A Theoretical Study of the Relationship Between the Electrophilicity Ω Index and Hammett Constant Σp in [3+2] Cycloaddition Reactions of Aryl Azide/Alkyne Derivatives

Article A Theoretical Study of the Relationship between the Electrophilicity ω 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 ω 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 ω 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 electrophileω = 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 [14]. A very recent report shows that the substituent effect could changeneed further the reaction theoretical mechanism investigation from [concerted14]. A very single-step recent report to stepwise shows that pathway the substituent for some effectof the couldTAC change the reaction mechanism from concerted single-step to stepwise pathway for some of the TAC azidechange compounds the reaction [15]. mechanism The linear from free concerted energy relati single-steponship tois among stepwise the pathway empirical for methods some of thethat TAC can azide compounds [15]. The linear free energy relationship is among the empirical methods that can helpazide to compounds develop an [understanding15]. The linear of free the energysubstituent relationship effects on is the among reactivity the empirical of both azides methods and thatalkynes. can help to develop an understanding of the substituent effects on the reactivity of both azides and alkynes. Linearhelp to free-energy develop an relationships understanding are of empirical the substituent relationships effects onbetween the reactivity thermodynamic of both azides quantities and alkynes.known Linear free-energy relationships are empirical relationships between thermodynamic quantities known asLinear extra-thermodynamic free-energy relationships equations are [16]. empirical They have relationships been invaluable between inthermodynamic the investigation quantities of the structural known as extra-thermodynamic equations [16]. They have been invaluable in the investigation of the structuralσ propertiesas extra-thermodynamic and reactivities equations of organic [16 compounds]. They have in been solution. invaluable Among in thethem, investigation the Hammett of the constants structural p properties and reactivities of organic compounds in solution. Among them, the Hammett constants σp propertieshave been andpermanently reactivities used of organic in relating compounds the nature in solution. of the substituents Among them, to thetheir Hammett electronic constants effects (inductivehave been andpermanently resonance) used on chemicalin relating reactivity the nature and ofother the propertiessubstituents [17]. to Today,their electronic these constants effects remain(inductive an excellentand resonance) guide for on structure–property chemical reactivity and and structure–activity other properties studies[17]. Today, [18]. Thethese fact constants that the remain an excellent guide for structure–property and structure–activity studies [18]. The fact that the Molecules 2016, 21, 1434 3 of 9

σp have been permanently used in relating the nature of the substituents to their electronic effects (inductive and resonance) on chemical reactivity and other properties [17]. Today, these constants remain an excellent guide for structure–property and structure–activity studies [18]. The fact that the constants derived from these equations were empirical led to efforts to look for correlations between them and other theoretically-derived parameters which might be obtained from quantum chemical calculations. Several indices derived from conceptual density functional theory (DFT) have beenMolecules increasingly 2016, 21, used1434 in the interpretation of organic reactivity. They include reactivity indices3 of 8 like chemical potential, hardness, softness, electrophilicity, and nucleophilicity indices [19]. constantsIt is known derived that from the Hammettthese equations equation were [empirica2,3] relatesl led theto efforts relative to look magnitude for correlations of the between equilibrium them and other theoretically-derived parameters which might be obtained from quantum chemical constants to a reaction constant (ρ) and a substituent constant (σp), according to Equation (1) [20]. calculations. Several indices derived from conceptual density functional theory (DFT) have been increasingly used in the interpretation of organic reactivity. They include reactivity indices like log(K/K ) = ρ σp (1) chemical potential, hardness, softness, electrophilicity,0 and nucleophilicity indices [19]. It is known that the Hammett equation [2,3] relates the relative magnitude of the equilibrium From a theoretical point of view, the electrophilic and nucleophilic behaviors of organic constants to a reaction constant (ρ) and a substituent constant (σp), according to Equation (1) [20]. molecules can be characterized by using the reactivity indices defined within the conceptual DFT framework [19,21]. Parr et al. [22] introducedlog(K/K the following0) = ρ σp definition of the electrophilicity ω index(1) of a moleculeFrom in termsa theoretical of its chemicalpoint of view, potential the electrophiliµ and chemicalc and nucleophilic hardness behaviorsη through of organic Equation molecules (2). can be characterized by using the reactivity indices defined within the conceptual DFT framework 2 [19,21]. Parr et al. [22] introduced the followingω =definitionµ /2η of the electrophilicity ω index of a molecule (2) in terms of its chemical potential μ and chemical hardness η through Equation (2). where µ and η are the electronic chemical potential and chemical hardness of the ground state of the ⍵ = μ2/2η (2) atoms and molecules, respectively [23]. Electrophilicity index ω measures the stabilization in energy whenwhere the system μ and ηacquires are the electronic an additional chemical electronic potential chargeand chemical from thehardness environment of the ground [22]. state Bydefinition, of the it encompassesatoms and molecules, both the respectively ability of an[23]. electrophile Electrophilicity to acquireindex ω additionalmeasures the electronic stabilization charge in energy and the when the system acquires an additional electronic charge from the environment [22]. By definition, it resistance of the system to exchanging electronic charge with the environment. encompasses both the ability of an electrophile to acquire additional electronic charge and the Linear relationships between σ and ω have recently been obtained for para-substituted benzyl resistance of the system to exchangingp electronic charge with the environment. cations. Domingo et al. have systematically compared the experimental σp values and electronic Linear relationships between σp and ω have recently been obtained for para-substituted benzyl ω electrophilicitycations. Domingo index et foral. ahave series system of forty-twoatically compared substituted the ethylene experimental derivatives σp values [24 ].and They electronic developed a statisticalelectrophilicity procedure index toω for obtain a series intrinsic of forty-two electronic substituted contributions ethylene derivatives to σp based [24]. onThey the developed comparison betweena statistical the experimental procedure Hammettto obtain intrinsic constant electronicσp and the contributions electrophilicity to σ indexp basedω on, evaluated the comparison for a series of functionalbetween the groups experimental that are presentHammett in constant organic compounds.σp and the electrophilicity index ω, evaluated for a seriesHerein, of functional we present groups a theoretical that are present model in organic to quantitatively compounds. describe the Hammett substituent Herein, we present a theoretical model to quantitatively describe the Hammett substituent constants σp in terms of the global electrophilicity ω of azides and alkynes used in 32CA reactions by usingconstants a global σ electrophilicityp in terms of the global index electrophilicityω as well as the ω of logarithm azides and of alkynes the global used electrophilicityin 32CA reactions ratios by of using a global electrophilicity index ω as well as the logarithm of the global electrophilicity ratios of para-substituted and unsubstituted compounds (see Figure1). The global electrophilicity index ω of a para-substituted and unsubstituted compounds (see Figure 1). The global electrophilicity index ω of series of aromatic azides and alkynes is classified within an absolute scale in order to illustrate the a series of aromatic azides and alkynes is classified within an absolute scale in order to illustrate the rationalizationrationalization of theof the substituent substituent effects effects on on the the electrophilicelectrophilic activation/deactivation activation/deactivation of the of substrates. the substrates. Indeed,Indeed, such such aromatic aromatic substrates substrates were were chosen chosen insteadinstead of aliphatic aliphatic substrates substrates because because of the of thesubstantial substantial electronicelectronic effect effect of theof thepara para-substituted-substituted group group onon eithereither azide azide or or carbon–carbon carbon–carbon triple triple bond bond facilitated facilitated by theby electronicthe electronic transmission transmission through through the the aromatic aromatic π-conjugated-conjugated system. system.

N N N R

Ai A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12 R H CH3 OCH3 Br F Cl COOH COOCH3 COCH3 C4H9 CONH2 CN

Bi B1 B2 B3 B4 B5 B6 B7 B8 B9 B10 B11 B12 R H CH3 F COOCH3 OPh CHO Br Cl COOH COCH3 CN C4H9

Figure 1. General structures of the (A) azide and (B) alkyne derivatives used in the 32CA reactions Figure 1. General structures of the (A) azide and (B) alkyne derivatives used in the 32CA reactions studied in this work. studied in this work. 2. Results and Discussion The global electrophilicity patterns of the substituted azide (A) and alkyne (B) derivatives used in the 32CA reactions are ranked in Figure 2. It can be seen that compounds with electron-withdrawing (EW) substituents occupy the top of the scale, while compounds with electron-releasing (ER) substituents are in the bottom. Alkynes display slightly higher electrophilicity values than azides Molecules 2016, 21, 1434 4 of 9

2. Results and Discussion The global electrophilicity patterns of the substituted azide (A) and alkyne (B) derivatives used in the 32CA reactions are ranked in Figure2. It can be seen that compounds with electron-withdrawing (EW) substituents occupy the top of the scale, while compounds with electron-releasing (ER) Moleculessubstituents 2016, 21 are, 1434 in the bottom. Alkynes display slightly higher electrophilicity values than azides4 of with8 similar EW substituents, and it is a little lower when using ER ones. It is also possible to rationalize with similar EW substituents, and it is a little lower when using ER ones. It is also possible to the electrophilic activating/deactivating effects promoted by substituent groups in both azide and rationalize the electrophilic activating/deactivating effects promoted by substituent groups in both azide alkyne compounds. For instance, the unsubstituted reference TAC A1(–H) has an electrophilic value and alkyne compounds. For instance, the unsubstituted reference TAC A1(–H) has an electrophilic value of (ω = 1.26 eV). Its para-substitution by the weak ER methyl (–CH3) group results in an electrophilic of (ω = 1.26 eV). Its para-substitution by the weak ER methyl (–CH3) group results in an electrophilic deactivation as shown in compound A2 (ω = 1.20 eV). deactivation as shown in compound A2 (ω = 1.20 eV).

FigureFigure 2. 2. TheoreticalTheoretical scale scale of of global global electrophilicity electrophilicity ω ωforfor substituted substituted alkynes alkynes and and azides azides studied studied in in 32CA32CA reactions. reactions.

By substitution of the same para position with the stronger ER methoxy (–OCH3) group, an even By substitution of the same para position with the stronger ER methoxy (–OCH ) group, an even higher electrophilic deactivation is observed in compound A3 (ω = 1.13 eV). As 3expected, the ω substitutionshigher electrophilic with EW deactivation groups show iselectrophilic observed inactivation. compound For example,A3 ( = substitution 1.13 eV). As with expected, fluorine the causessubstitutions an activation with EW of about groups 0.09 show eV in electrophilic compound activation.A5 with respect For example, to the unsubstituted substitution compound with ﬂuorine A1causes. Whereas an activation the most of aboutefficient 0.09 activation eV in compound with respectA5 with to compound respect to theA1 unsubstitutedis achieved by compound the cyano A1. groupWhereas (–CN) the as most found efﬁcient in compound activation A12 with (ω = respect 1.93 eV). to compound A1 is achieved by the cyano group (–CN)For as the found series in of compound alkynes, a similarA12 (ω picture= 1.93 is eV). obtained. So, starting from the reference compound B1 (ω = 1.13 eV), the para substitution with fluorine (–F), chlorine (–Cl), and bromine (–Br) atoms results in an electrophilic activation in compounds B3 (ω = 1.14 eV), B7 (ω = 1.32 eV), and B8 (ω = 1.33 eV). The highest activation effect is achieved by EW carbonyl (–CHO) substitution, in compound B6 (ω = 2.10 eV). In this series, the electrophilic deactivation was caused by ER groups as found, for example, with the methyl substituting –CH3 in compound B2 (ω = 1.05 eV). In line with that, the substitution by a stronger ER group such as (–t-Bu) results in a higher electrophilic deactivation, as found for compound B12 (ω = 0.92 eV). As in single-substituted molecules, a low electrophilicity index ω has been correlated with good nucleophiles [25]. It is expected that the more favorable azide/alkyne zw-type 32CA reactions take Molecules 2016, 21, 1434 5 of 9

For the series of alkynes, a similar picture is obtained. So, starting from the reference compound B1 (ω = 1.13 eV), the para substitution with ﬂuorine (–F), chlorine (–Cl), and bromine (–Br) atoms results in an electrophilic activation in compounds B3 (ω = 1.14 eV), B7 (ω = 1.32 eV), and B8 (ω = 1.33 eV). The highest activation effect is achieved by EW carbonyl (–CHO) substitution, in compound B6 (ω = 2.10 eV). In this series, the electrophilic deactivation was caused by ER groups as found, for example, with the methyl substituting –CH3 in compound B2 (ω = 1.05 eV). In line with that, the substitution by a stronger ER group such as (–t-Bu) results in a higher electrophilic deactivation, as found for compound B12 (ω = 0.92 eV). As in single-substituted molecules, a low electrophilicity index ω has been correlated with good nucleophiles [25]. It is expected that the more favorable azide/alkyne zw-type 32CA reactions take place when both regents are located at the extreme of Figure2 (i.e., good electrophilic azides with good nucleophilic alkyne, or vice versa). The global values of electrophilicity indexes ω for both azides and alkynes series for the ground state of the substituting agents as well as the Hammett substituent constants σp are listed in Table1. The utility of a reactivity scale has been clearly illustrated by Mayr et al. [26,27]. Such a reactivity scale should be able to address fundamental questions concerning reaction feasibility, intramolecular selectivity, and other important reactivity aspects.

Table 1. Electronic chemical potential (µ), chemical hardness (η), global electrophilicity (ω), in eV, a Hammett constants σp , and the logarithm of the global electrophilicity ratio (ω/ωH).

a Compound R µ η ω σp Log(ω/ωH) A1 H −3.62 5.14 1.27 0.00 0.000 A2 Me −3.48 5.03 1.21 −0.17 −0.019 A3 MeO −3.29 4.76 1.13 −0.27 −0.046 A4 Br −3.75 5.01 1.42 0.23 0.048 A5 F −3.67 5.03 1.34 0.06 0.025 A6 Cl −3.78 5.03 1.42 0.23 0.052 A7 COOH −4.82 4.79 1.79 0.45 0.152 A8 COOMe −4.05 4.82 1.71 0.45 0.130 A9 COMe −4.16 4.65 1.86 0.50 0.169 A10 tert-butyl −3.46 5.03 1.19 −0.20 −0.020 A11 CONH2 −3.97 4.93 1.60 0.36 0.103 A12 CN −4.33 4.82 1.94 0.66 0.187 B1 H −3.51 5.52 1.13 0.00 0.000 B2 Me −3.37 5.39 1.06 −0.17 −0.028 B3 F −3.54 5.47 1.14 0.06 0.003 B4 COOMe −4.11 4.84 1.74 0.45 0.187 B5 PhO −3.24 5.12 1.03 −0.03 −0.042 B6 CHO −4.41 4.63 2.10 0.42 0.269 B7 Br −3.73 5.22 1.33 0.23 0.070 B8 Cl −3.75 5.28 1.32 0.23 0.067 B9 COOH −4.22 4.87 1.82 0.45 0.206 B10 COMe −4.22 4.71 1.90 0.50 0.225 B11 CN −4.38 4.90 1.97 0.66 0.241 B12 tert-butyl −3.35 6.07 0.92 −0.20 −0.089 a Hammett substituent constants σp obtained from reference [20].

Figures3 and4 show a positive slope in the relationship between the Hammett constants σp of para-substituents in the azide/alkyne derivatives and the global electrophilicity index ω. It should be noted that the para position is the best one that leads to the activation of the azide and carbon–carbon triple bond groups and then to a nice correlation ω = f (σp), by comparison with the ortho- and meta-positions. Molecules 2016, 21, 1434 6 of 8 Molecules 2016, 21, 1434 6 of 8 takingtaking intointo accountaccount thethe catalystcatalyst used,used, particularlyparticularly underunder thethe clickclick regimeregime ofof 32CA32CA reactions,reactions, andand evaluatingevaluating the the global global electrophilicity electrophilicity of of both both substrat substrateses at at a a more more realistic realistic stage stage of of the the reaction—namely, reaction—namely, thethe transition transition state state (TS). (TS). The The electrophilicity electrophilicity scale scale correctly correctly accounts accounts for for the the electrophilic electrophilic activation/ activation/ deactivationdeactivation effects effects promoted promoted by by th thee substituents substituents in in the the ground ground state state of of the the electrophiles electrophiles involved involved in in 32CA32CA reactions. reactions. Indeed, Indeed, it it is is proven proven that that the the EW EW su substituentsbstituents increase increase the the global global electrophilicity electrophilicity of of thethe reagent reagent (either (either azide azide or or alkyne), alkyne), unlike unlike ER ER subs substituents,tituents, which which behave behave o oppositely.ppositely. This This behavior behavior isis due due to to the the great great activation activation of of the the azide, azide, and and al alkyne’skyne’s carbon–carbon carbon–carbon triple triple bond bond function function promoted promoted byby electronicelectronic resonanceresonance effectseffects ofof thethe EWEW substitusubstituents,ents, insteadinstead ofof thethe greatgreat stabilizationstabilization andand thenthen deactivationdeactivation promotedpromoted byby thethe ERER groupsgroups inin ththee alkynealkyne andand azideazide derivatives.derivatives. InIn lightlight ofof thethe above-mentionedabove-mentioned results, results, it it appears appears that that the the 32CA 32CA reaction reaction of of a a 4-substitued 4-substitued phenyl phenyl azide azide with with an an activating EW substituent to a 4-substituted phenyl alkyne with a deactivating ER group is more Moleculesactivating2016 EW, 21, 1434substituent to a 4-substituted phenyl alkyne with a deactivating ER group is more6 of 9 favorable,favorable, and and may may lead lead to to a a fast fast and and quantitative quantitative reaction, reaction, and and vice-versa. vice-versa.

CN 22 CN COMeCOMe COOHCOOH 1.81.8

COOMeCOOMe 1.61.6 CONH2CONH2 (eV) Br , Cl N

(eV) Br , Cl N N ω 1.4 N ω 1.4 F N F N H tButBu MeMe H 1.21.2 R R MeOMeO 11 -0.3-0.3 -0.1 -0.1 0.1 0.1 0.3 0.3 0.5 0.5 0.7 0.7 σ σpp Figure 3. Plot of the global electrophilicity ω versus the Hammett constants for para substituents in the FigureFigure 3. Plot of the global electrophilicity ω versus the Hammett constants for parapara substituentssubstituents inin thethe azide series. The value of the regression coefficient for the least-squares fit to a linear plot is R2 = 0.96. azideazide series. The value of of the the regression regression coeffici coefﬁcientent for for the the least-squares least-squares fit ﬁt to to a alinear linear plot plot is is RR2 =2 0.96.= 0.96.

2.12.1 COMeCOMe COOHCOOH CNCN 1.71.7 COOMeCOOMe

1.3 BrBr (eV) 1.3 Cl (eV) H Cl ω H ω F MeMe F PHO 0.9 PHO 0.9 R tButBu R

0.50.5 -0.25-0.25 -0.05 -0.05 0.15 0.15 0.35 0.35 0.55 0.55 0.75 0.75 σ σpp FigureFigure 4. 4. Plot Plot of of the the global global ω ω electrophilicity electrophilicity against against the the Hammett Hammett constants constants for for para para substituents substituents in in the the Figure 4. Plot of the global ω electrophilicity against the Hammett constants for para substituents2 in the alkynealkyne series. series. The The value value of of the the regression regression coefficient coefficient for for the the least-squares least-squares fit fit to to a a linear linear plot plot is is R R 2= = 0.95. 0.95. alkyne series. The value of the regression coefﬁcient for the least-squares ﬁt to a linear plot is R2 = 0.95.

The resulting regression equations of the logarithm of the global electrophilicity ratio (ω/ωH) versus the Hammett substituent constants σp of the substituted and unsubstituted molecules at the ground state for the same series of azides and alkynes, evaluated at the DFT/6-31G(d) level are also represented in Figures S1 and S2 (Supplementary Materials), obeying Equations (3) and (4), respectively.

Log (ω/ωH) = 0.26 σp + 0.02 (3)

Log (ω/ωH) = 0.40 σp − 0.01 (4) The two plots represented in Figures2 and3, as well as those represented in Figures S1 and S2, conﬁrm the existence of good linear relationships between both variable parameters, namely the Molecules 2016, 21, 1434 7 of 9

global electrophilicity ω descriptor of reactivity and the Hammett substituent constants σp of the series of azides and alkynes involved in 32CA reactions. However, some improvements can still be made by taking into account the catalyst used, particularly under the click regime of 32CA reactions, and evaluating the global electrophilicity of both substrates at a more realistic stage of the reaction—namely, the transition state (TS). The electrophilicity scale correctly accounts for the electrophilic activation/deactivation effects promoted by the substituents in the ground state of the electrophiles involved in 32CA reactions. Indeed, it is proven that the EW substituents increase the global electrophilicity of the reagent (either azide or alkyne), unlike ER substituents, which behave oppositely. This behavior is due to the great activation of the azide, and alkyne’s carbon–carbon triple bond function promoted by electronic resonance effects of the EW substituents, instead of the great stabilization and then deactivation promoted by the ER groups in the alkyne and azide derivatives. In light of the above-mentioned results, it appears that the 32CA reaction of a 4-substitued phenyl azide with an activating EW substituent to a 4-substituted phenyl alkyne with a deactivating ER group is more favorable, and may lead to a fast and quantitative reaction, and vice-versa.

3. Computational Details All chemical structures discussed in this study are depicted in Figure1. They were optimized at the B3LYP/6-31G(d) level of theory using the Gaussian 09 suite of programs [28]. The global electrophilicity index, ω [22], which measures the stabilization in energy when the system acquires an additional electronic charge ∆N for the environment, is given by the following expression, ω = µ2/2η in terms of the electronic chemical potential (µ) and the chemical hardness (η). Both quantities may be approached in terms of the one-electron energies of the frontier molecular orbital HOMO and LUMO, and εH and εL as µ = (εH + εL)/2 and η = (εL − εH) respectively [23]. Although absolute values of the reactivity indices can change with the computational level, functionals, and bass sets, the relative position of the compounds in the corresponding scales does not modify. So, we have selected the B3LYP/6-31G(d) level used in most of the scales of the reactivity indices [14,29].

4. Conclusions In conclusion, the linear correlation between the global electrophilicity indices ω and its logarithm for a series of para-substituted phenyl azide and para-substituted phenyl alkyne compounds participating in 32CA reactions exhibit a high correlation coefﬁcient with the experimental Hammett substituent constants σp. The reactivity of both azide and alkyne derivatives is promoted by the electronic withdrawing and releasing effects of the substituents, leading to their stabilization or destabilization. A theoretical scale of the global electrophilicity ω of the two series of azides and alkynes considered in this study by using the global electrophilicity index ω is nicely described for the ﬁrst time.

Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/ 11/1434/s1. Acknowledgments: This work was supported by the Université Cadi Ayyad (Morocco), the Spanish Ministerio de Economia y Competitividad (Projects CTQ2013-448449and CTQ2013-45646-P) and the Generalitat Valenciana (ISIC/2012/002). Author Contributions: H.B.E.A., H.A. and S.-E.S conceived and designed the idea and the related computational work; H.B.E.A. and H.A. performed the computational works; H.B.E.A., M.J., L.R.D. and S.-E.S analyzed the data and wrote the paper; M.L.E.I.M. participated in the discussion of the results. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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