Phosphine Complexes for the Microwave-Assisted Synthesis of 1,2,3-Triazoles

catalysts

Article The Catalytic Activity of Carbon-Supported Cu(I)-Phosphine Complexes for the Microwave-Assisted Synthesis of 1,2,3-Triazoles

Ivy L. Librando 1 , Abdallah G. Mahmoud 1,2,* ,Sónia A. C. Carabineiro 1,3,* , M. Fátima C. Guedes da Silva 1 , Carlos F. G. C. Geraldes 4,5 and Armando J. L. Pombeiro 1,6

1 Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal; [email protected] (I.L.L.); [email protected] (M.F.C.G.d.S.); [email protected] (A.J.L.P.) 2 Department of Chemistry, Faculty of Science, Helwan University, Ain Helwan, Cairo 11795, Egypt 3 LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal 4 Department of Life Sciences, Faculty of Science and Technology, Calçada Martim de Freitas, 3000-393 Coimbra, Portugal; [email protected] 5 Coimbra Chemistry Center, University of Coimbra, Rua Larga Largo D. Dinis, 3004-535 Coimbra, Portugal 6 Research Institute of Chemistry, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia * Correspondence: [email protected] (A.G.M.); [email protected] (S.A.C.C.)

Abstract: A set of Cu(I) complexes with 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo-[3.3.1]nonane (DAPTA) phosphine ligands viz. [CuX(κP-DAPTA)3](1: X = Br; 2: X = I) and [Cu(µ-X)(κP-DAPTA)2]2 Citation: Librando, I.L.; Mahmoud, (3: X = Br; 4: X = I) were immobilized on activated carbon (AC) and multi-walled carbon nanotubes A.G.; Carabineiro, S.A.C.; Guedes da (CNT), as well as on these materials after surface functionalization. The immobilized copper(I) Silva, M.F.C.; Geraldes, C.F.G.C.; complexes have shown favorable catalytic activity for the one-pot, microwave-assisted synthesis of Pombeiro, A.J.L. The Catalytic 1,2,3-triazoles via the azide-alkyne cycloaddition reaction (CuAAC). The heterogenized systems with Activity of Carbon-Supported a copper loading of only 1.5–1.6% (w/w relative to carbon), established quantitative conversions after Cu(I)-Phosphine Complexes for the 15 min, at 80 ◦C, using 0.5 mol% of catalyst loading (relative to benzyl bromide). The most efﬁcient Microwave-Assisted Synthesis of supports concerning heterogenization were CNT treated with nitric acid and NaOH, and involving 1,2,3-Triazoles. Catalysts 2021, 11, 185. complexes 2 and 4 (in the same order, 2_CNT-ox-Na and 4_CNT-ox-Na). The immobilized catalysts https://doi.org/10.3390/ can be recovered and recycled by simple workup and reused up to four consecutive cycles although catal11020185 with loss of activity.

Academic Editor: Fabio Ragaini Received: 7 January 2021 Keywords: Cu(I) complexes; phosphine; DAPTA ligands; carbon nanotubes; click chemistry; CuAAC; Accepted: 27 January 2021 triazoles; microwave Published: 31 January 2021

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- The interesting properties of 1,2,3-triazole based heterocycles have been a focus of iations. scientific interest due to their manifold potential to interact with diverse systems, not only from a synthetic point of view but also in the context of biological and pharmacological applications [1]. The triazole ring system has been shown to be compatible with many functional groups and to exhibit good stability under several reaction conditions [2]. Copyright: © 2021 by the authors. The copper catalyzed azide−alkyne cycloaddition approach (CuAAC) established Licensee MDPI, Basel, Switzerland. by Meldal [3] and Sharpless [4] constitutes the most important protocol to obtain 1,4- This article is an open access article disubstituted triazoles in a completely regioselective manner. Enormous efforts have distributed under the terms and been devoted to maximize the general efficiency of the CuAAC reaction during the last conditions of the Creative Commons two decades [5,6]. However, the presence of a significant amount of expensive copper Attribution (CC BY) license (https:// complexes in the end products remains a main challenge hampering the utilization of the creativecommons.org/licenses/by/ CuAAC reaction for large scale applications [7,8]. A way to overcome this difficulty is 4.0/).

Catalysts 2021, 11, 185. https://doi.org/10.3390/catal11020185 https://www.mdpi.com/journal/catalysts Catalysts 2021, 11, x FOR PEER REVIEW 2 of 16

Catalysts 2021, 11, 185 2 of 15 CuAAC reaction for large scale applications [7,8]. A way to overcome this difficulty is to support the catalyst on solid matrices, a method that was revealed to be effective in toachieving support more the catalyst sustainable on solid processes, matrices, by aprev methodenting that not wasonly revealed the accumulation to be effective of metal in achievingparticles, morebut also sustainable the excessive processes, use of reagen by preventingts [9–11]. not Byonly attaching the accumulation the complex ofto metala solid particles,support, butit is alsopossible the excessive to efficiently use of recover reagents and [9 –reuse11]. Byit in attaching consecutive the complex catalytic to reactions a solid support,and improve it is possible both catalytic to efficiently activity recover and stability and reuse [12–14]. it in Many consecutive solid supporting catalytic reactions matrices andhave improve been successfully both catalytic utilized activity for and catalyti stabilityc applications [12–14]. Many [15,16], solid among supporting which matrices carbon havestructures been successfullyhave been privileged utilized for due catalytic to their applications high surface [15 ,area,16], amongthermal which stability carbon and structuresporous surface have been [17,18]. privileged Commercially due to their availabl highe surface activated area, carbon thermal and stability carbon and nanotubes porous surface(CNTs)[ 17have,18]. already Commercially been applied available as activatedscaffold materials carbon and for carbon a variety nanotubes of metal-based (CNTs) havecatalysts already including been appliedcopper [19–23]. as scaffold materials for a variety of metal-based catalysts includingA significant copper [19 interest–23]. has been directed to the application of transition metal complexesA significant based interest on the hasneutral, been directedwater-soluble to the applicationand air-stable of transition 3,7-diacetyl-1,3,7-triaza-5- metal complexes basedphosphabicyclo on the neutral, [3.3.1] water-soluble nonane (DAPTA) and air-stable ligand 3,7-diacetyl-1,3,7-triaza-5-phosphabicycloin aqueous medium catalysis [24]. In this [3.3.1]context, nonane our (DAPTA)group has ligand reported in aqueous the set medium of copper(I)-DAPTA catalysis [24]. In thiscomplexes context, our[CuBr( groupκP- hasDAPTA) reported3] (1 the), [CuI( set ofκP-DAPTA) copper(I)-DAPTA3] (2), [Cu( complexesμ-Br)(κP-DAPTA) [CuBr(κP-DAPTA)2]2 (3) and3]( 1[Cu(), [CuI(μ-I)(κκP-P- DAPTA)DAPTA)3](2]22 (),4) [Cu( (Schemeµ-Br)( 1)κP-DAPTA) that demonstrated2]2 (3) and to [Cu( be efficientµ-I)(κP-DAPTA) homogeneous2]2 (4) (Schemecatalysts1 )for that the demonstratedmicrowave-assisted to be efficient CuAAC homogeneous reaction [25]. The catalysts use of for microwave the microwave-assisted heating, as compared CuAAC to reactionconventional [25]. Themethods, use of has microwave been shown heating, to dram as comparedatically reduce to conventional reaction times, methods, increase has beenproduct shown yields to dramaticallyand enhance reduceproduct reaction purity by times, reducing increase unwanted product side yields reactions and enhance [26–29]. productIn continuation purity by of reducingour efforts unwanted to develop side efficient reactions catalytic [26–29 Cu].AAC In continuation systems [25,30–32] of our effortscompounds to develop 1–4 were efficient heterogenized catalytic CuAACin carbon systems materials [25 ,(AC30–32 and] compounds CNT) and utilized1–4 were as heterogenizedheterogeneous in catalysts carbon materialsfor the microwave-assi (AC and CNT)sted and synthesis utilized as of heterogeneous triazoles. The catalysts catalytic forpotential the microwave-assisted of the supported synthesis species of triazoles.are compared The catalytic with potentialthe previously of the supported studied specieshomogeneous are compared counterparts with the [25]. previously studied homogeneous counterparts [25].

Scheme 1. Synthesis of Cu(I)-DAPTA complexes. Adapted from [25] with permission from The Royal Society of Chemistry.

Catalysts 2021, 11, 185 3 of 15

2. Results and Discussion 2.1. Characterization of the Carbon Materials The carbon materials used were the commercially purchased AC and CNT. They were subjected to chemical treatments in order to modify the nature and concentration of the surface functional groups. Surface modification was done by nitric acid treatment, by the addition of 5 M HNO3 and reflux, to give the oxidized AC-ox and CNT-ox materials. These could subsequently be treated with 20 mM NaOH under reflux to produce the AC-ox-Na and CNT-ox-Na carbon supports. Table1 shows the BET surface area, pore volume, and pore size of the commercial AC and CNT materials and their treated forms AC-ox, CNT-ox, AC-ox-Na and CNT-ox- Na. Indeed, the treatments have made significant structural modifications to the carbon materials [10,33–37]. In the case of AC there was a significant decrease of the surface area, pore volume and pore size. Nitric acid treatment has been proved to be effective for the creation of surface oxygen-containing functionalities such as carboxylic groups which could inhibit the access of N2 to the micropores [10,33]. The subsequent NaOH treatment (AC-ox-Na) further reduced the surface area of the material. For CNTs, having a cylindrical structure and the pores result from the free space in the bundles, and the acid treatment opens the CNT end tips (as seen for CNT-ox). Surface oxygen functionalities such as carboxylic groups can be introduced on the outer and possibly the inner walls which result in the formation of edges and steps on the graphene sheets [9,38]. The oxidant effectively opened the carbon nanotubes, and aggregation of the individual CNTs results in a lower value of pore volume and size than in the untreated sample [10,39,40]. Subsequent NaOH treatment (to achieve CNT-ox-Na) appeared not to revert the effect since the essential features were still present at the end of the treatment.

Table 1. Characterization of carbon materials using BET analysis.

2 −1 3 −1 Carbon Material SBET, m g Pore Volume, cm g Pore Size, nm AC 866 0.45 5.2 AC-ox 223 0.22 5.0 AC-ox-Na 191 0.15 4.9 CNT 256 2.54 30.9 CNT-ox 288 1.37 17.4 CNT-ox-Na 253 1.16 16.3

2.2. Heterogenization Efficiency The copper compounds 1–4 were heterogenized on the six carbon materials in at- tempts to obtain ~2% Cu. The surface treatments were proved to provide significant structural modifications on the carbon supports and to enhance the immobilization process. Anchoring of the metal-containing species to the carbon materials was done by the wet impregnation method, whereby a solution containing the precursor of the active phase (the copper complex) is contacted with the solid support. The suspension was continuously stirred for 24 h, after which the solid was separated by filtration and dried to remove the absorbed solvent. As shown in Table2, the different treatments affect the porous structure and surface chemistry of the supports, but the obtained materials were able to anchor the Cu complexes, although with different efficiencies. Heterogenization of the complexes was better observed in the ox-Na supports, followed by the -ox and the least effective were the original materials. This suggests that the increase in the number of surface groups brought by the treatments acts as a scaffold that increases the capacity of the complex to anchor effectively. The formation of phenolate and carboxylate groups obtained with the -ox-Na treatment can probably explain the higher heterogenization levels considering that these groups might act as coordination sites for the copper complexes [11,14]. Possible coordination and other interacting modes of Cu(I)-phosphine complexes onto the carbon materials are shown in Figures S10–S13. They can involve replacement of the halo (X) ligand by a carboxylate Catalysts 2021, 11, 185 4 of 15

or phenolate group of the carbon matrix (Figure S10), addition of one of these groups to the Cu atom (Figure S11), or a non-covalent interaction such as H-bonding (Figure S12) or ionic interaction (Figure S13).

Table 2. Metal loading of Cu on the carbon materials a.

Cu Complex Carbon Material 1 2 3 4 g/L % g/L % g/L % g/L % AC 0.01 0.1 0.02 0.3 0 0 0.01 0.1 AC-ox 0.07 0.9 0.06 0.8 0.05 0.6 0.04 0.5 AC-ox-Na 0.11 1.5 0.11 1.5 0.09 1.2 0.12 1.6 CNT 0 0 0.01 0.1 0 0 0 0 CNT-ox 0.06 0.8 0.02 0.3 0.03 0.4 0 0 CNT-ox-Na 0.06 0.8 0.11 1.5 0.06 0.8 0.10 1.3 a Values obtained from ICP analysis.

The nature of the surface groups and the immobilization of the copper complexes were further investigated using FTIR spectroscopy. Figures S7–S9 show the corresponding FTIR spectra of the CNT-ox-Na support and the heterogenized complexes 2 and 4, respectively. The presence of the peak at ~1720 cm−1 is related to C=O carboxylate group vibrations from the HNO3 treatment to increase the functionalization of the nanotubes. These functional groups are usually found attached to the ends of the nanotubes due to the enhanced reactivity of these areas [41]. By comparing the FTIR spectra before and after heterogenization, an observed shift in the peak of the carbonyl group from 1631 cm−1 to 1613 and 1618 cm−1 could be related to the chemical bond formed between the carboxylate group and Cu+ [42,43]. The peak at ~1400–1450 cm−1, present in the heterogenized samples but not on the support, suggests that there is O–H bending deformation in carboxylic and phenolic groups while the peak at ~1160–1200 cm−1 may be associated with the C–O stretching in the same functionalities [44]. Hence, these observations may indicate that the Cu(I)-phosphine complex is immobilized on CNT-ox-Na support via interactions between the terminal carboxylate groups on the surface of CNT-ox-Na. The main advantages of the immobilization technique include the absence of any com- plication in the heterogenization process, the widespread availability of carbon materials, the lack of any tedious procedure to alter the catalyst to facilitate the immobilization, the rapidity and experimental simplicity of the methodology by which heterogenization can be completed.

2.3. Microwave-Assisted One-Pot Synthesis of 1,2,3-Triazoles To exploit the activity of the Cu complexes 1–4 immobilized on the different carbon materials, the solid systems were used as catalysts for the one-pot synthesis of 1,4- disubstituted-1,2,3-triazoles. The reaction of benzyl bromide, sodium azide and phenylacetylene was chosen as model (Table3). The heterogenized materials with 1.2–1.6% Cu loadings (see Table2) were tested as catalysts for this reaction. The initial experimental conditions included a catalyst loading of 0.5% (relative to benzyl bromide), the temperature of 80 ◦C, 1.5 mL of H2O:MeCN 1:1 solvent mixture, 30 W microwave (MW) irradiation and a reaction time of 15 min (Table3, entries 1–8). Raising the temperature to the previously chosen value of 125 ◦C for the homogeneous systems [25] did not signiﬁcantly improve the results (Table3, entries 9–14). Different reaction times, catalyst loadings, and volumes of solvent were then screened to determine the optimum reaction conditions (Table3, entries 15–24). Catalysts 2021, 11, x FOR PEER REVIEW 5 of 16

3, entries 9–14). Different reaction times, catalyst loadings, and volumes of solvent were then screened to determine the optimum reaction conditions (Table 3, entries 15–24). The product was isolated by extraction with ethyl acetate followed by solvent removal to obtain the solid product. Structural assignments were determined by comparing the 1H- and 13C NMR spectra of the obtained triazole with those reported previously. In particular, the resonance of the proton in the 5-position of the 1,2,3-triazole ring as shown in the 1H NMR spectrum perfectly agrees with literature data [25,42] (see the Supporting Information for details). According to the data given in Table 3, the catalysts bearing the mononuclear complexes 1 and 2 are more active than those containing the dinuclear compounds 3 and 4 when immobilized on AC-ox-Na support (Table 1, entries 1–4). The substantially lower BET surface area and micropore volume of AC-ox-Na materials in comparison with the others and the bulkiness of the dinuclear compounds could have been possible causes of inaccessibility of the reactants to the active centers resulting in the decreased yields obtained from complexes 3 and 4 on the AC-ox-Na support. However, when the complexes 1–4 were immobilized on the CNT-ox-Na support, those bearing the iodo ligand (2 and 4) gave higher product yields regardless of their nuclearity (Table 1, entries 5–8). A plausible justification concerns the higher metal loading of complexes 2 and 4 on the CNT-ox-Na support (shown in Table 2) which eventually can result from a higher lability of the Cu-I bond (than that of Cu-Br) which would be favorable to the immobilization of the catalyst on this support or to the accessibility of the reagents to the metal centers upon iodo-ligand displacement. A related finding was observed with NHC- complexes [(NHC)CuX] (NHC = N-heterocyclic carbene; X = Cl, Br, I), as catalysts for CuAAC reaction with the general trend iodine> bromine> chlorine [45]. This can be accounted for by the formation, in the catalytic cycle, of copper-acetylide and -acetylide- azide intermediate species that requires the replacement of labile co-ligands [46]. Among the carbon materials used as support, the CNT-Ox-Na (Table 3, entries 6 and 8) gave the most satisfactory yields. Regardless of the type of carbon support being used for 2 (Table 3, entries 2 and 6) the yields (31.4% and 41%) and TONs (63 and 82) are higher than those obtained homogeneously (26% and TON of 52) [25] under identical experimental conditions. Significant effects of attaching the catalytic complex to a solid support include confinement, site-isolation, prevention of dimerization, cooperative effect of support, among others [47]. The presence of phenolate and carboxylate surface groups, due to the -ox-Na treatment, might explain the increased conversion since these moieties act as a scaffold for the complexes to anchor effectively [9–14]. The CNT materials gave the most satisfactory yields among the supports. Possible reasons might be due to the nature and concentration of surface functional groups, the absence of porosity for easy access to the active centers by the reactants, or an electronic Catalysts 2021, 11, 185 effect caused by the graphitic structure of CNT that can lead to enhanced interactions5 with of 15 the reactants or intermediate radicals [9,14].

Table 3. The 1,3-dipolar azide-alkyne cycloaddition catalyzed by Cu(I)-DAPTA complexes (1–4) anchored on different Tablecarbon 3. supportsThe 1,3-dipolar a. azide-alkyne cycloaddition catalyzed by Cu(I)-DAPTA complexes (1–4) anchored on different carbon supports a.

Entry Complex Support Catalyst Loading b, mol% Time, min Total Volume of Solvent, mL Yield c,% TON d Catalyst Loading b, Total Volume of Entry Complex Support Time, min Yield c, % TON d 1 1 AC-ox-Namol% 0.5 15Solvent, mL 1.5 30.5 61 2 2 AC-ox-Na 0.5 15 1.5 31.4 63 1 3 1 3 AC-ox-NaAC-ox-Na 0.5 0.5 15 15 1.5 1.5 30.5 2261 44 4 4 AC-ox-Na 0.5 15 1.5 20 39 5 1 CNT-ox-Na 0.5 15 1.5 23 46 6 2 CNT-ox-Na 0.5 15 1.5 41 82 7 3 CNT-ox-Na 0.5 15 1.5 29 59 8 4 CNT-ox-Na 0.5 15 1.5 33 66 9 1 AC-ox-Na 0.5 15 1.5 27 e 54 10 2 AC-ox-Na 0.5 15 1.5 32 e 65 11 2 CNT-ox-Na 0.5 15 1.5 40 e 80 12 3 AC-ox-Na 0.5 15 1.5 29 e 59 13 4 AC-ox-Na 0.5 15 1.5 38 e 75 14 4 CNT-ox-Na 0.5 15 1.5 40 e 80 15 2 CNT-ox-Na 0.5 30 1.5 29 59 16 2 CNT-ox-Na 0.1 15 1.5 21 207 17 2 CNT-ox-Na 0.5 15 2.0 32 65 18 2 CNT-ox-Na 0.5 30 2.0 27 55 19 2 CNT-ox-Na 0.5 15 1.0 17 34 20 2 CNT-ox-Na 0.5 30 1.0 23 46 21 4 CNT-ox-Na 0.1 30 1.5 23 230 22 4 CNT-ox-Na 0.5 30 1.5 25 50 23 4 CNT-ox-Na 0.5 60 1.5 42 84 24 4 CNT-ox-Na 1.0 15 1.5 48 48

a ◦ Reaction conditions: benzyl bromide (0.30 mmol), phenylacetylene (0.33 mmol), NaN3 (0.33 mmol), H2 O: MeCN (1:1 v/v), 80 C. b Calculated vs. benzyl bromide. c Isolated yield. d Turnover number = moles of product per mol of metal content in the catalyst (as obtained from ICP). e Reaction temperature: 125 ◦C. The product was isolated by extraction with ethyl acetate followed by solvent removal to obtain the solid product. Structural assignments were determined by comparing the 1H- and 13C NMR spectra of the obtained triazole with those reported previously. In particular, the resonance of the proton in the 5-position of the 1,2,3-triazole ring as shown in the 1H NMR spectrum perfectly agrees with literature data [25,42] (see the Supporting Information for details). According to the data given in Table3, the catalysts bearing the mononuclear complexes 1 and 2 are more active than those containing the dinuclear compounds 3 and 4 when immobilized on AC-ox-Na support (Table1, entries 1–4). The substantially lower BET surface area and micropore volume of AC-ox-Na materials in comparison with the others and the bulkiness of the dinuclear compounds could have been possible causes of inaccessibility of the reactants to the active centers resulting in the decreased yields obtained from complexes 3 and 4 on the AC-ox-Na support. However, when the complexes 1–4 were immobilized on the CNT-ox-Na support, those bearing the iodo ligand (2 and 4) gave higher product yields regardless of their nuclearity (Table1, entries 5–8). A plausible justiﬁcation concerns the higher metal loading of complexes 2 and 4 on the CNT-ox-Na support (shown in Table2) which eventually can result from a higher lability of the Cu-I bond (than that of Cu-Br) which would be favorable to the immobilization of the catalyst on this support or to the accessibility of the reagents to the metal centers upon iodo-ligand displacement. A related ﬁnding was observed with NHC-complexes [(NHC)CuX] (NHC = N-heterocyclic carbene; X = Cl, Br, I), as catalysts for CuAAC reaction with the general trend iodine> bromine> chlorine [45]. This can be accounted for by the formation, in the catalytic cycle, of copper-acetylide and -acetylide-azide intermediate species that requires the replacement of labile co-ligands [46]. Catalysts 2021, 11, 185 6 of 15

Among the carbon materials used as support, the CNT-Ox-Na (Table3, entries 6 and 8) gave the most satisfactory yields. Regardless of the type of carbon support being used for 2 (Table3, entries 2 and 6) the yields (31.4% and 41%) and TONs (63 and 82) are higher than those obtained homogeneously (26% and TON of 52) [25] under identical experimental conditions. Significant effects of attaching the catalytic complex to a solid support include confinement, site-isolation, prevention of dimerization, cooperative effect of support, among others [47]. The presence of phenolate and carboxylate surface groups, due to the -ox-Na treatment, might explain the increased conversion since these moieties act as a scaffold for the complexes to anchor effectively [9–14]. The CNT materials gave the most satisfactory yields among the supports. Possible reasons might be due to the nature and concentration of surface functional groups, the absence of porosity for easy access to the active centers by the reactants, or an electronic effect caused by the graphitic structure of CNT that can lead to enhanced interactions with the reactants or intermediate radicals [9,14]. Since the CNT-ox-Na anchored complexes 2 and 4 (hereafter denoted as 2_CNT-ox- Na and 4_CNT-ox-Na) gave the highest yields for the CuAAC reaction under the initial experimental conditions (Table3, entries 6 and 8), they were further used to explore the effect of variation of other experimental factors i.e., catalyst loading, irradiation time, and total volume of solvent. In the case of 2_CNT-ox-Na, an increase in both the total volume of solvent and irradiation time (Table3, entry 18) dropped the yield to 27%. A drop in yield to 21% or to 17% was observed when the catalyst loading or the solvent volume was decreased (Table3, entries 16 and 19, respectively). The solvent effect in the reaction yield may be tentatively explained by substrate-solvent interactions and concentration effects. Decreasing the solvent volume to 1.0 mL gave a poor yield possibly due to the low solubility of the reactants with partial precipitation, while increasing to 2.0 mL would dilute the reaction mixture and eventually hinder the interaction between substrates, with a decrease in the kinetics of the reaction. With 4_CNT-ox-Na, the yield significantly improved to 42% when the irradiation time was increased to 60 min (Table3, entry 23), and to 48% when the catalyst loading was set to 1.0 mol% (Table3, entry 24). Further increases of catalyst loading were not explored since it would defeat the TON values and the purpose of doing away with stoichiometric excess of expensive catalysts, which is one of the main fundamentals of heterogenization. To investigate the generality and versatility of 2_CNT-ox-Na and 4_CNT-ox-Na as catalysts for the CuAAC reaction to furnish the triazole derivatives, we explored the effect of substituted benzyl bromides using the aforementioned optimized experimental conditions (Table3, entries 6 and 23). The results are shown in Table4. The effect of the benzyl substituents on the yield of the reaction depended on the catalyst. With 2_CNT-ox-Na the use of 2-bromobenzyl bromide instead of the non-substituted aromatic substrate decreased the yield of the corresponding triazole product (compare entry 1 in Table4 with entry 6 in Table3). However, when nitrobenzyl bromides were used, the yields increased regardless of the substituent position (ortho or meta) in the aromatic ring (Table4, entries 2–3). The opposite was observed for catalyst 4_CNT-ox-Na (Table4 , entries 4–8): when 2-bromobenzyl bromide was used the yield increased from 48% (Table3 , entry 22) to 51% (Table4, entry 4), but with 3-bromobenzyl bromide it decreased to 37% (Table4, entry 5); with the nitro group, a stronger electron-withdrawing moiety, the obtained yields of product dropped with a decreasing trend conceivably following the ortho > meta > para group position (Table4, entries 6–8). Further details on the characterization of compounds can be found in the Supporting Information. Catalysts 2021, 11, x FOR PEER REVIEW 7 of 16 Catalysts Catalysts 2021 2021, 11, ,11 x ,FOR x FOR PEER PEER REVIEW REVIEW 7 of7 16of 16 CatalystsCatalysts Catalysts 2021 2021, 202111, ,11 x ,FOR11 x FOR PEER PEER REVIEW REVIEW 7 of7 of16 16 Catalysts Catalysts 2021 2021, 11,, ,11 x, ,,FOR xx ,FORFOR 185 PEER PEERPEER REVIEW REVIEWREVIEW 7 of7 of167 16 of 15 Catalysts Catalysts 2021 2021, 11, ,11 x ,FOR x FOR PEER PEER REVIEW REVIEW 7 of7 of16 16

Table 4. Synthesis of triazoles using phenylacetylene and substituted benzyl bromides a. Table 4. Synthesis of triazoles using phenylacetylene and substituted benzyl bromidesa a. TableTable 4. Synthesis4.Synthesis Synthesis ofof oftriazolestriazoles triazoles usingusing using phenylacetphenylacet phenylacetyleneylene and and substituted substituted benzyl benzyl bromides bromides a.. a. TableTable 4. 4.Synthesis Synthesis of oftriazoles triazoles using using phenylacet phenylacetyleneylene and and substituted substituted benzyl benzyl bromides bromides a. aa. a TableTableTable 4. 4.Synthesis Synthesis 4. Synthesis of oftriazoles oftriazoles triazoles using using using phenylacet phenylacet phenylacetyleneyleneylene and and substituted and substituted substituted benzyl benzyl benzyl bromides bromidesTime, bromides a. a. . Entry Catalyst Benzyl Bromide Product Time, Yield b, % TON Time,Time, b Entry Catalyst Benzyl Bromide Product Time,Time, Yieldb b, %b TON EntryEntryEntry Catalyst CatalystCatalyst Benzyl Benzyl Benzyl Bromide Bromide Bromide Product Product Product Time,Time, Time,min min YieldYield bYield,, %b%, % ,% TON TON TON TON EntryEntry CatalystCatalyst Benzyl Benzyl Bromide Bromide Product Product Time,Time,min YieldYield b, b%, % TON TON EntryEntry CatalystCatalyst Benzyl Benzyl Bromide Bromide Product Product minmin YieldYield b, b%,, %% TON TON TON EntryEntry CatalystCatalyst Benzyl Benzyl Bromide Bromide Product Product minmin YieldYield , %, % TON TON minmin

1 2_CNT-ox-Na 15 38 76 1 1 1 2_CNT-ox-Na22_CNT-ox-Na 1515 15 3838 387676 76 1 1 2_CNT-ox-Na2_CNT-ox-Na 1515 3838 7676 1 1 2_CNT-ox-Na2_CNT-ox-Na 1515 3838 7676

2 2_CNT-ox-Na 15 48 97 2 2 2 2_CNT-ox-Na22_CNT-ox-Na 1515 15 4848 489797 97 2 2 2_CNT-ox-Na2_CNT-ox-Na 1515 4848 9797 2 2 2_CNT-ox-Na2_CNT-ox-Na 1515 4848 9797

3 2_CNT-ox-Na 15 49 98 3 3 3 2_CNT-ox-Na22_CNT-ox-Na 1515 15 4949 499898 98 3 3 2_CNT-ox-Na2_CNT-ox-Na 1515 4949 9898 3 3 2_CNT-ox-Na2_CNT-ox-Na 1515 4949 9898

4 4_CNT-ox-Na 60 51 101 4 4_CNT-ox-Na 60 51 101 4 4 4 4_CNT-ox-Na44_CNT-ox-Na 6060 60 5151 51101101 101 4 4 4_CNT-ox-Na4_CNT-ox-Na 6060 5151 101101 4 4 4_CNT-ox-Na4_CNT-ox-Na 6060 5151 101101

5 4_CNT-ox-Na 60 37 74 5 4_CNT-ox-Na 60 37 74 5 5 4_CNT-ox-Na4_CNT-ox-Na 6060 3737 7474 5 5 5 4_CNT-ox-Na44_CNT-ox-Na 6060 60 3737 377474 74 5 5 4_CNT-ox-Na4_CNT-ox-Na 6060 3737 7474

6 4_CNT-ox-Na 60 39 79 6 6 4_CNT-ox-Na4_CNT-ox-Na 6060 3939 7979 6 6 4_CNT-ox-Na4_CNT-ox-Na 6060 3939 7979 6 6 6 4_CNT-ox-Na44_CNT-ox-Na 6060 60 3939 397979 79

7 4_CNT-ox-Na 60 37 74 7 4_CNT-ox-Na 60 37 74 7 7 4_CNT-ox-Na4_CNT-ox-Na 6060 3737 7474 7 7 4_CNT-ox-Na4_CNT-ox-Na 6060 3737 7474 7 7 7 4_CNT-ox-Na44_CNT-ox-Na 6060 60 3737 377474 74

8 4_CNT-ox-Na 60 32 64 8 8 4_CNT-ox-Na4_CNT-ox-Na 6060 3232 6464 8 8 4_CNT-ox-Na4_CNT-ox-Na 6060 3232 6464 8 8 8 4_CNT-ox-Na44_CNT-ox-Na 6060 60 3232 326464 64 a Reaction conditions: benzyl bromide (0.30 mmol), phenylacetylene (0.33 mmol), NaN 3 (0.33 mmol), H2O: MeCN (1.5 mL, a a 3 2 a Reactiona Reaction conditions: conditions: benzyl benzyl bromide bromide (0. (0.30 30mmol), mmol), phenylacetylene phenylacetylene (0.33 (0.33 mmol), mmol), NaN NaN3 (0.333 (0.33 mmol), mmol), H2 HO:2 O:bMeCN MeCN (1.5 (1.5 mL, mL, a Reaction1:1a Reaction v/v), 80conditions: conditions:°C, 0.5 mol% benzyl benzyl of catalystsbromide bromide ((0.2_CNT-ox-Na (0.3030 mmol), mmol), phenylacetylene andphenylacetylene 4_CNT-ox-Na) (0.33 (0.33 vs.mmol), mmol), benzyl NaN NaNbromide3 (0.333 (0.33 mmol),derivatives. mmol), H 2HO:2 O: MeCN Isolated MeCN (1.5 yield.(1.5 mL, mL, a Reactiona Reaction conditions: conditions: benzyl benzyl bromide bromide (0. (0.3030 mmol), mmol), phenylacetylene phenylacetylene (0.33 (0.33 mmol), mmol), NaN NaN3 (0.333 (0.33 mmol), mmol), H 2HO:2O: bMeCN MeCN (1.5 (1.5 mL, mL, a Reactiona1:1 Reaction v/v), conditions:80 conditions: °C, 0.5 mol% benzyl benzyl of bromidecatalysts bromide (0.(2 (0._CNT-ox-Na3030 mmol), mmol), phenylacetylene phenylacetyleneand 4_CNT-ox-Na) (0.33 (0.33 mmol),vs. mmol), benzyl NaN NaN bromide3 (0.333 (0.33 mmol), derivatives. mmol), H 2HO:b 2O: bMeCN Isolated MeCN (1.5 (1.5yield. mL, mL, 1:11:1 Reaction1:1 vReactionv//a vvv),),/v 8080), conditions:80 °C,°C, conditions: °C, 0.50.5 0.5 mol%mol% mol% benzyl benzylofof ofcatalystscatalysts catalystsbromide bromide ((22 _CNT-ox-Na_CNT-ox-Na(0.(2 _CNT-ox-Na(0.3030 mmol), mmol), phenylacetyleneandand phenylacetyleneand 44_CNT-ox-Na)_CNT-ox-Na) 4_CNT-ox-Na) (0.33 (0.33 vs. mmol),vs. benzyl mmol), benzyl NaN bromide NaN bromide3 (0.333 (0.33 derivatives. mmol), derivatives. mmol), H 2H O:b 2IsolatedIsolatedO: bMeCN Isolated MeCN (1.5yield.yield. (1.5yield. mL, mL, ◦ 1:11:1 v/ vvReaction),/v 80), 80 °C, °C, conditions:0.5 0.5 mol% mol% benzylof ofcatalysts catalysts bromide (2 _CNT-ox-Na( (0.302_CNT-ox-Na mmol), phenylacetylene and and 4_CNT-ox-Na) 4_CNT-ox-Na) (0.33 mmol), vs. vs. benzyl NaNbenzyl3 bromide(0.33 bromide mmol), derivatives. derivatives. H2O: MeCN b Isolated (1.5b Isolated mL, 1:1yield. yield.v/v ), 80 C, 1:11:1 v/ vv),/v 80), 80 °C, °C, 0.5 0.5 mol% mol% of ofcatalysts catalysts (2 _CNT-ox-Na(2_CNT-ox-Na and and 4_CNT-ox-Na) 4_CNT-ox-Na) vs. vs. benzyl benzyl bromide bromide derivatives. derivatives. b Isolated b IsolatedIsolated yield. yield.yield. 1:11:1 v/0.5 vv),/v mol%80), 80 °C, °C, of 0.5 catalysts 0.5 mol% mol% ( 2of_CNT-ox-Na ofcatalysts catalystsThe (2 and _CNT-ox-Na( 2effect_CNT-ox-Na4_CNT-ox-Na) of the and andbenzyl vs. 4_CNT-ox-Na) benzyl4_CNT-ox-Na) substituents bromide vs. derivatives. vs. benzyl onbenzyl the bromideb bromideIsolatedyield derivatives.of yield. derivatives. the reaction Isolated Isolated depended yield. yield. on the TheThe effect effect of ofthe the benzyl benzyl substituents substituents on on the the yield yield of ofthe the reaction reaction depended depended on on the the catalyst.TheThe effect Witheffect of 2of _CNT-ox-Nathe the benzyl benzyl substituents substituentsthe use of on 2-bromobenon the the yield yield ofzyl of the bromidethe reaction reaction instead depended depended of theon on thenon- the catalyst.TheThe Theeffect effectWith 1,3-dipolar of 2of the_CNT-ox-Na the benzyl benzyl cycloaddition substituents substituentsthe use is aof well-knownon 2-bromobenon the the yield yield reaction ofzyl of the thebromide reaction that reaction can instead bedepended depended catalyzed of theon byon thenon- hetero- the catalyst.catalyst.substitutedcatalyst. WithWith With aromatic 2 _CNT-ox-Na2_CNT-ox-Na substrate the thedecreased use use of of2-bromoben the 2-bromoben yield ofzyl thezyl bromidecorresponding bromide instead instead triazole of ofthe theproduct non- non- catalyst.catalyst.substitutedgeneous With With copperaromatic 2 _CNT-ox-Na2_CNT-ox-Na metal substrate such the as thedecreased copperuse use of of nanoparticles,2-bromoben the2-bromoben yield ofzyl the nanoclusters,zyl bromide corresponding bromide instead orinstead copper triazole of of the wire the product non- [7non-]. Car- substitutedcatalyst.substitutedcatalyst.substituted With With aromaticaromatic aromatic 2 _CNT-ox-Na2_CNT-ox-Na substratesubstrate substrate thedecreaseddecreased thedecreased use use of of thethe2-bromoben the2-bromoben yield yield of ofthezyl thezyl corresponding bromidecorresponding bromide instead instead triazole triazole of of the product the product non- non- substituted(comparesubstituted entryaromatic aromatic 1 in substrateTable substrate 4 with decreased decreased entry 6 inthe theTable yield yield 3). of However,of the the corresponding corresponding when nitrobenzyl triazole triazole productbromides product (comparesubstitutedsubstituted(comparebon nanomaterials entry aromaticentry aromatic 1 in 1 inTable substrateTable substrate with 4 with 4immobilized with decreased entry decreased entry 6 in 6 inthe copperTable the Table yield yield 3). complexes 3). However,of However,of the the corresponding corresponding based when when on nitrobenzyl nitrobenzylN-heterocyclic triazole triazole bromides product bromides product carbenes (comparewere(compare used, entry entry the 1 yields in1 in Table Table increased 4 with4 with entry regard entry 6 inless6 in Table ofTable the 3). 3).substituent However, However, whenposition when nitrobenzyl nitrobenzyl (ortho or metabromides bromides) in the were(compare(comparewere(NHC) used, used, entry the entry have the yields 1 yields in been1 in Table increasedTable reported increased 4 with4 with regard asentry regard entry recyclable less6 in6less in Tableof Table ofthe catalysts the 3).substituent 3). substituentHowever, However, for CuAAC position when position when reactionsnitrobenzyl ( nitrobenzylortho (ortho or by ormeta bromides Niameta bromides) in et) inthe al. the [48 ]. werearomaticwere used, used, ringthe the yields (Table yields increased 4, increased entries regard2–3). regard Thelessless opposite of of the the substituent substituentwas observed position position for catalyst (ortho (ortho or 4or _CNT-ox-Nameta meta) in) in the the werewerearomaticSpeciﬁcally, used, used, thering the yields (Table yields Cu(I) increased 4, nanoparticlesincreased entries regard 2–3). regard immobilizedThelessless oppositeof of the the substituent substituent was on CNT observed onlyposition position for achieved catalyst(ortho (ortho or a or4or 30%meta_CNT-ox-Na meta conversion) in) in the the aromaticwerearomatic used, ring ring the (Table (Table yields 4, 4,entries increased entries 2–3). 2–3). regard The The oppositeless opposite of the was substituent was observed observed position for for catalyst catalyst (ortho 4_CNT-ox-Na 4or_CNT-ox-Na meta) in the aromatic(Tablearomaticwith 4, ring 2–5 entriesring mol%(Table (Table 4–8): catalyst 4, 4,entries when entries loading 2–3).2-bromobenzyl 2–3). The at The 40 opposite ◦oppositeC for bromide 96 was h.was Yieldsobserved observedwas improvedused for forthe catalyst catalyst yield to 60% 4increased_CNT-ox-Na 4 with_CNT-ox-Na an from 8 mol% (Tablearomaticaromatic(Table 4, 4,entriesring ringentries (Table (Table 4–8): 4–8): 4, when 4,entries when entries 2-bromobenzyl 2–3).2-bromobenzyl 2–3). The The opposite opposite bromide bromide was was observedwas observedwas used used forthe for the catalyst yield catalyst yield increased 4 increased_CNT-ox-Na 4_CNT-ox-Na from from (Table48%(Table (Table4, 4,entries entries 3, entry4–8): 4–8): when22) when to 2-bromobenzyl51% 2-bromobenzyl (Table 4, entrybromide bromide 4), butwas was withused used 3-bromobenzylthe the yield yield increased increased bromide from from it (Table(Table48%catalyst 4,(Table 4,entries entries loading 3, entry4–8): 4–8): for when22) 24when hto reaction2-bromobenzyl 51%2-bromobenzyl (Table time. 4, Nasrollahzadeh bromideentry bromide 4), wasbut was etwithused used al. [3-bromobenzylthe49 the] preparedyield yield increased increased a heterogeneous bromide from from it 48%decreased48% (Table (Table 3,to 3,37%entry entry (Table 22) 22) to 4, to51% entry 51% (Table 5);(Table with 4, the4,entry entry nitro 4), 4),group, but but with awith stronger 3-bromobenzyl 3-bromobenzyl electron-withdrawing bromide bromide it it 48%48%decreased catalyst(Table (Table 3,to consisting 3, entry37% entry (Table 22) 22) of to copper4,to 51% entry 51% (Table nanoparticles 5);(Table with 4, 4,theentry entry nitro on 4), 4), amorphous group,but but with witha stronger 3-bromobenzyl carbon3-bromobenzyl electron-withdrawing to be used bromide bromide for the it click it decreased48%48%decreased (Table (Table to 3, to37% 3, entry37% entry (Table (Table 22) 22) 4,to 4,entryto 51% entry 51% 5);(Table 5); (Tablewith with 4,the 4,theentry nitroentry nitro 4),group, 4), group, but but awith strongerwitha stronger 3-bromobenzyl 3-bromobenzyl electron-withdrawing electron-withdrawing bromide bromide it it decreasedmoiety,decreasedreaction theto to 37% to obtained 37% synthesize (Table (Table yields4, 4,entry 1,2,3-triazoles. entry of 5); product5); with with the Despite thedr nitroopped nitro group, the group, with long a strongera reaction strongerdecreasing electron-withdrawing time electron-withdrawing trend of 4 h, conceivably the best result moiety,decreaseddecreasedmoiety, the theto to obtained37% obtained37% (Table (Table yields 4,yields 4,entry entryof of product5); 5);product with with thedr the dr oppednitro oppednitro group, withgroup, with a strongeraadecreasing strongerdecreasing electron-withdrawing electron-withdrawing trend trend conceivably conceivably moiety,followingmoiety, the the theobtained obtained ortho > yieldsmeta yields > ofpara of product productgroup drposition droppedopped (Tablewith with a4, adecreasing en decreasingtries 6–8). trend Furthertrend conceivably conceivably details on moiety,moiety,followinggave the thethe theobtained productobtained ortho > withyields metayields a > yieldof paraof product ofproductgroup 97%, drposition obtained droppedopped (Tablewith with with 1.0a 4, adecreasing mmolendecreasingtries of 6–8). starting trend trendFurther conceivably materials conceivably details with on a followingfollowingfollowing thethe the orthoortho ortho > metameta> meta > parapara> para groupgroup group◦ positionposition position (Table(Table (Table 4,4, 4,enen entriestriestries 6–8).6–8). 6–8). FurtherFurther Further detailsdetails details onon on followingthefollowingcatalyst characterization the the loading ortho ortho > of meta>of 0.5metameta compounds mol%> para> parapara atgroup group 70group canC. position be Hosseinzadehpositionposition found (Table in(Table(Table the 4,et Supporting 4,4,en al. enentries [50tries] 6–8). employed 6–8). Information. Further Further Cu(OAc) details details /MCM-on on thefollowingfollowingthe characterization characterization the the ortho ortho >of meta> of compoundsmeta compounds > para> para group groupcan can beposition be positionfound found (Tablein (Table inthe the Supporting 4, Supporting 4,en entriestries 6–8). Information.6–8). Information. Further Further details details 2 on on thethe characterization characterization of of compounds compounds can can be be found found in in the the Supporting Supporting Information. Information. thethe characterization41 characterization (Mobil Composition of of compounds compounds of Matter can can No.41) be be found found catalyst in in the for the Supporting the Supporting one-pot Information. synthesis Information. of 1,2,3-triazoles

Catalysts 2021, 11, 185 8 of 15

in water. The optimum product yield of 98% was achieved at 90 ◦C for 15 min. Yet, the need for 45 mol% sodium ascorbate as reducing agent for Cu(II) to Cu(I) makes it an unattractive procedure. Shargi et al. [42] attempted to immobilize copper nanoparticles on charcoal for the multicomponent catalytic synthesis of 1,2,3-triazole derivatives. The use of 1 mol% of Cu/C in water as catalyst for the CuAAC reaction, furnished the 1,4-disubstituted triazole product in 91% yield after stirring for 45 min at 100 ◦C. Although the catalyst loading was low, the metal loading used for Cu/C was found to contain ~10% (w/w) of Cu based on ICP analysis [42]. Despite the numerous publications on the heterogeneous copper-catalyzed azide- alkyne coupling reaction, the carbon-supported Cu-DAPTA complexes with a copper loading of only 1.5–1.6% immobilized on the carbon materials were able to establish quantitative conversions, which were obtained at a shorter reaction time of 15 min, a lower temperature of 80 ◦C, a lower catalyst loading of 0.5 mol%, and no additional reducing agent. A proposed mechanism for the CuAAC reaction is depicted in Scheme2, based on several studies that have been reported toward its elucidation [51,52]. Subsequent kinetic experiments [53] and theoretical investigations [54,55] have been carried out leading basically to similar qualitative conclusions that reflect the up-to-date understanding of this reaction. In the first step of the mechanism, a terminal alkyne binds to a copper(I) center as a π-ligand. This coordination increases the acidity of the alkyne terminal proton, hence a stable σ,π-di(copper) acetylide complex can be formed upon deprotonation [31,56]. The reaction of azide replaces one of the ligands and binds reversibly to the copper atom via the nitrogen proximal to carbon, forming a bridging dicopper µ-acetylide intermediate [53,57]. Subsequently, the distal nitrogen of the azide attacks the C-2 carbon of the acetylide forming an intermediate six-membered cupracycle [58]. The next step involves reductive ring contraction to afford the triazolide intermediate. The last step corresponds to a fast protonation of the copper(I) triazolide leading to the release of the triazole product and the active copper species catalyst is regenerated, thereby completing the catalytic cycle. By attaching the catalytic complex to a solid support, it is possible to efficiently recover the catalyst to be used for further catalytic cycles. The recyclabilities of 2_CNT-ox-Na and 4_CNT-ox-Na were explored for up to 4 consecutive cycles (Figures1 and2). On completion of each stage, the triazole product was analyzed and the heterogenized solid catalyst was recovered by filtration, washed thoroughly with distilled water, and dried overnight. The subsequent cycle was initiated upon the addition of new standard portions of all other reagents. As shown in Figures1 and2, the yields and corresponding TON values decrease in each successive cycle, conceivably due to leaching of the catalyst from the support. Indeed, the triazole functionality of the product of the azide-alkyne click reaction has a strong complexing ability for Cu catalyst and can compete with the solid support. Hence, this release-recapture reaction mechanism could invoke some leaching and explain the decrease in the yield [7]. The 2_CNT-ox-Na recyclability is limited but still represents a considerable progress in view of the ca.19% yield obtained after the 4th cycle, as compared to only a value of 5.1% yield achieved after the 4th recycling process of complex 2 working homogeneously as a catalyst for the CuAAC reaction [25]. Catalysts 2021, 11, 185 9 of 15 Catalysts 2021, 11, x FOR PEER REVIEW 9 of 16

Scheme 2. Postulated mechanism of the Cu–AACCu–AAC reaction.

By attaching the catalytic complex to a solid support, it is possible to efficiently recover the catalyst to be used for further catalytic cycles. The recyclabilities of 2_CNT-ox- Na and 4_CNT-ox-Na were explored for up to 4 consecutive cycles (Figures 1 and 2). On completion of each stage, the triazole product was analyzed and the heterogenized solid catalyst was recovered by filtration, washed thoroughly with distilled water, and dried overnight. The subsequent cycle was initiated upon the addition of new standard portions of all other reagents. As shown in Figures 1 and 2, the yields and corresponding TON values decrease in each successive cycle, conceivably due to leaching of the catalyst from the support. Indeed, the triazole functionality of the product of the azide-alkyne click

Catalysts 2021, 11, x FOR PEER REVIEW 10 of 16

Catalysts 2021, 11, 185 reaction has a strong complexing ability for Cu catalyst and can compete with the solid 10 of 15 support. Hence, this release-recapture reaction mechanism could invoke some leaching and explain the decrease in the yield [7].

50 45 40 35 30 25

Yield (%) 20

Yield (%) 20 15 10 5 0 cycle 1 cycle 2 cycle 3 cycle 4

Figure 1. Effect of catalyst recycling on the yield of the product for the MW-assisted synthesis of Figure 1. EffectFigure of catalyst 1. Effect recycling of catalyst on the recycling yield of the on product the yield for of the the MW-assisted product for synthesis the MW-assisted of 1,2,3-triazole synthesis catalyzed of by 1,2,3-triazole catalyzed by 2_CNT-ox-Na () and 4_CNT-ox-Na (). Reaction conditions: 0.5 mol% 2_CNT-ox-Na () and 4_CNT-ox-Na (). Reaction conditions: 0.5 mol% of 2_CNT-ox-Na vs. benzyl bromide, 1.0 mol% of of 2_CNT-ox-Na vs. benzyl bromide, 1.0 mol% of 4_CNT-ox-Na vs. benzyl bromide, 15 min, 30 W 4_CNT-ox-Na vs. benzyl bromide, 15 min, 30 W microwave irradiation, 80 ◦C. microwave irradiation, 80 °C.

90 80 70 60 50 40 Overall TON Overall Overall TON Overall 30 20 10 0 cycle 1 cycle 2 cycle 3 cycle 4

Figure 2. EffectFigure of catalyst 2. Effect recycling of catalyst on therecycling overall on TON the overall of the TON product of the for product the MW-assisted for the MW-assisted synthesis synthesis of 1,2,3-triazole of 1,2,3-triazole catalyzed by 2_CNT-ox-Na () and 4_CNT-ox-Na (). Reaction conditions: 0.5 catalyzed by 2_CNT-ox-Naof 1,2,3-triazole () andcatalyzed4_CNT-ox-Na by 2_CNT-ox-Na (). Reaction () conditions: and 4_CNT-ox-Na 0.5 mol% of().2_CNT-ox-Na Reaction conditions: vs. benzyl 0.5 bromide, mol% of 2_CNT-ox-Na vs. benzyl bromide, 1.0 mol% of 4_CNT-ox-Na vs. benzyl bromide, 15 min, 1.0 mol% of 4_CNT-ox-Namol% of 2_CNT-ox-Na vs. benzyl bromide, vs. benzyl 15 bromide, min, 30 W 1.0 microwave mol% of 4 irradiation,_CNT-ox-Na 80 vs.◦C. benzyl bromide, 15 min, 30 W microwave irradiation, 80 °C. 3. Materials and Methods The 2_CNT-ox-Na3.1. General recyclability Procedures is limited but still represents a considerable progress in view of the ca.19% yield obtained after the 4th cycle, as compared to only a value of in view of the caAll.19% procedures yield obtained were performed after the 4th in air. cycl Reagentse, as compared and solvents to only were a value obtained of from com- 5.1% yield achieved after the 4th recycling process of complex 2 working homogeneously 5.1% yield achievedmercial sources after the and 4th used recycling without process further of complex puriﬁcation. 2 working Infrared homogeneously spectra (4000–400 cm−1) as a catalyst for the CuAAC reaction [25]. as a catalystwere for the recorded CuAAC on reaction a Vertex [25]. 70 (Bruker) instrument in KBr pellets. 1H, 13C and DEPT NMR spectra were obtained using Bruker Avance II 300 MHz and 400 MHz spectrometers at ambient temperature. The chemical shifts were reported in ppm using tetramethylsilane as an internal reference. Electrospray mass (ESI-MS) spectra were obtained on a Varian 500-MS LC Ion Trap Mass Spectrometer equipped with an electrospray ion source. The compounds were observed and reported in the positive mode (capillary voltage = 80–105 V). Catalysts 2021, 11, 185 11 of 15

The microwave irradiation was done using the Anton Paar Monowave 300 microwave reactor. The loading of Cu on the carbon materials was determined by Inductively Coupled Plasma (ICP) at the Laboratório de Análises of Instituto Superior Técnico. The carbon materials were characterized by N2 adsorption at 77 K in Micrometrics ASAP 2060 gas sorption instrument. Materials were previously degassed at 150 ◦C for 48 h. The multi- point Brunauer–Emmett–Teller (BET) theory and the t-plot method procedure were used for estimating the total and the external surface areas of the materials. The complexes [CuBr(κP-DAPTA)3](1), [CuI(κP-DAPTA)3](2), [Cu(µ-Br)(κP-DAPTA)2]2 (3) and [Cu(µ- I)(κP-DAPTA)2]2 (4) were prepared according to the literature methods [25].

3.2. Treatments of the Carbon Materials Two different carbon materials were employed as starting supporting matrices, activated carbon (AC) and multi-walled carbon nanotubes (CNT), used as such or subjected to surface treatments. These included oxidation by refluxing for 3 h 1 g of carbon in 75 mL of a 5 M HNO3 solution, followed by filtration and washing with distilled water until neutral pH [9,11,12,37,59,60] in this way, the AC-ox and CNT-ox supports were obtained. When AC-ox or CNT-ox were mixed with 75 mL of a 20 mM NaOH solution, refluxed for 1 h followed by filtration and washing with distilled water until neutral pH [10–13,37,47,59–61], the set of AC-ox-Na and CNT-ox-Na supports were attained. In this way, a total of six different carbon materials were used in the work.

3.3. Heterogenization Protocol Immobilization of complexes 1–4 on the carbon supports was carried out by dissolving a calculated amount of each complex in 20 mL of a 1:1 (v/v)H2O:MeCN solvent mixture and, subsequently, 0.15 g of the carbon material were added so as to achieve 2 wt% Cu per mass of carbon. The mixture was stirred continuously for 24h and then ﬁltered, washed with water, and dried overnight at 120 ◦C.

3.4. Catalytic Essays In a typical procedure, a tightly capped 10 mL borosilicate glass vial equipped with a magnetic stir bar and containing the heterogenized catalysts (0.5 mol% relative to benzyl bromide), benzyl bromide (0.30 mmol), phenylacetylene (0.33 mmol), and NaN3 (0.33 mmol, 0.0215 g) in 1.5 mL of the solvent mixture (H2O:MeCN, 1:1 v/v), was placed in a microwave reactor. This was stirred (600 rpm) and simultaneously irradiated (30 W) for 15 min at 80 ◦C. After the set reaction time, the mixture was allowed to cool at room temperature and two phases were observed. After extraction with ethyl acetate, the organic phase was collected and taken to dryness to afford the corresponding triazole product; it was washed with petroleum ether and no further puriﬁcation step was performed. The heterogenized catalyst was separated by ﬁltration, washed with water, oven-dried, and reused as suitable.

4. Conclusions A simple and reproducible synthetic method for recyclable heterogeneous catalysts based on Cu(I)-DAPTA complexes (1–4) on carbon materials (AC and CNT) was developed. The carbon nanotubes treated with nitric acid and NaOH (CNT-ox-Na) provided the most effective support concerning heterogenization. The treatments with HNO3 and NaOH have modiﬁed the nature and concentration of surface functional groups of the carbon solid support. The total surface area of all materials was reduced by NaOH treatment and the surface modiﬁcation brought by ox-Na surface oxidation was favorable in terms of catalytic activity. It is noteworthy that all the reactions were done without using an inert atmosphere. The immobilized iodo-Cu(I)-DAPTA complexes 2 and 4 on CNT-ox-Na affording the 2_CNT-ox-Na and 4_CNT-ox-Na supports have shown particularly favorable catalytic activity for the multicomponent synthesis of 1,2,3-triazoles, which can eventually relate to a higher lability of the Cu-I bond. The conditions and yields of the heterogenized systems Catalysts 2021, 11, 185 12 of 15

with a copper loading of only 1.5–1.6% (w/w) concern a promising route to establish quantitative conversions obtained at 15 min, 80 ◦C, 0.5 mol% catalyst loading. Furthermore, the process avoids the isolation of organic azides and affords the products without tedious puriﬁcation steps. The 2_CNT-ox-Na and 4_CNT-ox-Na can be recovered and recycled by simple ﬁltration of the reaction solution and reused for up to four consecutive cycles.

Supplementary Materials: The following are available online at https://www.mdpi.com/2073-4 344/11/2/185/s1, Characterization NMR data and spectra of the triazoles, Figure S1: ESI-MS+ spectrum of 1-benzyl-4-phenyl-1H-1,2,3-triazole, Figure S2: ESI-MS+ spectrum of bromobenzyl-4- phenyl-1H-1,2,3-triazole, Figure S3: ESI-MS+ spectrum of nitrobenzyl-4-phenyl-1H-1,2,3-triazole, Figure S4: FTIR spectrum of 1-benzyl-4-phenyl-1H-1,2,3-triazole, Figure S5: FTIR spectrum of bromobenzyl-4-phenyl-1H-1,2,3-triazole, Figure S6: FTIR spectrum of nitrobenzyl-4-phenyl-1H-1,2,3- triazole, Figure S7: FTIR spectrum of CNT-ox-Na support (2000-400 cm−1), Figure S8: FTIR spectrum of 2_CNT-ox-Na (2000-400 cm-1), Figure S9: FTIR spectrum of 4_CNT-ox-Na (2000-400 cm−1), Figure S10: Coordination at the Cu centre through a carboxylate group upon replacement of an iodo ligand, Figure S11: Coordination at the Cu centre through a carboxylate or a phenolate group, Figure S12: Via hydrogen bonding from a carboxylic or a phenolic group, Figure S13: Via ionic interactions. Author Contributions: Conceptualization, A.G.M., S.A.C.C. and M.F.C.G.d.S.; methodology, I.L.L., A.G.M., S.A.C.C. and M.F.C.G.d.S.; validation, M.F.C.G.d.S., C.F.G.C.G. and A.J.L.P.; formal analysis, I.L.L. and A.G.M.; investigation, I.L.L., A.G.M. and S.A.C.C.; resources, M.F.C.G.d.S. and C.F.G.C.G.; data curation, I.L.L.; writing—original draft preparation, I.L.L., A.G.M. and S.A.C.C.; writing—review and editing, M.F.C.G.d.S., C.F.G.C.G. and A.J.L.P.; visualization, I.L.L., S.A.C.C., M.F.C.G.d.S. and A.J.L.P.; supervision, S.A.C.C., M.F.C.G.d.S., C.F.G.C.G. and A.J.L.P.; project administration, S.A.C.C. and A.J.L.P.; funding acquisition, S.A.C.C. and A.J.L.P. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Fundação para a Ciência e a Tecnologia (FCT), Portugal, through project UIDB/00100/2020 of the Centro de Química Estrutural. It was also funded by national funds though FCT, under the Scientific Employment Stimulus-Institutional Call (CEECINST/ 00102/2018). We also acknowledge the Associate Laboratory for Green Chemistry—LAQV financed by national funds from FCT/MCTES (UIDB/50006/2020 and UIDP/50006/2020). I.L.L. is grateful to the CATSUS Ph.D. Program for her grant (PD/BD 135555/2018). AGM is grateful to Instituto Superior Técnico, Portugal for his post-doctoral fellowship through the project CO2usE-1801P.00867.1.01 (Contract No. IST-ID/263/2019). It was also supported by the RUDN University Strategic Academic Leadership Program. Acknowledgments: The authors acknowledge the Portuguese NMR Network (IST-UL Centre) for access to the NMR facility and the IST Node of the Portuguese Network of Mass-spectrometry for the ESI-MS measurements. The authors are also grateful to the support of RUDN University Strategic Academic Leadership Program. Conflicts of Interest: The authors declare no conflict of interest.

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