole 1,5-triazole Scheme 1. Mechanism of the Huisgen azide–alkyne 32CA reaction. Scheme 1. Mechanism of the Huisgen azide–alkyne 32CA reaction. TAC TAC H H H H H N H N H CNC N H N H2C CH2 CNC H H2C O H2C CH2 H H2C O Azomethine Nitrile nitrone Azomethineylide NitrileYlide nitrone ylide Ylide Structure Structure pseudodiradical carbenoid zwitterioinic pseudodiradical carbenoid zwitterioinic Reactivity pr-type Reactivitycb-type zw-type pr-type cb-type zw-type Scheme 2.Electronic structure of three-atom-components (TACs) and the proposed reactivity types inScheme [3+2] cycloaddition 2.ElectronicElectronic structure (32CA) reactions. of three-atom-componentsthree-atom-component s (TACs)(TACs) and and the the proposed proposed reactivity reactivity types types in in[3+2] [3+2] cycloaddition cycloaddition (32CA) (32CA) reactions. reactions. Molecular Electron Density Theory [10,11] studies devoted to the understanding of the mechanisms Molecular Electron Density Theory [10,11] studies devoted to the understanding of the mechanisms of 32CAMolecular reactions Electron have allowed Density the Theory establishment [10,11] studiesof a useful devoted classification to the understandingof these reactions of into the of 32CA reactions have allowed the establishment of a useful classification of these reactions into pseudodiradicalmechanisms of-type 32CA (pr-type reactions)[9], havecarbenoid-type allowed the (cb-type establishment) [10], and of azwitterionic-type useful classification (zw-type of these) [9] pseudodiradical-type (pr-type)[9], carbenoid-type (cb-type) [10], and zwitterionic-type (zw-type) [9] reactions,reactions intoin suchpseudodiradical a manner -typethat TACs (pr-type with)[9 a], pseudodiradical carbenoid-type character (cb-type)[ participate10], and zwitterionic-type in pr-type 32CA reactions, in such a manner that TACs with a pseudodiradical character participate in pr-type 32CA (reactionszw-type)[ taking9] reactions, place easily in such through a manner earlier that transi TACstion with states a pseudodiradical (TSs) with a verycharacter low polar participate character in reactions taking place easily through earlier transition states (TSs) with a very low polar character [9,12];pr-type TACs32CA reactionswith a carbenoid taking place character easily through participate earlier in transitioncb-type 32CA states reactions (TSs) with whose a very feasibility low polar [9,12]; TACs with a carbenoid character participate in cb-type 32CA reactions whose feasibility dependscharacter on [9, 12the]; TACspolar withcharacter a carbenoid of the reaction character (i.e., participate the nucleophilic in cb-type 32CAcharacter reactions of the whose carbenoid feasibility TAC depends on the polar character of the reaction (i.e., the nucleophilic character of the carbenoid TAC anddepends the electrophilic on the polar character character of of the the ethylene reaction derivative)[10]; (i.e., the nucleophilic and finally, character TACs of with the carbenoid a zwitterionic TAC and the electrophilic character of the ethylene derivative)[10]; and finally, TACs with a zwitterionic characterand the electrophilic participate characterin zw-type of 32CA the ethylene reactions derivative) controlled[ 10by]; nucleophilic/electrophilic and finally, TACs with a zwitterionicinteractions character participate in zw-type 32CA reactions controlled by nucleophilic/electrophilic interactions takingcharacter place participate at the TSs, in similarlyzw-type 32CA to cb-type reactions reactions controlled [9,13]. by nucleophilic/electrophilic interactions taking place at the TSs, similarly to cb-type reactions [9,13]. takingThe place simplest at the TSs,azide, similarly HNNN—which to cb-type reactionshas a zwitterionic [9,13]. structure—presents low nucleophilic The simplest azide, HNNN—which has a zwitterionic structure—presents low nucleophilic character,The simplest N = 1.81 azide, eV, and HNNN—which very low electrophilic has a zwitterionic character, structure—presentsω = 0.66 eV [13]. Consequently, low nucleophilic it is character, N = 1.81 eV, and very low electrophilic character, ω = 0.66 eV [13]. Consequently, it is expectedcharacter, thatN = it 1.81participates eV, and neither very low as nucleophile electrophilic nor character, as electrophile! = 0.66 in eVzw-type [13]. 32CA Consequently, reactions [13]. it is expected that it participates neither as nucleophile nor as electrophile in zw-type 32CA reactions [13]. Consequently,expected that it the participates simplest azide neither must as nucleophile be electronically nor as activated electrophile in order in zw-type to easily32CA participate reactions [in13 a]. Consequently, the simplest azide must be electronically activated in order to easily participate in a zw-typeConsequently, 32CA reaction the simplest with low azide activation must be energy. electronically activated in order to easily participate in a zw-type 32CA reaction with low activation energy. zw-typeSubstituent32CA reaction effects with on the low TACs activation (regarded energy. as a zwitterionic species), and alkynes’ reactivities in Substituent effects on the TACs (regarded as a zwitterionic species), and alkynes’ reactivities in the 32CASubstituent reaction effects rate and on the stereoselectivity TACs (regarded leadin as ag zwitterionic to triazoles species),remain unfortunately and alkynes’ reactivitiesunclear, and in the 32CA reaction rate and stereoselectivity leading to triazoles remain unfortunately unclear, and needthe 32CA further reaction theoretical rate andinvestigation stereoselectivity [14]. A very leading recent to report triazoles shows remain that unfortunatelythe substituent unclear, effect could and need further theoretical investigation