2-Aminobenzothiazole-Containing Copper(II) Complex As Catalyst in Click Chemistry: an Experimental and Theoretical Study

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Article 2-Aminobenzothiazole-Containing Copper(II) Complex as Catalyst in Click Chemistry: An Experimental and Theoretical Study

Lahoucine Bahsis 1,2,* , Meryem Hrimla 2 , Hicham Ben El Ayouchia 2 , Hafid Anane 2 , Miguel Julve 3 and Salah-Eddine Stiriba 2,3,* 1 Département de Chimie, Faculté des Sciences d’El Jadida, Université Chouaïb Doukkali, B.P.:20, El Jadida 24000, Morocco 2 Laboratoire de Chimie Analytique et Moléculaire/LCAM, Faculté Polydisciplinaire de Safi, Université Cadi Ayyad, Safi 46030, Morocco; [email protected] (M.H.); [email protected] (H.B.); ananehafi[email protected] (H.A.) 3 Instituto de Ciencia Molecular/ICMol, Universidad de Valencia, C/Catedrático José Beltrán 2, Paterna, 46980 Valencia, Spain; [email protected] * Correspondence: [email protected] (L.B.); [email protected] (S.-E.S.)

Received: 21 June 2020; Accepted: 7 July 2020; Published: 11 July 2020

Abstract: The reaction of copper(II) acetate with the 2-aminobenzothiazole (abt) heterocycle aﬀords the new copper(II) complex of formula [Cu(abt)2(OOCCH3)2](1) in a straightforward manner. Compound 1 served as a precatalyst for azide/alkyne cycloaddition reactions (CuAAC) in water, leading to 1,4-disubstituted-1,2,3-triazole derivatives in a regioselective manner and with excellent yields at room temperature. The main advantages of the coordination of such a heterocyclic ligand in 1 are its strong σ-donating ability (N-Cu), nontoxicity and biological properties. In addition, the click chemistry reaction conditions using 1 allow the formation of a great variety of 1,2,3-triazole-based heterocyclic compounds that make this protocol potentially relevant from biological and sustainable viewpoints. A molecular electron density theory (MEDT) study was performed by using density functional theory (DFT) calculations at the B3LYP/6-31G(d,p) (LANL2DZ for Cu) level to understand the observed regioselectivity in the CuAAC reaction. The intramolecular nature of this reaction accounts for the regioselective formation of the 1,4-regioisomeric triazole derivatives. The ionic nature of the starting copper-acetylide precludes any type of covalent interaction throughout the reaction, as supported by the electron localization function (ELF) topological analysis, reaﬃrming the zwitterionic-type (zw-type) mechanism of the copper(I)/aminobenzothiazole-catalysed azide-alkyne cycloaddition reactions.

Keywords: 2-aminobenzothiazole; click chemistry; CuAAC; MEDT; regioselectivity; ELF

1. Introduction Triazole-containing heterocycles have found many applications in several disciplines, such as medicine, biology and materials science [1]. In general, these compounds are prepared through azide-alkyne cycloaddition (AAC) reactions [2,3]. Indeed, the non-catalyzed [3 + 2] cycloaddition (32CA) reaction, also known as “Huisgen’s 1,3-dipolar cycloaddition”, between azides and alkynes is characterized by low rates and small yields at room temperature, due to the high kinetic barrier of the reaction [4,5], as well as the formation of two isomers, that is, 1,4- and 1,5-disubstituted 1,2,3-triazoles. Later, the discovery by the groups of Meldal [6] and Sharpless [7] that copper(I) is capable of accelerating the 32CA reaction of azides and alkynes with high regioselectivity, to aﬀord the 1,4-disubstituted 1,2,3-triazole isomer under mild conditions, led to a breakthrough of such

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disubstituted 1,2,3-triazole isomer under mild conditions, led to a breakthrough of such a acycloaddition cycloaddition process. process. Since Since then, then, the the copper- copper-catalyzedcatalyzed azide-alkyne azide-alkyne cycloaddition (CuAAC) reactionreaction has has become become the the most most representative representative click click reaction reaction in the in panorama the panorama of click of chemistry click chemistry due to dueits mild to its conditions mild conditions and vast and applications, vast applications, in particular in particular in life in sciences life sciences [8–11]. [8 –11However,]. However, the thethermodynamic thermodynamic instabilityinstability of copper(I), of copper(I), as well as well as its as easy its easy oxidation oxidation to copper(II), to copper(II), have have led ledto the to thesearch search for suitable for suitable stabilizing stabilizing ligands ligands for Cu(I) for Cu(I)ion. Consequently, ion. Consequently, the formation the formation of the active of the Lewis- active Lewis-acidacid copper(I) copper(I) species species is becoming is becoming crucial crucial in deve in developingloping CuAAC CuAAC reactions reactions in in terms terms of of stability stability and activity [12[12].]. A A variety variety of homogeneousof homogeneous catalytic catalyti systemsc systems were reported were reported for the click for of the 1,4-disubstituted click of 1,4- 1,2,3-triazolesdisubstituted 1,2,3-triazoles [13–17]. In this [13–17]. regard, In several this regard, polydentate several ligandspolydentate containing ligands nitrogen containing atoms nitrogen have beenatoms used have to been thermodynamically used to thermodynamically stabilize copper stabilize ions againstcopper destabilizingions against destabilizing reactants found reactants in the reactionfound in medium. the reaction Some of thesemedium. interesting Some ligandsof these include interesting the tris-(benzyltriazolylmethyl)amine ligands include the tris- (TBTA)(benzyltriazolylmethyl)amine [18], dipicolinate [19], tris(triazolyl)methanol(TBTA) [18], dipicolinate (TBTM) [19], tris(triazolyl)methanol [20], 2-pyrrolecarbaldiminato (TBTM) [21 [20],] and 2- crowdedpyrrolecarbaldiminato tetradentate tris(2-dioctadecylaminoethyl)amine [21] and crowded tetradentate tris(2-dioctadecylaminoethyl)amine [22]. [22]. InspiredInspired byby Nature’sNature’s strategy,strategy, thethe useuse ofof ligandsligands withwith biologicalbiological activitiesactivities cancan broadenbroaden thethe CuAAC applications.applications. ManyMany heterocyclicheterocyclic nuclei, nuclei, such such as as benzothiazole, benzothiazole, have have been been recently recently reviewed reviewed as antimicrobialas antimicrobial agents agents [23 [23,24],24] and and 2-aminobenzothiazole 2-aminobenzothiazole derivatives derivatives were were reported reported with with aa varietyvariety ofof biological applicationsapplications [[25,26].25,26]. TheThe 2-aminobezothiazole2-aminobezothiazole ligand ligand (abt) (abt) contains contains sulfur sulfur and and nitrogen nitrogen in in a ring,a ring, an exocyclican exocyclic nitrogen nitrogen and π -electrons,and π-electrons, giving thegiving ligand the a highligand coordination a high coordination ability. Its coordination ability. Its tocoordination the metal center to the via metal the nitrogen center via atom the of nitrogen the ring occurs atom inof mostthe ring of the occurs reported in most crystal of structuresthe reported [27, 28crystal]. It is structures worth noting [27,28]. that It the is typeworth of noting complexes that havethe type been of widely comple studiedxes have as been they exhibitwidely interestingstudied as biologicalthey exhibit and interesting photophysical biological properties and photophysical [29–31]. properties [29–31]. Having in mindmind thethe aboveabove facts,facts, we presentpresent herehere thethe synthesissynthesis ofof aa Cu(II)-abtCu(II)-abt complexcomplex inin ethanolethanol/water/water and thethe studystudy ofof itsits catalyticcatalytic potentialpotential forfor thethe clickclick ofof 1,4-disubstituted-1,2,3-triazole1,4-disubstituted-1,2,3-triazole compoundscompounds viavia azide-alkyneazide-alkyne cycloadditioncycloaddition reactionsreactions inin waterwater atat roomroom temperature.temperature. AA theoreticaltheoretical studystudy byby the MEDT method and ELF topological analysisanalysis isis also carried out to explain the mechanism and intermediatesintermediates species that participateparticipate in thisthis chemicalchemical process.process. It deserves to be noted thatthat thethe regioselectiveregioselective clickclick ofof 1,2,3-triazoles1,2,3-triazoles is performed in absence of any reducing agent or additive bases, whilewhile thethe catalystcatalyst isis foundfound toto bebe highlyhighly activeactive atat lowerlower loadings.loadings.

2. Results and Discussion

The copper(II)-abtcopper(II)-abt complexcomplex ofof formulaformula [Cu(abt)[Cu(abt)22(OOCCH(OOCCH3))22]]( (11)) was was simply prepared by thethe addition ofof an an aqueous aqueous solution solution of copper(II) of copper(II) acetate ac toetate a methanolic to a methanolic solution ofsolution abt at room of abt temperature at room (Schemetemperature1). Green (Scheme crystals 1). Green of 1 were crystals grown of 1 fromwerethe grown resulting from solution.the resulting solution.

SchemeScheme 1.1. Schematic illustration of the synthesis of 11..

The optimizedoptimized structure of 1 withwith thethe atomatom numberingnumbering ofof thethe non-carbonnon-carbon atoms is shownshown inin Figure1 1.. Bond Bond distances distances and and angles angles of of the the complex complex1 1are are summarized summarized in in Table Table1. The1. The copper(II) copper(II) ion ion in 1inis 1 six-coordinateis six-coordinate with with two twotrans trans-positioned-positioned nitrogen nitrogen atoms atoms from from to to abt abt molecules molecules andand fourfour oxygenoxygen atoms ofof twotwo chelatingchelating acetateacetate ligandsligands buildingbuilding anan elongatedelongated octahedraloctahedral CuN CuN22OO44 environment.environment. Each acetate ligand in 1 adopts an asymmetrical didentate coordination, with one short (1.981 and 1.980 Å forfor Cu1-O1Cu1-O1 andand Cu1-O4,Cu1-O4, respectively)respectively) andand oneone longlong (2.554 Å for Cu1-O2 and Cu1-O3) copper-oxygen bond lengths.lengths. The Cu-NCu-Nabtabt bondbond distances distances [2.130 [2.130 Å Å for for Cu-N5 Cu-N5 and and Cu-N6, Cu-N6, respectively] respectively] are somewhat shorter than the longest copper to oxygen bonds. The value of the N5-Cu-N6 bond angle (179.9°) is Catalysts 2020, 10, 776 3 of 17

Catalysts 2020, 10, x FOR PEER REVIEW 3 of 19 shorter than the longest copper to oxygen bonds. The value of the N5-Cu-N6 bond angle (179.9◦) is veryvery close close to to linearity. linearity. These These ﬁndings findings are in are agreement in agreement with the with crystallographic the crystallographic data of this data compound, of this whosecompound, single-crystal whose single-crystal X-ray structure X-ray was structure reported was by Dojerreported et al. by in Dojer 2019 et [28 al.]. in 2019 [28].

Figure 1. Optimized structures of 1 at the B3LYP/6-31G(d,p) (LANL2DZ for Cu) level. Figure 1. Optimized structures of 1 at the B3LYP/6-31G(d,p) (LANL2DZ for Cu) level. Table 1. Some calculated and experimental structural parameters of 1. Table 1. Some calculated and experimental structural parameters of 1. Calculated Experimental a Calculated Experimental a Bond Lengths (Å) Bond Lengths (Å) Cu1—O1Cu1—O1 1.9811.981 1.961 1.961 Cu1—O2 2.554 2.548 Cu1—O2Cu1—O4 1.9802.554 1.961 2.548 Cu1—O4Cu1—O3 2.5541.980 2.548 1.961 Cu1—O3Cu1—N5 2.1302.554 2.018 2.548 Cu1—N5Cu1—N6 2.1302.130 2.018 2.018 BondCu1—N6 Angles (◦) 2.130 2.018 BondO4—Cu1—N5 Angles (°) 89.668 88.715 O4—Cu1—N5O3—Cu1—N5 92.64089.668 91.256 88.715 O4—Cu1—N6 90.332 91.285 O3—Cu1—N5 92.640 91.256 O3—Cu1—N6 87.359 88.743 O4—Cu1—N6O1—Cu1—N5 90.33290.332 91.285 91.285 O3—Cu1—N6O2—Cu1—N5 87.35987.359 88.744 88.743 O1—Cu1—N5O1—Cu1—N6 89.66890.332 88.714 91.285 O2—Cu1—N5O2—Cu1—N6 92.64087.359 91.256 88.744 N5—Cu1—N6 179.999 180.000 O1—Cu1—N6 89.668 88.714 a Values from ref [28]. O2—Cu1—N6 92.640 91.256 N5—Cu1—N6 179.999 180.000 2.1. Catalytic Studies a Values from ref [28].

2.1. CatalyticThe as-prepared Studies copper(II) complex was then tested in 32CA reactions between a variety of azides and terminal alkyne derivatives. The reaction between benzyl azide (1a) and phenylacetylene (2a) in the waterThe atas-prepared room temperature copper(II) was complex chosen aswas the then model test reactioned in 32CA and it reactions was performed between under a variety a variety of ofazides conditions and terminal (see Scheme alkyne2 and derivatives. Table2). The controlledreaction between experiments benzyl showed azide (1a that) and the phenylacetylene 32CA reaction does(2a) in not the take water place at inroom the temperature absence of the was catalyst chosen (entry as the 1). model It was reaction observed and that it was the performed use of copper(II) under a variety of conditions (see Scheme 2 and Table 2). The controlled experiments showed that the 32CA reaction does not take place in the absence of the catalyst (entry 1). It was observed that the use of copper(II) acetate only in water as a reaction medium led to poor yields of the corresponding 1,2,3- Catalysts 2020, 10, 776 4 of 17

Catalysts 2020, 10, x FOR PEER REVIEW 4 of 19 acetate only in water as a reaction medium led to poor yields of the corresponding 1,2,3-triazole ca. 40%triazole after ca. stirring 40% after for stirring 24 h at room for 24 temperature h at room temperature (entry 2). Interestingly, (entry 2). Interestingly, the corresponding the corresponding 1,4-triazole was1,4-triazole formed was in highformed yields in high (98%) yields within (98%) 12 hwithin by using 12 h 5 by mol% using of 51 mol%and waterof 1 and as solventwater as (entry solvent 5) compared(entry 5) compared with copper(II) with copper(II) sulphate in sulphate the presence in the of pr 2-abtesence as aof ligand 2-abt as (entry a ligand 4). The (entry catalyst 4). The loading catalyst for 1loadingcould be for further 1 could reduced be further to 2mol%, reduced aﬀ ordingto 2 mol%, an excellent affording yield anof excellent the corresponding yield of the 1,4-disubstituted corresponding 1,2,3-triazole1,4-disubstituted (92%) 1,2,3-triazole in water within (92%) 4 h atin roomwater temperature within 4 h (Tableat room2, entry temperature 7). Further, (Table several 2, entry solvents 7). wereFurther, investigated several solvents for the modelwere investigated reaction (Table for2 ,th entriese model 9–14). reaction Hexane, (Table ethanol, 2, entries acetonitrile, 9–14). Hexane, acetone andethanol, toluene acetonitrile, as solvents acetone gave poor and totoluene moderate as solvents reaction gave yields poor (40–67%, to moderate respectively). reaction The yields ethanol (40–67%,/water solventrespectively). mixture The also ethanol/water gave a moderate solvent yield mixture ca. 62% alsowith gave2 amol% moderate of the yield catalyst. ca. 62% As with can be2 mol% seen inof Tablethe catalyst.2, the maximum As can be yield seen ofin theTable triazole 2, the productmaximum was yield obtained of the with triazole 2 mol% product of the was catalyst obtained in water with medium2 mol% of at the room catalyst temperature. in water medium at room temperature.

Scheme 2. Azide-alkyne cycloaddition in the presence of complex 1.

Table 2. Optimization of reaction conditions for complex 1-mediated benzyl azide-phenylacetylene Tablecycloaddition 2. Optimization a. of reaction conditions for complex 1-mediated benzyl azide-phenylacetylene cycloaddition a. Entry Catalyst Catalyst Loading (mol%) Solvent Time (h) Yield (%) b b 1 Entryabt Catalyst Catalyst Loading - (mol%) Solvent Water Time (h) 24 Yield (%) Traces 2 1Cu(OAc) abt2 5 - Water Water 2424 Traces 40 2 Cu(OAc) 5 Water 24 40 3 CuSO4 2 5 Water 24 30 3 CuSO 4 5 Water 24 30 c 4 CuSO4 5 Water 12 c 85 4 CuSO4 5 Water 12 85 5 5 1 1 5 5 WaterWater 1212 98 98 6 6 1 1 3 3 WaterWater 44 96 96 7 7 1 1 2 2 WaterWater 44 92 92 8 1 1 Water 4 74 8 1 1 Water 4 74 9 1 2 Hexane 4 40 9 10 1 1 2 2 TolueneHexane 44 51 40 10 11 1 1 2 2 EthanolToluene 44 67 51 11 12 1 1 2 2 AcetonitrileEthanol 44 64 67 12 13 1 1 2 2Acetonitrile Acetone 44 56 64 14 1 2 Ethanol/water 4 62 13 1 2 Acetone 4 56 a Reaction conditions: benzyl azide (0.6 mmol), phenylacetylene (0.5 mmol), solvent (3 mL) and catalyst. b Isolated 14 yields. c Using1 2-abt as ligand. 2 Ethanol/water 4 62 a Reaction conditions: benzyl azide (0.6 mmol), phenylacetylene (0.5 mmol), solvent (3 mL) and b c Basedcatalyst. on Isolated the above-optimized yields. Using reaction2-abt as ligand. conditions, the scope of our method was explored by using different para-substituted phenyl acetylenes as well as different benzyl and alkyl azides. The 32CA Based on the above-optimized reaction conditions, the scope of our method was explored by reactions progressed effectively to afford the corresponding triazole derivatives in a short time for using different para-substituted phenyl acetylenes as well as different benzyl and alkyl azides. The all cases and the corresponding 1,2,3-triazoles were isolated in good to excellent yields (see Table3). 32CA reactions progressed effectively to afford the corresponding triazole derivatives in a short time Interestingly, the clicking reaction between alkyne-containing polycyclic and benzyl or alkyl azides for all cases and the corresponding 1,2,3-triazoles were isolated in good to excellent yields (see Table was conducted and the corresponding 1,2,3-triazoles were obtained in excellent yields by precipitation 3). Interestingly, the clicking reaction between alkyne-containing polycyclic and benzyl or alkyl in water and without need for any further purification by conventional methods (see Table3, entries azides was conducted and the corresponding 1,2,3-triazoles were obtained in excellent yields by 11 and 12). The products were fully characterized by 1H and 13C NMR spectroscopy and mass precipitation in water and without need for any further purification by conventional methods (see spectrometry (see Supplementary Materials for details). Table 3, entries 11 and 12). The products were fully characterized by 1H and 13C NMR spectroscopy and mass spectrometry (see Supplementary Materials for details).

Catalysts 2020, 10, x FOR PEER REVIEW 5 of 19 CatalystsCatalysts 2020 2020, 10, ,10 x ,FOR x FOR PEER PEER REVIEW REVIEW 5 of5 of19 19 CatalystsCatalystsCatalysts 2020 2020 2020, 10, ,10 x10 ,FOR ,x x FOR FOR PEER PEER PEER REVIEW REVIEW REVIEW 5 of55 of 19of 1919 Catalysts 2020, 10, x FOR TablePEER REVIEW 3. Click of 1,2,3-triazoles in the presence of complex 1a. 5 of 19 CatalystsCatalysts 2020 2020, 10,, 10x FOR, x FOR PEER PEERTable REVIEW REVIEW 3. Click of 1,2,3-triazoles in the presence of complexa 1a. 5 of5 19of 19 TableTableTable 3. 3.Click 3. Click Click of of1,2,3-triazoles of 1,2,3-triazoles 1,2,3-triazoles in inthe in the thepresence presence presence of ofcomplex of complex complex 1 .1 1a.a . Catalysts 2020, 10, x FOR PEERTableTable REVIEW 3. Click 3. Click of 1,2,3-triazolesof 1,2,3-triazoles in thein the presence presence of complexof complex 1a. 1a. 5 of 19 Table 3. Click of 1,2,3-triazoles in the presence of complexa 1a. Catalysts 2020, 10, x FOR PEERTable REVIEW 3. Click of 1,2,3-triazoles in the presence of complex 1 . 5 of 19 a CatalystsCatalysts2020, 10 2020, 776, 10, x FOR PEERTable REVIEW 3. Click of 1,2,3-triazoles in the presence of complex 1 . 5 of 519 of 17 CatalystsCatalysts 2020 2020, 10,, x10 FOR, x FOR PEER PEER REVIEW REVIEW a 5 of5 19of 19 CatalystsCatalysts 2020 2020,, 10, 10,, xx, FORFORx FOR PEERPEER PEERTable REVIEWREVIEW REVIEW 3. Click of 1,2,3-triazoles in the presence of complex 1 . 5 of5 of19 19 a Catalysts 2020, 10, x FOR PEERTable REVIEW 3. Click of 1,2,3-triazoles in the presence of complex 1 . 5 of 19 a a TableTable 3.TableClick 3. Click 3. Click of of 1,2,3-triazoles 1,2,3-triazoles of 1,2,3-triazoles inin the in thepresence presence of of complex of complex complex 1aa.1 1a.. b Entry Alkyne TableTable 3. 3.Click Click of of Azide1,2,3-triazoles 1,2,3-triazoles in in the the presence Time presence (h) of of complex complexProduct 1a .1. a. Yield (%) b Entry Alkyne Azide Time (h) Producta Yieldb (%) CatalystsEntry 2020 , 10Alkyne, x FOR PEER REVIEW AzideN3 Time (h) Product Yield (%)b5b of 19 EntryEntry AlkyneAlkyne Table 3. Click of 1,2,3-triazolesAzideAzide in the presence Time Time (h)of (h) complex ProductProduct 1 . Yield Yieldb b (%) (%) EntryEntry AlkyneAlkyne AzideNAzide Time Time (h) (h) ProductProduct Yield Yield (%) (%) 1 N3 3 4 3a 92 NN3 3 b Entry Alkyne N AzideN Time (h) Producta Yield b (%) 1EntryCatalysts 1 2020Alkyne, 10, x FOR TablePEER REVIEW 3. Click of Azide1,2,3-triazoles3 3 in the presence4 Time 4 (h) of complex3aProduct3a 1 . 92 Yield92 (%) 5 of 19 Catalysts11 2020, 10, x FOR PEER REVIEW 44 3a3a 9292 b 5 of 19 1 Entry1 Alkyne N AzideN3 4 Time4 (h) 3aProduct 3a 92 Yield 92 (%) N3 N a 1 1 Table 3. ClickN ofN 1,2,3-triazoles3 in the4 presence4 of complex3a 3a 1 . 92 92 b Entry2 Alkyne Azide3NN Time4 (h) Product3b a Yield94 (%) Table 3. Click ofN 1,2,3-triazolesN3 3 in the presence of complex 1 . CatalystsEntry21 2020Alkyne, 10, x FOR PEER REVIEW 3Azide3 Time4 (h) Product3b3a Yield9492 b (%)5 of 19 Catalysts2 22 2020, 10, x FOR PEER REVIEW N3 4 44 3b3b 3b 94 94 94 5 of 19 2 N 4 3b 94 b Entry2 Alkyne NAzide3N 3 Time4 (h) Product3b Yield94 bbb (%)b Entry1 EntryEntry Alkyne AlkyneAlkyne AzideAzide 3 3 Azide Time4 Time Time (h) (h) (h) Product3a Product Product Yield 92 Yieldb (%)(%)b (%) EntryEntry AlkyneAlkyne Azide AzideN Time Time (h) (h) ProductProduct Yield Yield (%) (%) 2 2 N N3 4 4 3b3b a 94 94 3 1 Table 3. ClickN of33NN 1,2,3-triazoles3 in the4 4 presence of complex3c3a a 1 . 9392 b Entry Alkyne Table 3. Click of AzideN1,2,3-triazoles3N33 3 in the presence Time (h) of complexProduct 1 . Yield (%) 31 23 33 N3 4 4 3c3a3b3c 9392 9493 1 331 N3 4 44 3a3c 3c3a 9293 9392 13 1 N3 N 4 44 3a3c 3a3a 929392 3 N3 3 4 3c 93 b Entry Alkyne AzideN3 Time (h) Product Yield (%) 12 N 4 3a3b 9294 3 3N3 4 3c 93 3 2 NN3 N 4 4 3c3b 9394 O N333NN 3 4 3 N33N3N3 4 4 3d3c 9293 b 2 Entry Alkyne N Azide3 3 4 Time (h) 3b Product 94 Yield (%) 12 2 2 O N3 N3 44 44 3a3b 3b 3b 929494 94 24 Entry24 AlkyneO OO 3 Azide 4 Time44 (h) 3b3dProduct3b3d 9492 Yield9492 b (%) 44 O O NN3 3 44 3d3d 9292 34 4 N N3 4 4 3d3c 3d 9293 92 2 3N 4 3b 94 31 N3 3N 44 3c3a 9392 O O N33NN 3 4 4 N33 33 4 4 3d3d 92 92 3 31 N 4 44 3c 3c3a 939392 23 34 Entry3 AlkyneO N3 Azide 44 44 Time4 (h) 3b3c3c3d Product3c 94939392 Yield93 b b (%) Entry3 Alkyne AzideN3 Time4 (h) Product3c Yield93 (%) 3NN3 F 5 N3NN3 8 3e 86 3 O N N 3 33 4 3c 93 4 5 33NN33 3 F F 4 8 3d3e 9286 5 2 N3 FF 8 4 3e 3b 86 94 1 4551 O N3 N F F 4 4884 3a 3d3e 3e3a 9286 8692 5 245 N 3NN33 8 48 3e3b3d 3e 869492 86 3 N33 3 4 3c 93 4 O O F 4 3d 92 45 54 O O N NN3 F 48 84 3d3e 3e 3d 9286 8692 4 4 3 N3 4 4 3d3d 9292 N33N 3 F 4 53 O 3 4 84 3d3e 3c 9286 93 5 2 F N3N3 F 84 3e3b 86 94 26 3 N 3NN 48 4 3b3f3c 947993 N3N 3 3 5 6 F F 3 N3 3 F F 8 8 3e3f 8679 46 66 FF O F F 48 88 3d3f3f 3f 927979 79 6 5 F F N3 NN F FF 8 8 3f3e 7986 6 N 33N N33 8 3f 79 N3 N3 3 5 F F F 8 3e 86 5 665 F NN3 F FF 8 888 3e 3f 3f3e 7986 7986 536 54 3 O O N3 3 F 84 84 4 3e3c3f3e 3d3c 86937986 9293 F OO F 5 46 O F 8 48 3e3d3f 869279 OOO N3 7 O O N 3 8 3g 84 3N 6 F O N33 F 8 3f 79 7 OO N3 N3 8 3g 84 57 77 O OO N3 NN33 F 8 88 3e3g3g 3g 868484 84 76 F O O N3 NN F 8 3g3f 8479 7 7 O N33N 33 8 8 3g 3g 84 84 4 O O N3 N3 3 4 3d 92 4 F F F F 4 3d 92 6 76 F F O O O N NN3 F F 8 88 3f 3g3f 79 8479 67 65 F N3 3 F F 8 88 3f3g3f 3e 798479 86 O 7 O O O N3 F 8 3g 84 Catalysts68 5 2020, 10F , x FOROO PEER REVIEW N3 F 8 8 3f3h3e 797886 5 of 19 O O O N N3 8 8 O O N33NN 8 8 3h3h 7878 7 888 O O O O N3 NN33 8 88 3g 3h3h 3h 788478 78 68 8 F O O O N33 33 F 8 8 3f3h 3h 7978 78 O O TableO 3. Click of 1,2,3-triazolesN3 in the presence of complex 1a. 7 OOO F 8 3g 84 5 85 O O N N3 F 8 88 3e 3h3e 86 7886 87 O O O N3 N 8 3h3g 7884 7 7 OS O N33N 3 8 8 3g 3g 84 84 79 76 F O N3N3 F 8 88 3g3i3g 3f 848184 79 8 O S N3 8 3h 78 9 F SO N3 3 F 8 3i 81 97 969 9 O O SS 3NN33 8 88 8 3i3g 3i3f 3i 3i 81847981 81 9 O S S N3 N 8 3i 81 8 9 N3 3 8 8 3h 3i 78 81 O O O O S S N NN3N3 79 89 OO O OO N33 3 8 88 3g3i3h 3i 848178 81 O OO F O S N3N O F 6108 9 68 F O O O OO N3N N3 3 F 88 8 8 3f3j3h 3i 3f3h 79897881 7978 8 8 N3 3 8 8 3h3h 7878 10 O O OO N NN3 O O 8 3j 89 1010 7 O OO O OO N3NN3 O O 8 88 3j 3j 3g 89 84 8 1010 O O OS O N3 N33 O O 8 88 3h3j 3j 7889 89 109 7 10 O 3N3 3 8 88 3j3i3g 3j 898184 89 O O b Entry9 AlkyneO SO AzideN3 Time8 (h) Product3i Yield81 (%) O O N3 N O O 10 10 O O N 3 3 8 8 3j 3j 89 89 8 S SO N33 N 8 3h 78 9 9 S OO N33N3 3 O 8 8 3i 3i 81 81 911 910 O O S S OO N3NNN33 812 88 3i3k3i 3j 81908189 9 O O OO N 3 3 8 3i 81 11 O OO O N 3 NN33 12 3k 90 7111 11 7 S O N33 4812 12 8 3a3g3k3k 3g 92849090 84 9 1111 O N3 8 1212 3i 3k3k 8190 90 1011 8 O O O OO N3 N O 128 8 3k3j 3h 9089 78 11 O O O N3N 3 12 3k 90 8 O O OO O 3 8 3h 78 10 OO O N3 O 8 3j 89 11 S O N N3 12 3k 90 911 O O O O O O N33 O 812 3i3k 8190 1210 O O OOO O N3 N O O 128 3l3j 8889 1012 10 O O OO O N33N 3 O O 8 128 3j 3l 3j 8889 89 210 101211 O N3N33 O O 48 812 3b3j3j 3k3l 9489899088 12 O O N3NN O O 12 3l 88 1212 O S OO N NN33 O O 1212 3l3l 8888 81210 1298 O O O OO N33N 33 812 1288 3h3l3j 3l3i3h 788988 888178 11 a Reaction conditions:S azidesO O (0.6 mmol),N3 alkynes (0.5 mmol), 12 water (3 mL),3k 2 mol% of catalyst,90 and a 9 OO N3 O 8 3i 81 Reaction12a conditions:O O azidesO (0.6 mmol), alkynesNN3 3 (0.5 mmol),O water (312 mL), 2 mol% of catalyst,3l and room88 temperature. 1211 a Reaction conditions:b O azidesO O (0.6 mmol),N3 N alkynes (0.5 mmol),1212 water (3 mL),3l3k 2 mol% of catalyst,8890 and b roomReactiona a temperature. conditions:O IsolatedO azidesOO O yields.(0.6 mmol), N3N 3alkynes O(0.5 mmol), water (3 mL), 2 mol% of catalyst, and 10 a ReactionReaction conditions: conditions: azides azides (0.6 (0.6 mmol), mmol),3 N3 alkynes alkynes O(0.5 (0.5 mmol), mmol),8 water water (3 (3 mL),3j mL), 2 2 mol% mol% of of 89catalyst, catalyst, and and Isolated3 12Reaction a yields. conditions:O b azides (0.6 mmol),3 alkynes (0.5 mmol), 4 12 water (3 mL),3c3l 2 mol% of catalyst,9388 and 11 11room Reaction temperature. conditions:b OIsolatedO azidesO yields. (0.6 mmol), alkynes (0.5 mmol),12 12 water (3 3kmL), 3k 2 mol% of90 catalyst, 90 and 1111 room temperature.O Isolatedb b O O yields. N3 1212 3k3k 9090 roomaroom temperature. temperature.b bIsolated OIsolatedO yields. yields. rooma9 roomReaction temperature. temperature. conditions:S Isolated SOIsolated azides yields. yields.(0.6 Nmmol), N3 alkynes O (0.5 mmol),8 water (3 mL),3i 2 mol% of catalyst,81 and 2.2.91211 Comparison 10Reaction conditions: of ComplexO azides 1 with (0.6 other mmol), Catalysts33 N3 alkynes (0.5 O mmol),812 8 water (3 mL),3i3k3l 23j mol% of catalyst,819088 89 and a O b OOOb N O 2.2. Comparison1012room roomReaction temperature. oftemperature. Complex conditions: IsolatedO1 Isolatedwith azidesO yields. other (0.6yields. Catalystsmmol),N3 3 alkynes (0.5 mmol),812 water (3 mL),3j3l 2 mol% of catalyst,8988 and 2.2.2.2. Comparison Comparison of ofComplex ComplexO O 1 Owith1 with other otherN Catalysts3 Catalysts 2.2.2.2. Comparison Comparison of of Complex Complexb 1 1 with with other otherN Catalysts Catalysts O 2.2.11122.2. Comparison Comparisonroom temperature. of ComplexofO ComplexO Isolated 1 with 1 with yields.other other NCatalysts 3 NCatalysts3 O O 1212 3k3l 9088 412 a12 O O OO O N 3N O O 412 12 3d3l 3l 9288 88 1212 Reaction conditions: azidesOOO (0.6 mmol),3 3 alkynes (0.5 mmol),1212 water (3 mL),3l3l 2 mol% of catalyst,8888 and In ordera to prove the effiOciency of theN complex3 1-mediated azide-alkyne cycloaddition reaction, a 2.2.2.2. Comparison Comparison of Complexof Complexb 1 with 1 with other other NCatalysts Catalysts O 12 roomReaction temperature. conditions: IsolatedOO azides yields. (0.6 mmol), 3N N alkynes (0.5 O mmol),12 water (3 mL),3l 2 mol% of catalyst,88 and 10 10 O O N3 3 3 O 8 8 3j 3j 89 89 comparison2.2.a11 ComparisonReaction a of this conditions: catalyst of ComplexOb azides with 1O with other(0.6 othermmol), copper(II) Catalysts alkynes complexes(0.5 mmol),12 water for the(3 mL), reaction 3k2 mol% of of phenylacetylene catalyst,90 and (1a) aa Reactionaroom Reaction temperature. conditions: conditions: azidesIsolated azides (0.6 yields. (0.6 mmol), mmol), alkynes alkynes (0.5 (0.5 mmol), mmol), water water (3 mL), (3 mL), 2 mol% 2 mol% of catalyst, of catalyst, and and 11Reaction Reaction conditions: conditions: azides azidesO (0.6 (0.6 mmol), mmol), alkynes alkynes (0.5 (0.5 mmol), mmol),12 water water (3 (3mL), mL),3k 2 mol% 2 mol% of of catalyst, catalyst,90 and and 12 room temperature. b Isolatedb yields. N3 O 12 3l 88 and benzylaroom azideroom temperature. temperature. (2a) to abb ffIsolatedb ord OIsolated 1,4-disubstituted yields. yields. 1,2,3-triazoles was done (see Scheme2 and Table4). 2.2. ComparisonroomReactionroom temperature. temperature. conditions: of Complex IsolatedIsolated Isolatedazides 1O with yields.yields.(0.6 yields.other mmol), N Catalysts 3 alkynes (0.5 mmol), water (3 mL), 2 mol% of catalyst, and O O N It was2.2. observedroom Comparison temperature. that of the Complex presenceb IsolatedO 1 with yields. of other a N reducing3 Catalysts3 agent,F high temperatures and inert atmosphere are 5 12 N3 O 8 12 3e 3l 86 88 2.2.112.2. Comparison a 11Reaction Comparison conditions: of Complex of Complex azides 1 with O1 (0.6with other mmol), other Catalysts Catalysts alkynes (0.5 mmol),12 12 water (3 mL),3k 23k mol% of catalyst,90 90 and 2.2. Comparison of Complex O 1 withO other CatalystsN3 O 1 requisites2.2.2.2. Comparison12 Comparison to operate of of someComplex Complex catalytic 1 Owith1 with other systems. other Catalysts Catalysts Importantly, complex12 occurs3l in an effective88 manner for room temperature. b Isolated yields. the synthesis2.2. Comparisona of 1,2,3-triazole, of Complex 1 workingwith other Catalysts in air and at room temperature in water, followed by an easy Reaction conditions:O Oazides (0.6 mmol), alkynes (0.5 mmol), water (3 mL), 2 mol% of catalyst, and a Reaction conditions:b azides (0.6 mmol), alkynes (0.5 mmol), water (3 mL), 2 mol% of catalyst, and work-up protocolroom temperature. for the final Isolated separation yields.N3 ofN the product.O 2.2.12 Comparison 12 of Complex 1 withO other NCatalysts3 3 O 12 12 3l 3l 88 88 room temperature.F b IsolatedO yields. F 6 8 3f 79

2.2.a Comparisona Reaction conditions: of Complex azides 1 with (0.6 other mmol), Catalysts alkynes (0.5 mmol), water (3 mL), 2 mol% of catalyst, and 2.2. ComparisonReaction conditions: of Complex azides 1 with (0.6 othermmol), Catalysts alkynes (0.5 mmol), water (3 mL), 2 mol% of catalyst, and room temperature.b b Isolated yields. room temperature.O Isolated yields.

2.2.72.2. Comparison Comparison of Complex of ComplexO 1 with 1 with other other NCatalysts3 Catalysts 8 3g 84

8 N3 8 3h 78 O

9 S N3 8 3i 81

10 O N3 O 8 3j 89

O N3

11 O 12 3k 90

O N O 12 O 3 12 3l 88

a Reaction conditions: azides (0.6 mmol), alkynes (0.5 mmol), water (3 mL), 2 mol% of catalyst, and room temperature. b Isolated yields.

2.2. Comparison of Complex 1 with other Catalysts Catalysts 2020, 10, 776 6 of 17

Table4. Comparison of the catalytic performance of 1 with other literature reports in CuAAC reactions a.

Cu Entry Loading Additives Solvent T (◦C) Time (h) Yield (%) Ref. (mol %)

Complex 1 2 - H2O r.t. 4 92 This work Cu(NO ) 3H O 20 - H O r.t. 20 13 [32] 3 2· 2 2 Cu(II)-tren 0.2 - n-Octane r.t. 24 84 [33] Cu(II)-MBHTM 1 Sodium-ascorbate DMSO/H2O r.t. 4 94 [34] Cu(II)-BPPA 0.2 Sodium-ascorbate MeOH/N2 r.t. 16 99 [35] [Cu(II)(Phox)2] 1.4 - H2O 70 12 75 [36] [(C2H5)4N]4[V8Cu2O24] 0.34 - H2O 70 4 88 [37] a Tren = Tris(2-dioctadecylaminoethyl)amine; MBHTM = (1-(4-methoxybenzyl)-1-H-1,2,3-triazol-4-yl) methanol; BPPA = bipyridine pyrazole amine; Phox: 2-(20-hydroxyphenyl)-2-oxazoline.

2.3. Mechanistic Studies Based on the reported mechanism [38–44], the reaction mechanism for the synthesis of 1,4-disubstituted 1,2,3-triazoles in the presence of 1 is shown in Scheme3. Firstly, the catalytic copper(I) species arises through the reduction of the copper(II) complex by the terminal alkyne via the oxidative alkyne homocoupling process [45]. Then, the in-situ coordination of the terminal alkyne to the copper(I) species leads to the dinuclear acetylide-copper intermediate. The reaction of this dinuclear complex and organic azide conducts to a six-membered ring, forming the triazolide ring intermediate. Finally, this intermediate easily provides the 1,4-disubstituted 1,2,3-triazole under slightly acidic Catalystsconditions 2020, and 10, x regeneratesFOR PEER REVIEW the catalyst (Scheme3). 7 of 19

Scheme 3. Generally accepted mechanism of CuAAC catalyzed by complex 1 (L = abt).abt).

2.3.1. MEDT MEDT Study Study Recently, the molecular electron density theory [46] [46] (MEDT) was proved to be a powerful tool for the the theoretical theoretical understanding understanding of of 32CA 32CA reactions reactions allowing allowing the the explanation explanation of the of thereactivity reactivity of the of simplestthe simplest three-atom-components three-atom-components (TACs) (TACs) towards towards ethylene, ethylene, based based on on their their respective respective electronic structure [47]. [47]. Accordingly, Accordingly, the CuAAC reaction catalyzed by the Cu(I)-abt complex was investigated investigated through the the MEDT MEDT study study (Scheme (Scheme 4).4). The The terminal terminal al alkynekyne is isfirstly ﬁrstly metallated metallated with with copper(I) copper(I) via via an easyan easy deprotonation deprotonation of ofthe the alkyne, alkyne, yielding yielding a abinu binuclearclear copper(I)-acetylide copper(I)-acetylide species species (see (see Scheme Scheme 44).). After coordination of the azide to the copper(I)-acetylide, the cycloaddition subsequently affords the corresponding 1,2,3-triazole compounds. Herein, the reaction path associated to the CuAAC reaction of propyne (4) with methyl azide (5) yielding 1,4-dimethyl-1,2,3-triazole (6) is investigated within MEDT through DFT methods at level B3LYP/6-31G(d,p) (LANL2DZ for Cu) (see Scheme 4).

Catalysts 2020, 10, 776 7 of 17

After coordination of the azide to the copper(I)-acetylide, the cycloaddition subsequently aﬀords the correspondingCatalysts 2020, 10, x 1,2,3-triazole FOR PEER REVIEW compounds. Herein, the reaction path associated to the CuAAC reaction8 of 19 of propyne (4) with methyl azide (5) yielding 1,4-dimethyl-1,2,3-triazole (6) is investigated within MEDT through DFT methods at level B3LYP/6-31G(d,p) (LANL2DZ for Cu) (see Scheme4).

Scheme 4. CuAAC reaction between 4 and 5 catalyzed by Cu(I)-abt complex.

Azide components (TACs) participate in the zw-type 32CA with high activation energies [48], [48], whichwhich cancan be be favored favored through through a more a more polar processpolar process by the increaseby the ofincrease the electrophilic of the electrophilic and nucleophilic and characternucleophilic of thecharacter reagents. of the Consequently, reagents. Consequently, the 32CA reaction the 32CA catalyzed reaction by Cu(I)-abtcatalyzed complexby Cu(I)-abt was analyzedcomplex was using analyzed the global using reactivity the global indices reactivity deﬁned indices within defined Conceptual within DFT Conceptual (CDFT) [49 DFT,50] and(CDFT) the results[49,50] and are shownthe results in Table are shown5. Compound in Table 5.4 Compoundwas found 4 as was a marginal found as electrophile a marginal electrophile and a marginal and nucleophilea marginal nucleophile within the electrophilicity within the electrophilicity [51] and nucleophilicity [51] and nucleophilicity scales [52], a scales feature [52], that a explainsfeature that the non-participationexplains the non-participation of 4 in polar cycloaddition of 4 in polar reactions. cycloaddition In contrast, reactions. compound In contrast,5 is astrong compound electrophile 5 is a (strongω = 1.22 electrophile eV) and a moderate(ω = 1.22 eV) nucleophile and a moderate (N = 2.15 nucleophile eV). However, (N = the2.15 coordination eV). However, of 4 theto copper(I)-abtcoordination increasesof 4 to copper(I)-abt the values of increases the ω and theN valuesindexes of to the 1.14 ω andand 3.11N indexes eV being to thus1.14 classiﬁedand 3.11 aseV bothbeing strong thus electrophileclassified as andboth nucleophile. strong electrophile Therefore, and the nu CuAACcleophile. reactions Therefore, of 5 thewith CuAACAc are reactions polar reactions of 5 with due Ac to theare strongpolar reactions nucleophilic due (toAc the) and strong the strongnucleophilic electrophilic (Ac) and (5) the characters strong electrophilic (see Table5). (5) characters (see Table 5). Table 5. Global reactivity indices (in eV) of the reagents involved in CuAAC reactions catalyzed by Cu(I)-abt.Table 5. Global reactivity indices (in eV) of the reagents involved in CuAAC reactions catalyzed by Cu(I)-abt. Species µ η ω N

SpeciesPropyne (4) 2.68 8.71µ 0.42η 2.06 ω N − PropyneMethyl (4 azide) (5) 3.87 6.16−2.68 1.228.71 2.15 0.42 2.06 − Cu(I)-acetylide (Ac) 3.42 5.17 1.14 3.11 Methyl azide (5) − −3.87 6.16 1.22 2.15 Cu(I)-acetylide (Ac) −3.42 5.17 1.14 3.11 Recently, a lot of studies of polar 32CA reactions have shown that the analysis of the electrophilic and nucleophilicRecently, a lot Parr of studies functions of allowspolar 32CA us to reactions explain the have experimentally shown that the observed analysis regioselectivity of the electrophilic [53]. + Thus,and nucleophilic the electrophilic Parr functions Pk and nucleophilicallows us to Pexplaik− Parrn the functions experimentally at 4, 5 and observedAc were regioselectivity analyzed (see + - Figure[53]. Thus,2). The the electrophilic analysis of the Pk nucleophilicand nucleophilic P k− PParrk Parr functions functions at at4 4indicates, 5 and Ac that were the analyzed terminal (seeC5 - carbonFigure 2). is theThe most analysis nucleophilic of the nucleophilic center of thisPk Parr molecule functions (Pk −at= 4 0.54),indicates although that the the terminalC4 carbon C5 carbon is also - + nucleophilicallyis the most nucleophilic activated center (Pk− = of0.36). this Onmolecule the other (Pk hand,= 0.54), the although analysis ofthe the C4 electrophilic carbon is also Pk Parrnucleophilically functions at activated5 reveals that(Pk- = the 0.36). terminal On the N1 other nitrogen hand, is thethe mostanalysis electrophilic of the electrophilic center of this Pk+ TACParr functions+ at 5 reveals that the terminal N1 nitrogen is the most electrophilic center of this TAC (Pk+ = Catalysts(Pk = 20200.56,). 10 These, x FOR resultsPEER REVIEW suggest that along with a polar 32CA reaction, the 1,5-regioisomer will9 of be19 the0.56). main These reaction results product. suggest However, that along the with very a low polar polar 32CA character reaction, of this the non-catalyzed1,5-regioisomer AAC will reaction be the accountsmain reaction for its product. low regioselectivity. However, the very low polar character of this non-catalyzed AAC reaction accounts for its low regioselectivity.

++ - FigureFigure 2.2. ElectrophilicElectrophilic PPkk (red)(red) and and nucleophilic nucleophilic P Pk −(blue)(blue) Parr Parr functions functions at at 4,4 5, 5andand AcAc (L(L = =abt).abt).

Figure 3 shows electrophilic Pk+ and nucleophilic Pk- Parr functions of 4, 5 and Ac. The analysis of the nucleophilic Pk- Parr functions at 4 indicates that the terminal carbon (C5) is the most nucleophilic center of this molecule (Pk- = 0.57), while the most electrophilic center of 5 is the terminal N1 nitrogen (Pk+ = 0.57). Thus, the very low polar character of this non-catalyzed azide-alkyne cycloaddition reaction accounts for its low regioselectivity. The electrophilic Parr functions at Ac characterize the copper atom interacting with the abt ligand as the most electrophilic center (Pk+ = 0.44), while the nucleophilic Parr functions at 5 points out the substituted N3 nitrogen atom as the most nucleophilic center (Pk- = 0.64). These results show that the most favorable interaction is the Cu- N bond, conducting to the formation of a reactive complex (RC) (vide infra) and the increase in the electrophilicity value of the alkyne makes the use of the abt ligand in the CuAAC reactions more favorable.

Catalysts 2020, 10, 776 8 of 17

+ Figure3 shows electrophilic P k and nucleophilic Pk− Parr functions of 4, 5 and Ac. The analysis of the nucleophilic Pk− Parr functions at 4 indicates that the terminal carbon (C5) is the most nucleophilic center of this molecule (Pk− = 0.57), while the most electrophilic center of 5 is the terminal N1 nitrogen + (Pk = 0.57). Thus, the very low polar character of this non-catalyzed azide-alkyne cycloaddition reaction accounts for its low regioselectivity. The electrophilic Parr functions at Ac characterize the + copper atom interacting with the abt ligand as the most electrophilic center (Pk = 0.44), while the nucleophilic Parr functions at 5 points out the substituted N3 nitrogen atom as the most nucleophilic centerCatalysts (P 2020k− ,= 100.64)., x FOR These PEER REVIEW resultsshow that the most favorable interaction is the Cu-N bond, conducting10 of 19 to the formation of a reactive complex (RC) (vide infra) and the increase in the electrophilicity value of the alkyne makes the use of the abt ligand in the CuAAC reactions more favorable.

Figure 3. Optimized geometries of the stationary points involved in the dinuclear CuAAC reaction of AcFigurewith 3.5 .Optimized geometries of the stationary points involved in the dinuclear CuAAC reaction of Ac with 5. In the ﬁrst step of the CuAAC mechanism, 4 binds to a copper(I) cation as a π-ligand. This coordinationIn the first step increases of the the CuAAC acidity mechanism, of the terminal 4 binds alkyne, to favoringa copper(I) the cation formation as a of π mononuclear-ligand. This Cu(I)-acetylidecoordination increases upon deprotonation. the acidity of Then, the theterminal coordination alkyne, of favoring the C5 carbon the formation atom to a secondof mononuclear copper(I) centerCu(I)-acetylide leads to the upon dinuclear deprotonation.Ac species. Subsequently,theThen, the coordination coordination of the of C55 to carbon a copper(I) atom cation to a in secondAc via itscopper(I) N3 azide center nitrogen leads allows to the the dinuclear formation Ac of species. the reactive Subsequently, complex (RC the). coordination This intermediate of 5 to is thea copper(I) starting pointcation for in the Ac stepwise via its sequencesN3 azide representednitrogen allows in Figure the3 formation. This step isof highly the reactive exothermic complex at 17.31 (RC kcal). /Thismol. Theintermediate computed is barrierthe starting for the point formation for the ofstepwise the ﬁrst sequences N1-C4 single represented bondvia in FigureTS1 is 3. 2.66 This kcal step/mol, is ahighly value exothermic which is smallerat 17.31 thankcal/mol. the barrierThe computed for the barrier non-catalyzed for the formation reaction (ca.of the 30.3 first kcal N1-C4/mol) single [54]. Subsequently,bond via TS1 is the 2.66 formation kcal/mol,of a value the intermediate which is smaller complex than (theIC) barrier is exothermic for the non-catalyzed by ca. 13.74 kcal reaction/mol. From(ca. 30.3 this kcal/mol) intermediate, [54]. Subsequently, the barrier for the the formation ring contraction of the intermediate leading to the complex Cu(I)-triazolyl (IC) is exothermic derivative isby 11.17 ca. 13.74 kcal /kcal/mol.mol (TS2 From). Finally, this intermediate, the formation the of thebarrierAT derivativefor the ring is contraction exothermic leading by 112.14 to the kcal Cu(I)-/mol. Thesetriazolyl results derivative allow usis to11.17 explain kcal/mol the easy (TS2 formation). Finally, ofthe the formation corresponding of the triazolesAT derivative in water. is exothermic Moreover, by 112.14 kcal/mol. These results allow us to explain the easy formation of the corresponding triazoles in water. Moreover, the use of abt as ligand for copper(I) in the CuAAC process shows that this heterocyclic ligand causes a decrease of the energy barrier of about 3–6 kcal/mol in the aqueous phase, by comparison with our previously reported catalytic system using the water molecule as the only ligand [55].

2.3.2. ELF Topological Analysis In order to get more understanding of the CuAAC reactions catalyzed by Cu(I)-abt, all intermediates in the reaction between Ac and 5 were characterized by a topological analysis of the Catalysts 2020, 10, 776 9 of 17 the use of abt as ligand for copper(I) in the CuAAC process shows that this heterocyclic ligand causes a decrease of the energy barrier of about 3–6 kcal/mol in the aqueous phase, by comparison with our previously reported catalytic system using the water molecule as the only ligand [55]. Catalysts 2020, 10, x FOR PEER REVIEW 11 of 19 2.3.2. ELF Topological Analysis ELF [56]. The results are given in Table 6 and the ELF-based Lewis representations are illustrated in FigureIn order4. to get more understanding of the CuAAC reactions catalyzed by Cu(I)-abt, all intermediates in the reaction between Ac and 5 were characterized by a topological analysis of the ELF [56]. The results are givenTable in 6. Table ELF 6valence and the basin ELF-based populations Lewis in the representations average number are of illustrated electrons (e) in of Figure the intermediates4. involved in the CuAAC reaction of Ac with 5 Table 6. ELF valence basin populations in the average number of electrons (e) of the intermediates involved inStructures the CuAAC reaction5 of Ac Acwith 5. RC TS1 Cl TS2 AT V(N1,N2) 1.74 - 1.80 2.32 2.00 1.89 1.85 V′(N1,N2)Structures 2.22 5- Ac1.83 RC TS1- Cl- TS2 AT- - V(N2) V(N1,N2) - 1.74 - - - 1.80 2.32 2.60 2.002.84 1.89 1.852.82 3.34 V(N2,N3)V 0(N1,N2)2.51 2.22 - - 2.51 1.83 1.65 - -1.78 -2.01 - 1.58 V(N2) - - - 2.60 2.84 2.82 3.34 V(C4,C5) - 2.38 2.41 1.96 3.35 2.90 3.09 V(N2,N3) 2.51 - 2.51 1.65 1.78 2.01 1.58 V′(C4,C5)V(C4,C5) - 2.39 - 2.382.34 2.41 1.961.98 3.35- 2.90 3.09- - V(N3) V0(C4,C5) 3.53 - - 2.39 3.58 2.34 1.981.99 -1.85 -2.99 - 0.79 V (N3) V(N3) - 3.53 - - - 3.58 1.99 1.63 1.85 1.67 2.99 0.79 - 0.76 V(C4) V0(N3)------1.630.39 1.67- - 0.76- - V(C4) - - - 0.39 - - - V(C5) V(C5) - 3.37 - 3.373.45 3.45 2.342.34 3.003.00 2.21 3.212.21 3.21 V(N1,C4)V(N1,C4) ------1.97 1.97 2.17 2.112.17 2.11 V(N3,C5)V(N3,C5) ------2.20 - 2.20

FigureFigure 4.4. ELF-based LewisLewis structuresstructures ofof thethe intermediatesintermediates involvedinvolvedin inthe theCuAAC CuAACreaction reaction of ofAc Acwith with 55(L (L= = abt).abt).

The topological analysis of the ELF of 5 is characterized by the presence of two V(N1,N2) and The topological analysis of the ELF of 5 is characterized by the presence of two V(N1,N2) and V’(N1,N2) disynaptic basins integrating a total population of 4.00 e, two V(N1) and V(N3) monosynaptic V’(N1,N2) disynaptic basins integrating a total population of 4.00 e, two V(N1) and V(N3) basins integrating 3.94 and 3.53 e and one V(N2,N3) disynaptic basin integrating 2.51 e. Accordingly, monosynaptic basins integrating 3.94 and 3.53 e and one V(N2,N3) disynaptic basin integrating 2.51 Lewis’ bonding model for 5 is identified by one N1-N2 double bond, a N2-N3 single bond and two lone e. Accordingly, Lewis’ bonding model for 5 is identified by one N1-N2 double bond, a N2-N3 single pairs at the N1 and N3 azide-nitrogen atoms (see Table6 and Figure4), confirming that 5 participates as bond and two lone pairs at the N1 and N3 azide-nitrogen atoms (see Table 6 and Figure 4), confirming zwitterionic TAC in the 32CA reactions [57]. The electronic structure of Ac shows the presence of one that 5 participates as zwitterionic TAC in the 32CA reactions [57]. The electronic structure of Ac V(C5) monosynaptic basin, with a high electron population of 3.37 e and two V(C4,C5) and V’(C4,C5) shows the presence of one V(C5) monosynaptic basin, with a high electron population of 3.37 e and two V(C4,C5) and V’(C4,C5) disynaptic basins, with a total population of 4.75 e. These valence basins can be attributed to the C4–C5 double bond and the C5 carbanionic center, reveals the ionic nature of Ac (see Table 6 and Figure 4). The ELF analysis for the reactive complex (RC) shows non-appreciable topological changes with respect to the separated reagents. For example, a similar behavior is located at the azide framework for the V(N2,N3) disynaptic basin and the total population of the V(N1,N2) and V′(N1,N2) disynaptic Catalysts 2020, 10, 776 10 of 17 disynaptic basins, with a total population of 4.75 e. These valence basins can be attributed to the C4–C5 double bond and the C5 carbanionic center, reveals the ionic nature of Ac (see Table6 and Figure4). The ELF analysis for the reactive complex (RC) shows non-appreciable topological changes with respect to the separated reagents. For example, a similar behavior is located at the azide framework for the V(N2,N3) disynaptic basin and the total population of the V(N1,N2) and V0(N1,N2) disynaptic basins increases by an equivalent amount. A similar behavior is found for the two V(N1) and V(N3) monosynaptic basins. The V(C4,C5) and V’(C4,C5) disynaptic basins in the alkyne framework are slightly depopulated by 0.03 and 0.05 e, respectively. Several changes occur in the azide framework at TS1, while a new V(N2) monosynaptic basin, associated with the N2 nitrogen non-bonding electron density, was created, integrating 2.60 e. The total population of the V(N2,N3) disynaptic basin, as well as that of the two V(N1,N2) and V0(N1,N2) disynaptic basins, strongly decreased by 0.86 and 1.64 e, respectively. In addition, the V(N3) monosynaptic basin split into two V(N3) and V0(N3) monosynaptic basins integrating 1.99 and 1.63 e, although their total population only increased by 0.04 e. Otherwise, the population of the V(N1) monosynaptic basin more markedly increased to 3.62 e, but the N1 nitrogen non-bonding electron density remained characterized by one single V(N1) monosynaptic basin. A strong depopulation of the two V(C4,C5) and V0(C4,C5) disynaptic basins was achieved for the acetylide framework by a total of 0.81 e. The V(C5) monosynaptic basin reached 2.34 e and a new V(C4) monosynaptic basin was created integrating 0.39 e, which can be attributed to a C4 pseudoradical center. At CI, a new V(N1,C4) disynaptic basin is observed integrating 1.97 e and the disappearance of the V(C4) monosynaptic basin located at TS1, which is related to the new N1-C4 single bond by sharing part of the electron population of the V(N1) monosynaptic basin and that of the V(C4) one (Table6). At TS2, the most relevant topological change is the merging of the two V(N3) and V0(N3) monosynaptic basins into one single V(N3) monosynaptic basin 3.50 e, with respect to the ELF topological characterization of CI. In addition, a slight depopulation of 0.13 e towards the V(N2,N3) disynaptic basin, increasing to 2.01 e also occurred. It was also found that the population of the V(C5) monosynaptic basin, which was decreased at TS1, has decreased to 3.00 e. Finally, at AT, a new disynaptic basin V(N3,C5) was observed integrating 2.20 e. The creation of this disynaptic basin, which is associated to the new N3-C5 single bond, was accompanied by a notable depopulation of the V(N3) by 2.20 e and the increasing of the total population of V(C5) monosynaptic basins by 1.00 e. These results suggest that the creation of the V(N3,C5) disynaptic basin took place by displacement of part of the electron populations of both V(N3) to V(C5) monosynaptic basins. On the other hand, the two V(N1,N2) and V(N2,N3) disynaptic basins in the azide framework have decreased to less than 2 e and the V(N2) monosynaptic basins integrates 3.34 e. All these results show that the ionic nature of all chemical intermediates rules out any covalent interaction involving the copper(I)-complexes, as supported by the ELF topological analysis, reaffirming the zw-type mechanism of the Cu(I)-abt complex catalyzed AAC reactions.

3. Materials and Methods

3.1. Materials All chemicals and reagents employed in this work were purchased from Sigma Aldrich and all organic solvents were used without additional puriﬁcation. The reactions were monitored by thin-layer chromatography (TLC) carried out on commercial glass-backed TLC plates (aluminum plates coated with silica gel 60 F254, 0.25 mm thickness, Merck). FT-IR spectra were performed on a FTIR spectrophotometer (FT-IR Nicolet 5700, ThermoFischer, Madrid, Spain). The NMR spectra were recorded on a BRUKER DRX-300 AVANCE spectrometer in CDCl3 using the tetramethylsilane (TMS) as an internal standard. Catalysts 2020, 10, 776 11 of 17

3.2. Synthesis of [Cu(abt)2(OOCCH3)2] (1)

In a typical experiment, 0.10 g of abt was dissolved in 10 mL of methanol then 5 mL of Cu(OAc)2 water solution (2 10 2 M) was added slowly under continuous stirring at room temperature. × − The solution took a green color during the addition of the copper(II) acetate solution. A precipitate was formed and the mixture was stirred for 12 h at room temperature. The solid was ﬁltered, washed with water and dried at 40 ◦C overnight to aﬀord complex 1 as a green solid (Yield: 88%). FT-IR data 1 (KBr/cm− ): 3396 [ν(NH2)], 1623 [ν(C=N)], 1342 [ν(C-O)], 1592 and 1529 [ν(C=N)ar + ν(C=C)ar], 1467 and 1435 [ν(C-N)}, 508 [ν(Cu-O)] and 689 [ν(Cu-N)].

3.3. General Procedure for the CuAAC Reaction Azides (0.6 mmol), alkynes (0.5 mmol) and complex 1 (2 mol%) were mixed with water (3 mL) and stirred at room temperature. After completion of the catalytic cycloaddition reaction, as confirmed by TLC analysis, the reaction mixture was diluted with diethyl ether and extracted three times. The combined organic layers were then concentrated under reduced pressure to give the corresponding triazole derivatives that were purified by simple recrystallization, if needed. The reaction mixture was stirred at room temperature and the reaction was monitored through thin layer chromatography. After completion, the reaction mixture was diluted by diethyl ether and the combined organic layers were then concentrated under vacuum to give the corresponding triazole derivatives and, if required, the products were purified by recrystallization.

3.3.1. Synthesis of 1-Benzyl-4-phenyl-1H-1,2,3-triazole (3a)

1 White solid. H NMR (300 MHz, CDCl3, δ ppm): 5.59 (s, 2H, CH2), 7.31–7.44 (m, 8H, CHar), 13 7.69 (s, 1H, CHtriazole), 7.81–7.83(s, 2H, CHar). C NMR (75MHz, CDCl3, δ ppm): 54.6 (CH2), 120.0 (CHar), 126.1 (CHar), 128.5 (2 CHar), 128.6 (2 CHar), 129.2 (Car), 129.6 (CH ), 131.0 (Car), × × triazole 135.1 (Car). HRMS (ESI) [M + H] + found m/z = 236.1183. Calcd value for C15H13N3 = 236.1182.

3.3.2. Synthesis of 1- Benzyl-4-p-Tolyl-1H-1,2,3-Triazole (3b)

1 White solid. H NMR (300 MHz, CDCl3, δ ppm): 2.38 (s, 3H, CH3), 5.59 (s, 2H, CH2), 7.22–7.42 13 (m, 7H, CHar), 7.66 (s, 1H, CHtriazole), 7.70–7.73 (d, 2H, CHar). C NMR (75MHz, CDCl3, δ ppm): 21.7 (CH3), 54.6 (CH2), 126.0 (CHar), 128.2 (2 CHar), 128.5 (2 CHar), 129.2 (2 CHar), 129.6 (2 CHar), × × × + × 129.9 (Car), 131.7 (CHtriazole), 135.2 (2Car), 138.4 (Ctriazole). HRMS (ESI) [M + H] found m/z = 250.1339. Calcd value for C16H15N3 = 250.1339.

3.3.3. Synthesis of 1-(4-Methylbenzyl)-4-Phenyl-1H-1,2,3-Triazole (3c)

1 White solid. H NMR (300 MHz, CDCl3, δ ppm): 2.28 (s, 3H, CH3); 5.46 (s, 2H, CH2); 7.13–7.35 13 (m, 7H, CHar); 7.57 (s, 1H, CHtriazole); 7.71–7.73 (d, 2H, CHar). C NMR (75 MHz, CDCl3, δ ppm): 21.2 (CH3); 54.1 (CH2); 125.70 (2CHar); 128.2 (3 CHar); 129.8 (4 CHar); 129.8 (Car); 130.6 (CHtriazole); × + × 131.6 (Car); 138.8 (Car); 148.7 (Ctriazole). HRMS (ESI) [M + H] found m/z = 250.1345. Calcd value for C16H15N3 = 250.1344.

3.3.4. Synthesis of 1-Benzyl-4-(Phenoxymethyl)-1H-1,2,3-Triazole (3d)

1 White solid. H NMR (300 MHz, CDCl3, δ ppm): 5.21 (s, 2H, CH2); 5.55 (s, 2H,OCH2); 6.96–7.00 13 (m, 3H, CHar ); 7.28–7.41 (m, 7H, CHar ); 7.57 (s, 1H, CHtriazole ). C NMR (75 MHz, CDCl3, δ ppm): 54.7 (CH2); 62.5 (CH2); 115.2 (2*CHar); 116.2 (CHar); 121.7 (CHtriazole); 128.6 (CHar); 129.22 (2CHar); + 129.5 (4CHar); 129.9 (Car); 134.9 (Ctriazole); 158.6 (Car). HRMS (ESI) [M + H] found m/z = 266.1289. Calcd value for C16H15N3O = 266.1288. Catalysts 2020, 10, 776 12 of 17

3.3.5. Synthesis of 1-(4-Fluoro-Benzyl)-4-p-Tolyl-1H-[1,2,3]Triazole (3e)

1 White solid. H NMR (300 MHz, CDCl3, δ ppm): 2.39 (s, 3H, CH3); 5.55 (s, 2H, CH2); 7.06–7.17 (m, 2H, CHar); 7.22–7.29 (m, 2H, CHar); 7.39–7.45 (m, 2H, CHar); 7.64 (s, 1H, CHtriazole); 13 7.69–7.72 (m, 2H, CHar). C NMR (75 MHz, CDCl3, δ ppm): 21.3 (CH3); 53.5 (CH2); 116.0 (CHar); 116.3 (CHar); 119.1 (CHar); 125.62 (CHar); 127.63 (Car); 129.52 (2 CHar); 129.88 (CHar); 129.99 (CHar); × + 130.62 (CHtriazole); 130.7 (2CHar); 138.1 (2Car); 148.5 (Ctriazole); 161.2 (Car-F). HRMS (ESI) [M + H] found m/z = 268.1249. Calcd value for C16H14FN3 = 268.1245.

3.3.6. Synthesis of 1-(4-Fluorobenzyl)-4-(4-Fluorophenyl)-1H-1,2,3-Triazole (3f)

1 White solid. H NMR (300 MHz, CDCl3, δ ppm): 5.55 (s, 2H, CH2); 7.08–7.15 (m, 4H, CHar); 13 7.31–7.36 (m, 2H, CHar); 7.63 (s, 1H, CHtriazole); 7.77–7.82 (m, 2H, CHar). C NMR (75 MHz, CDCl3, δ ppm): 53.6 (CH2); 115.7 (CHar); 116.0 (CHar); 116.1 (CHar); 116.4 (CHar); 119.0 (Ctriazole); 127.4 (Car); 127.5 (2 CHar); 129.9 (2 CHar); 130.0 (Car); 137.8 (CHtriazole); 161.5 (Car-F); 163.5 (Car-F). HRMS (ESI) ×+ × [M + H] found m/z = 272.0996. Calcd value for C15H11F2N3 = 272.0994.

3.3.7. Synthesis of (1-(4-Isopropylphenyl)-1H-1,2,3-Triazol-4-yl)Methyl Benzoate (3g)

1 White solid. H NMR (300 MHz, CDCl3, δ ppm): 1.29 (s, 3H, CH3); 1.31 (s, 3H, CH3); 2.95–3.04 (m, 1H, CH); 5.58 (s, 2H, CH2); 7.37–7.40 (d, 2H, CHar); 7.43–7.48 (t, 2H, CHar); 7.56–7.60 (d, 1H, 13 CHar); 7.64–7.67 (d, 2H, CHar); 8.07–8.10 (d, 2H, CHar); 8.12 (s, 1H,CHtriazole). C NMR (75 MHz, CDCl , δ ppm): 24.3 (2 CH ); 34.2 (CH); 58.5 (CH ); 121.1 (CH ); 122.7 (Car); 128.1 (2 CHar); 3 × 3 2 triazole × 128.8 (2 CHar); 130.1 (2 CHar); 130.2 (2 CHar); 133.7 (Car); 135.2 (CHar); 143.8 (Ctriazole); 150.4 (Car); × × + × 166.9 (Cester). HRMS (ESI) [M + H] found m/z = 322.1562. Calcd value for C19H19N3O2 = 322.1550.

3.3.8. Synthesis of Methyl 1-(4-Isopropylphenyl)-1H-1,2,3-Triazole-4-Carboxylate (3h)

1 White solid. H NMR (300 MHz, CDCl3, δ ppm): 1.30 (s, 3H, CH3); 1.32 (s, 3H, CH3); 2.97–3.06 (m, 1H, CH); 4.01 (s, 3H, OCH3); 7.40–7.43 (d, 2H, CHar); 7.66–7.70 (d, 2H, CHAr); 8.50 (s, 1H, CHtriazole). 13 C NMR (75 MHz, CDCl3, δ ppm): 24.2 (2*CH3); 34.3 (CH); 52.7 (OCH3); 121.3 (Car); 126.0 (2 CHar); × + 128.3 (CH ); 134.7 (2 CHar); 141.3 (C ); 151.2 (Car); 161.6 (Cester). HRMS (ESI) [M + H] triazole × triazole found m/z = 246.1239. Calcd value for C13H15N3O2 = 246.1237.

3.3.9. Synthesis of 1-(4-Isopropylphenyl)-4-(Phenylthiomethyl)-1H-1,2,3-Triazole (3i)

1 White solid. H NMR (300 MHz, CDCl3, δ ppm): 1.29 (s, 3H, CH3); 1.31 (s, 3H, CH3); 2.94–3.03 (m, 1H, CH); 4.34 (s, 2H, CH2); 7.19–7.24 (d, 1H, CHar); 7.31–7.41 (m, 6H, CHar); 7.57–7.61 (d, 2H, CHar); 7.78 (s, 1H, CH ). 13C NMR (75 MHz, CDCl , δ ppm): 24.3 (2 CH ); 29.3 (CH); 34.2 (CH ); triazole 3 × 3 2 121.0 (CHtriazole); 126.59 (CHar); 126.98 (2 CHar); 128.06 (2*CHar); 129.45 (2 CHar); 130.03 (Ctriazole); × ×+ 133.76 (Car); 134.6 (2 CHar); 135.8 (Car); 150.2 (Car). HRMS (ESI) [M + H] found m/z = 310.1373. × Calcd value for C18H19N3S = 310.1372.

3.3.10. Synthesis of (1-(4-Methoxyphenyl)-1H-1,2,3-Triazol-4-yl)Methyl Benzoate (3j)

1 White solid. H NMR (300 MHz, CDCl3, δ ppm): 3.79 (s, 3H, CH3), 5.48 (s, 2H, CH2), 6.94 (d, 1H, CHar), 6.96 (d, 1H, CHar),7.36 (t, 1H, CHar),7.47 (t, 1H, CHar), 7.49 (s, 1H, CHtriazole),7.52 (t, 1H, CHar), 13 7.54 (d, 1H, CHar), 7.56 (d, 1H, CHar), 7.58 (d, 1H, CHar),8.0 (d, 1H, CHar). C NMR (75 MHz, CDCl3, δ ppm): 55.7 (CH3), 58.1 (CH2), 114.8 (2 CHar), 122.3 (2 CHar), 128.4 (2 CHar), 129.7 (3 CHar), × × × × + 129.8 (Cq), 133.3 (CHtriazole), 136.0 (Cq), 151.3 (Cq), 160.0 (Cq), 166.6 (Ccarbonyl). HRMS (ESI) [M + H] found m/z = 310.1198. Calcd value for C17H15N3O3 = 310.1186.

3.3.11. Synthesis of Naphthalen-2-yl 1-Benzyl-1H-1,2,3-Triazole-4-Carboxylate (3k)

1 White solid. H NMR (300 MHz, CDCl3, δ ppm): 5.57 (s, 2H, CH2); 7.19 (s, 1H, CHar); 7.25–7.29 (m, 3H, CHar); 7.35–7.38 (m, 2H, CHar); 7.40–7.44 (m, 3H, CHar); 7.62 (s, 1H, CHtriazole); 7.83 (d, 2H, Catalysts 2020, 10, 776 13 of 17

13 CHar); 8.09 (s, 2H, CHar). C NMR (75MHz, CDCl3, δ ppm): 55.0 (CH3); 103.4 (CHar); 118.8 (CHar); 121.0 (CHar); 125.9 (CHar); 126.7 (2CHar); 127.8 (3 CHar); 128.1 (CHtriazole); 128.4 (2 CHar); 129.3 (Car); × × + 129.6 (CHar); 136.5 (2Car); 141.9 (Ctriazole); 147.6 (Car); 159.7 (Ccarbonyl). HRMS (ESI) [M + H] found m/z = 330.1198. Calcd value for C20H15N3O2 = 330.1237.

3.3.12. Synthesis of Naphthalen-2-yl 1-(4-Methoxyphenyl)-1H-1,2,3-Triazole-4-Carboxylate (3l)

1 White solid. H NMR (300 MHz, CDCl3, δ ppm): 3.82 (s, 3H, CH3); 6.98–7.01 (d, 2H, CHar); 7.18 (d, 1H, CHar); 7.41–7.45 (m, 1H, CHar); 7.62–7.67 (m, 4H, CHar); 7.76–7.86 (m, 3H, CHar); 8.54 (s, 1H, 13 CHtriazole). C NMR (75 MHz, CDCl3, δ ppm): 55.7 (CH3); 108.9 (CHar); 115.1 (2*CHar); 118.8 (CHar); 121.0 (CHar); 122.6 (CHar); 126.0 (CHtriazole); 126.6 (2 CHar); 126.7 (CHar); 127.9 (CHar); 129.6 (2 Car); × × + 136.5 (CHar); 142.1 (Car); 147.6 (Ctriazole); 158.6 (Car); 159.7 (Ccarbonyl); 164.1 (Car). HRMS (ESI) [M + H] found m/z = 346.1206. Calcd value for C20H15N3O3 = 346.1186.

3.4. Computational Methods All computational calculations were conducted using the Gaussian 09 program [58]. Optimized geometries were performed with B3LYP [59,60], while the LANL2DZ basis set was used for the Cu atom [61] and the 6-31G(d,p) basis set for the other atoms. Frequency calculations were performed to verify the stationary points to be real minima and each TS had only one single imaginary frequency at the same level. The solvent eﬀects were performed with water as solvent using the polarizable continuum model (CPCM). All charge distributions were calculated by natural bond orbital (NBO) analysis [62]. All distances and energies are given in Å and kcal/mol, respectively. The global electrophilicity (ω) and nucleophilicity (N) indexes were measured at the same level, and are given by the following simple expressions: ω = µ2/2η and N = E E (TCE) [63,64]. H − H The electronic chemical potential (µ) and chemical hardness (η) were approached in terms of the one-electron energies of the frontier molecular orbitals HOMO and LUMO, EH and EL, using the expressions µ = (E + E )/2 and η = (E E ), respectively. H L L − H Both the electronic chemical potential (µ) and chemical hardness (η) may be further approached in terms of the one-electron energies of the frontier molecular orbitals HOMO and LUMO, EH and EL, using the expressions µ = (E + E )/2 and η = (E E ), respectively. H L L − H Recently, Domingo et al. introduced a new local reactivity index for the Parr functions, namely, + local electrophilic (Pk ), and nucleophilic (Pk−), obtained from the analysis of the Mulliken atomic spin density (ASD) of the corresponding reagents [65]. The ELF analysis was also carried out by means of Multiwfn software [66].

4. Conclusions In summary, a copper(II) complex containing the heterocyclic 2-aminobenzothiazole (abt) as ligand was prepared and used as a precatalyst for the regioselective synthesis of the corresponding 1,4-disubstituted 1,2,3-triazole under CuAAC strict click chemistry regime. A variety of azides and alkynes were employed in the CuAAC, aﬀording the desired products, which were easily separated in excellent yields. In addition, the 32CA reaction between 5 and 4 was chosen as reaction model and the CuAAC mechanism was studied at the B3LYP/6-31G(d,p) (LANL2DZ for Cu) computational level, choosing the abt as a ligand. The experimental ﬁndings are correctly explained by means of the local reactivity indexes obtained from the Parr functions, for regioselectivity synthesis of 1,4-triazoles. The reaction of Ac and 5 follows a two-step mechanism and an easy reaction in terms of energetics, which is in good agreement with the experimental observations. Importantly, the ionic nature of the starting Ac excludes any covalent interaction involving the copper(I) species throughout the reaction, as supported by the ELF topological analysis, indicating the zw-type pathway of the mechanism of CuAAC reactions, using abt as a ligand.

Supplementary Materials: The following are available online at http://www.mdpi.com/2073-4344/10/7/776/s1. Catalysts 2020, 10, 776 14 of 17

Author Contributions: Concept and work strategy were set up by L.B. and S.-E.S.; synthetic work was performed by L.B. and M.H.; computational calculations were done by L.B. and H.B.; data analysis and interpretation of experimental and theoretical results were carried out by L.B., H.A., M.J. and S.-E.S.; the writing of the manuscript was done by L.B., M.J. and S.-E.S. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Acknowledgments: Financial support from the Spanish Ministerio de Ciencia e Innovación (MCINN) (Project CTQ 2016-75068P) is gratefully acknowledged. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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