Review ReviewRecent Advances in Recoverable Systems for the RecentCopper-Catalyzed Advances in -Alkyne Recoverable SystemsCycloaddition for the Copper-CatalyzedReaction (CuAAC) Azide-Alkyne Cycloaddition

ReactionAlessandro Mandoli (CuAAC) 1,2 Alessandro1 Dipartimento Mandoli di Chimica1,2 e Chimica Industriale Università di Pisa, Via G. Moruzzi 13, Pisa 56124, Italy; [email protected]; Tel.: +39-050-221-9280 1 Dipartimento di Chimica e Chimica Industriale Università di Pisa, Via G. Moruzzi 13, Pisa 56124, Italy; 2 ISTM-CNR, Via C. Golgi 19, Milano 20133, Italy [email protected]; Tel.: +39-050-221-9280 2AcademicISTM-CNR, Editor: Via Maurizio C. Golgi Benaglia 19, Milano 20133, Italy Received: 1 August 2016; Accepted: 30 August 2016; Published: 3 September 2016 Academic Editor: Maurizio Benaglia Received: 1 August 2016; Accepted: 30 August 2016; Published: 5 September 2016 Abstract: The explosively-growing applications of the Cu-catalyzed Huisgen 1,3-dipolar Abstract:cycloadditionThe reaction explosively-growing between organic applications and alkynes of the (CuAAC) Cu-catalyzed have stimulated Huisgen an 1,3-dipolarimpressive cycloadditionnumber of reports, reaction in the between last years, organic focusing azides on and recoverable alkynes (CuAAC) variants haveof the stimulated homogeneous an impressive or quasi- numberhomogeneous of reports, catalysts. in the Recent last years,advances focusing in the onfield recoverable are reviewed, variants with ofparticular the homogeneous emphasis on or quasi-homogeneoussystems immobilized catalysts. onto polymeric Recent advancesorganic or in inorganic the field are supports. reviewed, with particular emphasis on systems immobilized onto polymeric organic or inorganic supports. Keywords: supported catalysts; click-; continuous-flow chemistry; 1,2,3-triazoles Keywords: supported catalysts; click-chemistry; continuous-flow chemistry; 1,2,3-triazoles

1. Introduction 1. Introduction Efforts towards selectivity, atom economy, generation of molecular diversity, and experimental convenienceEfforts towards have been selectivity, a constant atom drive economy, in modern generation organic ofsynthesis. molecular Still, diversity, their union and in experimental the context convenienceof bond-forming have been(”ligation”) a constant processes, drive in with modern the organicconceptualization synthesis. Still, of ”click-chemistry“ their union in the contextby Kolb, of bond-formingFinn, and Sharpless (”ligation”) [1], appears processes, to have with become the conceptualization a potent trigger of of chemists’ ”click-chemistry“ inventiveness by Kolb, in recent Finn, andyears. Sharpless [1], appears to have become a potent trigger of chemists’ inventiveness in recent years. Essential to this outcome was the parallel and in independentdependent introduction, by the groups of Meldal and Sharpless, of the copper-catalyzed azide-alkyne cycloaddition reaction reaction (Scheme 11))[ [2,3].2,3]. In In fact, the orthogonal character vs. the the reactivity of most functional groups, complete regioselectivity in favor of the 1,4-disustituted-1,2,3-triazole product product 11 (“triazole”(“triazole” hereafter, hereafter, if if not noted otherwise), mild reaction conditions, and easy installation of the required azide and terminal alkyne moieties in the reactive partners, render the metal-promotedmetal-promoted version of the long-standinglong-standing Huisgen 1,3-dipolar cycloaddition reaction the most prominent techniquetechnique inin thethe click-chemistryclick-chemistry toolboxtoolbox [[4,5].4,5].

R1 R1 2 cat. Cu(I) N 1 R 5 N 1 1 2 R N3 + R N + N (base, solvent) 2 N N R 4 12

Scheme 1. The copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC).

WithWith applications applications ranging ranging from from material material science science to tomedicinal medicinal chemistry chemistry it is itnot is surprising not surprising that thatinvestigations investigations connected connected with the with CuAAC the CuAACtopic, or ju topic,st making or just use makingof this technique, use of this are technique,appearing arewith appearing impressive with and impressive increasingly and increasinglyhigh frequency high frequencyin the literature. in the literature. As shown As in shown Figure in Figure1, these1, theseadvancements advancements comprise comprise long-standing long-standing topics topics and so andme some incompletely incompletely settled settled aspects aspects like, like,e.g., e.g.,the thereaction reaction mechanism, mechanism, as well as well as asnew new trends trends and and examples examples of of use use of of CuAAC CuAAC in unprecedentedunprecedented directions [[6–61].6–61].

Molecules 2016, 21, 1174; doi:10.3390/molecules21091174 www.mdpi.com/journal/molecules

Molecules 2016, 21, 1174; doi:10.3390/molecules21091174 www.mdpi.com/journal/molecules Molecules 2016, 21, 1174 2 of 43 Molecules 2016, 21, 1174 2 of 41 Molecules 2016, 21, 1174 2 of 41

Enzyme modification and modification and linking [6-10]. Enzymeimmobilization modification [60,61]. and Polymer modification and linking [6-10]. New polymer architectures [11-14]. immobilization [60,61]. NewSynthesis polymer of macrocyclesarchitectures [15,16]. [11-14]. Synthesis of macrocycles [15,16]. Immobilization of small molecules for catalysis [54,55], Immobilizationsensing [56,57], of small chromatography molecules for [58], catalysis and metal [54,55], Smart materials, including stimuli- sensing [56,57], chromatographysorption [59]. [58], and metal Smartresponsive materials, including [17,18] stimuli- and sorption [59]. carbonresponsive nanocomposites polymers [17,18] [19-21]. and carbon nanocomposites [19-21]. Solid-phase and combinatorial Solid-phasechemistry and [52,53].combinatorial Surface modification [22-24] chemistry [52,53]. Surfaceand modification coating [25]. [22-24] Polymerand coating adhesives [25]. [26]. Conjugation and labeling of bio-molecules [43], Polymer adhesives [26]. includingConjugation and labeling [44-46], of polysaccharides bio-molecules [43], [47- including49], peptides and nucleic [44-46], acids polysaccharides [50,51]. [47- New catalytic systems and 49], and nucleic acids [50,51]. reactionNew catalytic mechanism systems [27-30]. and reaction mechanism [27-30]. Synthesis of bio-compatible materials [36-38], drugs,Synthesis and ofother bio-compatible bio-active compounds materials [36-38], [39-42]. drugs, and other bio-active compounds [39-42]. Non-classical CuAAC reaction conditionsNon-classical (e.g. flow CuAAC and reaction microwave Enantioselective CuAAC [34,35]. conditionsactivation (e.g. flow [31-33]). and microwave Enantioselective CuAAC [34,35]. activation [31-33]).

FigureFigure 1. 1.Main Main publication publication areas areas ofof CuAAC-relatedCuAAC-related pape papersrs and and selected selected examples examples ofof recent recent trends. trends. Figure 1. Main publication areas of CuAAC-related papers and selected examples of recent trends. InIn addition addition of of being being an an effective effective way way for for linking linking together together different different molecules, molecules, the the appreciation appreciation that In addition of being an effective way for linking together different molecules, the appreciation thethat triazole the structuraltriazole structural motif may motif have may pharmacologic have pharmacologic relevance, e.g.,relevance, as a more e.g., stable as a replacementmore stable for that the triazole structural motif may have pharmacologic relevance, e.g., as a more stable peptidereplacement bonds andfor inpeptide virtue bonds of its dipole and in moment, virtue of hydrogen-bonding, its dipole moment, and hydrogen-bonding,π-π stacking capabilities and π-π [42 ], stackingreplacement capabilities for [42], improvedbonds and further in virtue the ofinterest its dipole towards moment, CuAAC hydrogen-bonding, in the medicinal chemistry and π-π improved further the interest towards CuAAC in the medicinal chemistry field. Even if less represented field.stacking Even capabilities if less represented [42], improved than thefurther isomeric the interest 1,2,4-triazole towards motif, CuAAC contained in the inmedicinal various chemistryapproved than the isomeric 1,2,4-triazole motif, contained in various approved drugs [62,63], examples of drugsfield. Even[62,63], if less examples represented of bio-active than the isomericcompounds 1,2,4-triazole that embed motif, the contained 1,2,3-triazole in various nucleus approved keep bio-active compounds that embed the 1,2,3-triazole nucleus keep appearing continuously in the appearingdrugs [62,63], continuously examples in ofthe bio-active literature orcompounds have already that an establishedembed the clinical1,2,3-triazole use (Figure nucleus 2) [40,42]. keep literatureappearing or havecontinuously already in an the established literature clinicalor have usealready (Figure an established2)[40,42]. clinical use (Figure 2) [40,42].

Figure 2. Selected examples of drugs and other bioactive compounds containing the 1,2,3-triazole nucleus. FigureFigure 2.2. SelectedSelected examples examples of drugs ofand drugsother bioactive and other compounds bioactive containing compounds the 1,2,3-triazole containing nucleus. the 1,2,3-triazole nucleus. Molecules 2016, 21, 1174 3 of 43

MoleculesDespite 2016, the 21, 1174 many successes of CuAAC, the underlying chemistry suffers from three3 of main 41 drawbacks that pose limits to its usefulness, not only in a medicinal chemistry perspective but often alsoDespite in the the case many of materialssuccesses forof specialCuAAC, applications: the underlying (i) usechemistry of organic suffers azides, from whichthree main are not easydrawbacks to purify that and pose handle limits atto scaleits usefulness, because not of theironly potentialin a medicina instability;l chemistry (ii) perspective contamination but often of the clickalso product in the case with of catalyst materials components, for special applicatio copper abovens: (i) all;use andof organic (iii) instability azides, which of the are Cu(I) not oxidationeasy to purify and handle at scale because of their potential instability; (ii) contamination of the click product state, which imposes inert-atmosphere handling techniques or the addition of an excess of a reducing with catalyst components, copper above all; and (iii) instability of the Cu(I) oxidation state, which agent like [64]. In the specific context of the modification of bio-molecules like, e.g., imposes inert-atmosphere handling techniques or the addition of an excess of a reducing agent like polysaccharides and polypeptides, further problems may arise then from the generation of highly sodium ascorbate [64]. In the specific context of the modification of bio-molecules like, e.g., reactive species (H O , hydroxyl radicals, and dehydroascorbic acid), which cause chain cleavage or polysaccharides and2 2 polypeptides, further problems may arise then from the generation of highly denaturation [65–67]. reactive species (H2O2, hydroxyl radicals, and dehydroascorbic acid), which cause chain cleavage or denaturationIn addition [65–67]. to the use of flow-chemistry [32], a potentially general solution for the former problem is representedIn addition by in to situ the generation use of flow-chemistry of the organic azide[32], a under potentially multi-component general solution reaction for conditions the former [68 ]. Inproblem principle, is withrepresented this approach by in situ it isgeneration possible toof realizethe organic the consumptionazide under multi-component of the organic azide reaction in the CuAACconditions step, [68]. as soon In principle, as it forms, with and this thenapproach avoid it anyis possible build-up to realize in the reactionthe consumption mixture. of Depending the organic on theazide nature in the of the CuAAC azide step, intermediate as soon as (e.g., it forms, aliphatic and then or aromatic) avoid any and build-up of the startingin the reaction material mixture. selected forDepending the purpose, on differentthe nature possibilities of the azide exists intermediate in this respect. (e.g., aliphatic As summarized or aromatic) in and Scheme of the2, thosestarting met morematerial frequently, selected and for discussed the purpose, in detail different in the possibilities followingsections, exists in involvethis respect. the use As of: summarized in Scheme 2, those met more frequently, and discussed in detail in the following sections, involve the • useAlkyl of: halides (Scheme2a), often of the “activated” type (benzyl, allyl, α-halocarbonyls) with respect to the nucleophilic substitution reaction; • Alkyl halides (Scheme 2a), often of the “activated” type (benzyl, allyl, α-halocarbonyls) with • Epoxides (Scheme2b), which can lead to the formation of differently substituted triazoles ( 3 and 4) respect to the nucleophilic substitution reaction; • inEpoxides dependence (Scheme of the 2b), regioselectivity which can lead of to attack the fo ofrmation azide of differently on the oxirane substituted ring; triazoles (3 and • Aromatic4) in dependence diazonium of saltsthe regioselectivity (Scheme2c), either of attack commercially of azide ions available on the (e.g.,oxirane tetrafluoroborate ring; salts) • orAromatic produced diazonium in situ by diazotisationsalts (Scheme of 2c), the either corresponding commercially aromatic available amine; (e.g., tetrafluoroborate • Aromaticsalts) or boronicproduced acids in situ (Scheme by diazotisation2d), which of may the undergo corresponding azido-deboronation aromatic amine; under the action of • theAromatic same copper boronic catalyst acids involved(Scheme 2d), in the which CuAAC may undergo process [azido-deboronation69]. under the action of the same copper catalyst involved in the CuAAC process [69].

Scheme 2. Three-components CuAAC reactions (a–d) discussed in this paper. Scheme 2. Three-components CuAAC reactions (a–d) discussed in this paper.

On the contrary, the problems associated with the use of the copper catalyst have been tackled On the contrary, the problems associated with the use of the copper catalyst have been tackled by by adopting widely different strategies, including the use of strained alkynes or highly reactive adopting widely different strategies, including the use of strained alkynes or highly reactive azides, azides, that do not require metal catalysis at all [65,70–72], and reactants with chelating capability, which allow to reduce the catalyst loading [73]. Besides, many efforts were committed to the Molecules 2016, 21, 1174 4 of 43 that do not require metal catalysis at all [65,70–72], and reactants with chelating capability, which allow to reduce the catalyst loading [73]. Besides, many efforts were committed to the development of more effective catalytic systems based on copper or other metals [30]. Especially in the case of rhodium-catalyzed process, the latter choice may display a useful complementary profile with respect to CuAAC in that –with the proper choice of the catalytic complex-1,5-disubstituted-1,2,3-triazole products or even trisubstituted ones can be obtained from the reaction of terminal and internal alkynes, respectively. However, these alternatives still suffer from contamination of the product with transition metals and, usually, require more expensive catalyst precursor than CuAAC itself. As far as copper is concerned, some of the shortcomings associated with traditional systems (e.g., CuX salts in the presence of an amine co-catalyst or CuSO4 with an excess of sodium ascorbate) were eliminated with the introduction of stabilizing for the +I oxidation state of the metal and proper scavenging of reactive by-products [66,74]. Under these conditions CuAAC proceeds often under air, with catalyst concentration in the µM range and copper loading that, in some cases, can be reduced down to 0.01 mol % with respect to the substrates. Even so, the use of low-molecular weight soluble catalytic systems leaves unanswered the problem of contamination of the crude product with metal and, possibly, residues. For instance, in the case above a copper content up to 25 ppm might be found in the crude from a CuAAC reaction forming a compound of average molecular weight. This concentration exceeds the metal amount often quoted as acceptable for pharmaceutical applications (15 ppm) [75]. Considering also that the use of 0.01 mol % of copper catalyst represents more the exception than the rule, especially when structurally complex triazoles have to be prepared, one may expect that such a threshold is surpassed by several order of magnitude when this chemistry is employed in scenarios of practical synthetic relevance. In this regard it is worth noting that while the possibility of running CuAAC reactions with catalysts loadings in the low ppm range has been reported with systems comprising self-assembled gel [76], dendrimeric ligands [77], and homogeneous catalysts comprising a molecularly-enlarged water-soluble tris-triazole ligand [78], demonstration of the scope of these approaches to molecules more complex of those usually employed for benchmarking new CuAAC protocols are just beginning to appear [78]. Together with the fact that copper removal can be difficult, in particular for highly functionalized or sensitive products [79], these problems tend to collide with the goal of prompt product purification underlying in the concept of click-chemistry. Therefore it is not surprising that many attempts have been described in the course of the years, aimed to separate the CuAAC catalytic system from the reaction mixture in more effective ways. Some of these approaches rely on known homogeneous catalysts employed under alternative conditions like, e.g., recent reports making use of supercritical CO2 [80], glycerol, poly(ethylene glycol) (PEG), room-temperature ionic liquids, and their combinations thereof, as neoteric reaction media [81–85]. Similarly, water-soluble catalytic systems can provide an excellent opportunity for separation and recycling [78,86]. Albeit straightforward, this choice shows occasional limitations in terms of catalytic activity, seamless general implementation and, above all, effectiveness in reducing the residual copper content to an extent that might cope with the said regulatory requirements. In an alternative strategy, catalytic systems specifically designed for easier separation were therefore developed, typically by immobilization of copper species onto insoluble supports or quasi-homogeneous materials, like . Even if the degree of success may greatly vary from case to case, as discussed in the next sections, on the average this route appears better fit for the effective removal of the catalytic system from the reaction mixture and for the abatement of copper content in the crude by techniques amenable of use even at scale, like filtration, centrifugation, and magnetic decantation. Of course, with this choice an opportunity arises also for catalyst recovery and reuse. In this respect it might be argued that, given the cheapness of most Cu(I/II) catalyst precursors, this goal is not necessarily the primary objective in the development of improved catalytic systems for CuAAC. Molecules 2016, 21, 1174 5 of 43

Nevertheless, the possibility of recycling the metal species and any associated ligand, recovered “for free” at the product purification stage, is an appealing feature that stimulated much work in this direction. The topic of recoverable systems for CuAAC has been briefly summarized before [87], up to the comprehensive reviews by Haldon et al. in 2015 [88], and Chassaing et al. [89], early this year. In addition, some specific aspects were covered in context like the use of supported ionic liquid phase catalyst [90], nanostructured and nanoporous Cu catalysts [91], CuO nanoparticles [92], and in the recent accounts by the groups of Alonso and of Astruc on the use of copper nanoparticles (CuNPs) [93], magnetic or dendritic catalysts [55], and present trends in azide-alkyne cycloaddition reactions [30]. Even so, the pace of research in the field of recoverable catalytic systems for CuAAC is so fast at present, that many more examples have appeared since the publication of the reference works above. The discussion of these recent advances, mostly published in the period 2015–mid 2016, is the aim of the present review. In this regard, it must be pointed out that while recoverable systems for CuAAC will be covered in the broadest sense, the focus will be essentially on catalysts on insoluble supports and quasi-homogeneous systems where the presence of an organic polymer plays a decisive role. In general, an effort will be made for summarizing preparation method, characterization, conditions of use, activity, and scope of the various systems. Whenever possible, and for the reasons discussed above, the specific issues of catalyst leaching and product contamination will be examined in detail.

2. Cu, Cu2O, CuO, and CuX Nanoparticles and Nanocomposites Like in many other catalytic processes [94], nanoparticles have received a great deal of attention in the context of CuAAC. Although just a fraction of the metal centers are actually exposed to the surrounding reaction medium (e.g., 28% for a spherical CuO with a diameter dp = 4.7 nm)[95], nano-sized systems may nonetheless display high specific activity that, in some cases, appears related with facet index [96]. Because Cu2O is chemically unstable in air and Cu(0) nanoparticles tend to sinter or dissolve under CuAAC reaction conditions [93,97], some kind of stabilization is normally required. Similarly to the oxide layer covering bulk copper [75], the same problem is apparently met with porous forms of the metal and CuNPs prepared in solution, for which recent reports do not describe any recycle at all or show relatively fast loss of catalytic activity [98–101]. In many instances a solution to these problems is provided by the use of an insoluble support with suitable complexing sites, like amino groups [102], which may be very effective in preventing particle aggregation and extensive metal leaching.

2.1. Carbon Supports Copper-in-charcoal (Cu/C) has been repeatedly employed as a cheap and relatively effective catalyst in CuAAC reactions [88,89]. While the occurrence of CuO and Cu2O particles is generally acknowledged in Cu/C obtained by calcination [103–105], recently Buckley et al. [106] identified unsupported gerhardite (Cu2(OH)3NO3) as the likely catalyst precursor in materials prepared by the Lipshutz0 low-temperature carbon impregnation method [107,108]. Upon exposure to CuAAC conditions, the Cu(II) salt was found to transform into the actual active form, deemed to be a polymeric Cu(I) acetylide. The latter could be recovered by filtration, along with unreacted gerhardite, but no recycling of the material was reported. In this context it is worth noting also that Decan and Scaiano provided a detailed picture of commercial Cu/C catalyst under in operando conditions [109]. The study, based on single fluorescence microscopy for mapping CuAAC events, suggested that 90% of the charcoal particles in the sample were devoid of any . Moreover, for the remaining 10% ones the active sites were estimated to represent just a minute fraction (approximate 0.003%) of the total surface. These results might help to explain the scarce catalytic activity, reported in some investigations for Cu/C samples from commercial sources [106,110]. Molecules 2016, 21, 1174 6 of 43

An on-purpose prepared Pd-Cu bimetallic catalytic system on charcoal was studied by Rossy et al. for one-pot sequential Sonogashira-click and click-Heck reactions [111]. Unfortunately, an attempt to recycle the material in the former reaction evidenced essentially complete loss of its catalytic activity. D’Haullin et al. prepared ultra-small copper oxide nanoparticles on graphite by stirring a suspension of the powdered support in a solution of Cu(OAc)2 in MeOH, kept under H2 [112]. The catalysts, which consisted of CuO, Cu(OH)2 and minor amounts of Cu2O, displayed fair activity in three-componentMolecules 2016, 21, 1174 CuAAC reactions of halides and styrene oxide (Scheme2a,b). Although no recycling6 of 41 of the material was apparently attempted, filtration of the reaction mixture through a Nylon membrane permittedmembrane the permitted prompt removalthe prompt of theremoval insoluble of the system insoluble and leftsystem only and trace left amounts only trace of copper amounts in the of filtratecopper (6in ppb).the filtrate (6 ppb). CuCu22O nanoparticles nanoparticles on on graphene graphene oxide oxide (GO, (GO, 6), 6were), were obtained obtained by Nia by et Nia al. etthrough al. through high- high-temperaturetemperature treatment treatment in an Ar in anstream Ar stream of GO ofimpregnated GO impregnated with Cu(OAc) with Cu(OAc)2 [110].2 The[110 material]. The material proved provedmore active more than active commercial than commercial Cu/C Cu/Cand Cu and2O Cuin two-components2O in two-components CuAAC CuAAC reactions reactions (Scheme (Scheme 1), but1), ◦ buta relatively a relatively large large catalyst catalyst loading loading (2 (2mol mol %) %) and and extended extended reaction reaction time time (48 (48 h h at at 40 40 °C)C) were stillstill necessarynecessary forfor attainingattaining goodgood results.results. Moreover, recycling experiments in thethe benchmarkbenchmark reactionreaction betweenbetween benzyl azide azide and and phenylacetylene in inTHF THF showed showed a marked a marked decrease decrease of the of product the product yield yieldalready already in the fourth in the run fourth (99% run → 55%). (99% Interestingly,→ 55%). Interestingly, 6 was effective6 was also effectivein the bulk also cross-linking in the bulk of cross-linkinga mixture of of alkyne a mixture and of azide alkyne trifunctional and azide trifunctional macromolecular macromolecular reactants reactants 7 and 87, andbased8, based on star on starpoly(isobutylene) poly(isobutylene) (PIB) (PIB) chains chains (Scheme (Scheme 3).3 ).Alth Althoughough in in these these cases cases trapping trapping of thethe coppercopper nanocompositenanocomposite inside the resulting resin 9 preventsprevents itsits reuse,reuse, itit isis worthworth mentioningmentioning thatthat aa kinetickinetic studystudy ofof click-polymerizationsclick-polymerizations promotedpromoted byby 66 waswas publishedpublished alsoalso [[113].113].

Scheme 3. Click polymerization of alkyne and azide PIB trifunctionaltrifunctional reactants.reactants.

MoreMore recently,recently, thethe samesame groupgroup reportedreported highlyhighly disperseddispersed coppercopper clustersclusters onon carboncarbon nano-tubesnano-tubes (CNT)(CNT) andand chemically-reducedchemically-reduced graphenegraphene oxideoxide (CRGO)(CRGO) [[114].114]. TheseThese systemssystems 1010,, supposedsupposed toto embedembed Cu(carbene)XCu(carbene)X or or Cu-Cu Cu-Cu fragments fragments on on the the basis basis of literature of literature preceden precedentsts for Ag(I) for Ag(I) analogs analogs [115], [were115], wereobtained obtained by a bystepwise a stepwise procedure procedure culminating culminating (Sch (Schemeeme 4)4 in) in the the decoration decoration of of the supportssupports withwith triazole-imidazoliumtriazole-imidazolium units and formationformation ofof Cu(I)-carbeneCu(I)-carbene clusters.clusters. Despite the not soso muchmuch dissimilardissimilar coppercopper content of of CNT CNT and and CRGO-based CRGO-based materials materials 1010, the, the latter latter displayed displayed a higher a higher catalytic catalytic activity activity and andbetter better recycling recycling profil profilee than than the former the former (respectively, (respectively, 99% 99% → 91%→ 91% and and 60% 60% → 45%→ 45% yield yield in 10 in 10runs) runs) in intwo-components two-components CuAAC CuAAC reactions reactions (Scheme (Scheme 1)1 )and and in in the click-reticulationclick-reticulation processprocess mentionedmentioned aboveabove (Scheme(Scheme3 3).). Even in this case, the runs had to be carried for long time (24–72 h at 40 ◦C) and with substantial amounts of catalyst (2 mol %–8 mol %). In spite of this, copper concentration in the filtrate from the reaction mixture was reportedly too low for accurate quantification. Another instance of copper oxide nanoparticles on GO was described by Reddy et al. [116]. The preparation of the supported system was achieved through a published procedure [117], whose key steps are the intercalation of Cu(II) between GO sheets and the subsequent exfoliation of the material, caused by nucleation and growth of CuO crystallites. TEM and XRD characterization of the nanocomposite confirmed the presence of CuO nanoparticles (15–50 nm) onto a graphene-like support. At variance with the examples discussed above and Cu2O on bare CRGO [118], the GO-CuO system proved highly active in water at 25 ◦C, even at 0.227 mol % loading. Under these conditions the addition of various benzyl or aryl azides to terminal alkynes (Scheme1) proceeded in 10–20 min

Scheme 4. Preparation of Cu(I)-carbene clusters 10 on carbon nano-materials.

Even in this case, the runs had to be carried for long time (24–72 h at 40 °C) and with substantial amounts of catalyst (2 mol %–8 mol %). In spite of this, copper concentration in the filtrate from the reaction mixture was reportedly too low for accurate quantification. Another instance of copper oxide nanoparticles on GO was described by Reddy et al. [116]. The preparation of the supported system was achieved through a published procedure [117], whose key Molecules 2016, 21, 1174 6 of 41

membrane permitted the prompt removal of the insoluble system and left only trace amounts of copper in the filtrate (6 ppb). Cu2O nanoparticles on graphene oxide (GO, 6), were obtained by Nia et al. through high- temperature treatment in an Ar stream of GO impregnated with Cu(OAc)2 [110]. The material proved more active than commercial Cu/C and Cu2O in two-components CuAAC reactions (Scheme 1), but a relatively large catalyst loading (2 mol %) and extended reaction time (48 h at 40 °C) were still necessary for attaining good results. Moreover, recycling experiments in the benchmark reaction between benzyl azide and phenylacetylene in THF showed a marked decrease of the product yield already in the fourth run (99% → 55%). Interestingly, 6 was effective also in the bulk cross-linking of a mixture of alkyne and azide trifunctional macromolecular reactants 7 and 8, based on star poly(isobutylene) (PIB) chains (Scheme 3). Although in these cases trapping of the copper nanocomposite inside the resulting resin 9 prevents its reuse, it is worth mentioning that a kinetic study of click-polymerizations promoted by 6 was published also [113].

Scheme 3. Click polymerization of alkyne and azide PIB trifunctional reactants. Molecules 2016, 21, 1174 7 of 43 More recently, the same group reported highly dispersed copper clusters on carbon nano-tubes (CNT) and chemically-reduced graphene oxide (CRGO) [114]. These systems 10, supposed to embed toCu(carbene)X give the corresponding or Cu-Cu fragments triazoles on in highthe basis yield of (85%–96%).literature preceden In additionts for Ag(I) to good analogs dispersion [115], were of the nanocomposite,obtained by a thestepwise result procedure was attributed culminating to hydrophobic (Scheme phenomena4) in the decoration at the carbon of the surfacesupports [119 with,120 ], relatedtriazole-imidazolium to the so called “Breslowunits and formation effect” [121 of]. Cu(I)-carbene Filtration through clusters. a 0.2Despiteµm PTFE the not membrane so much dissimilar allowed the separationcopper content of GO-CuO of CNT andand itsCRGO-based reuse in five materials cycles, 10 where, the latter some displayed decrease a higher of product catalytic yield activity was and noted evenbetter with recycling the adoption profile than of progressively the former (respectively, longer reaction 99% → time 91% (approximate and 60% → 45% 96% yield→ 90%). in 10 Theruns) effect in wastwo-components ascribed to leaching CuAAC of reactions CuO in the(Scheme water 1) phase, and in estimated the click-reticulation to occur at process a pace ofmentioned around 0.6above wt % per(Scheme cycle. 3).

Molecules 2016, 21, 1174 7 of 41 steps are the intercalation of Cu(II) between GO sheets and the subsequent exfoliation of the material, caused by nucleation and growth of CuO crystallites. TEM and XRD characterization of the nanocomposite confirmed the presence of CuO nanoparticles (15–50 nm) onto a graphene-like support. At variance with the examples discussed above and Cu2O on bare CRGO [118], the GO-CuO system proved highly active in water at 25 °C, even at 0.227 mol % loading. Under these conditions the addition of various benzyl or aryl azides to terminal alkynes (Scheme 1) proceeded in 10–20 min to give the corresponding triazoles in high yield (85%–96%). In addition to good dispersion of the nanocomposite, the result was attributed to hydrophobic phenomena at the carbon surface [119,120], related to the so called “Breslow effect” [121]. Filtration through a 0.2 μm PTFE membrane allowed the separation of GO-CuO and its reuse in five cycles, where some decrease of product yield was noted even with the adoptionSchemeScheme 4.of 4. Preparationprogressively Preparationof of Cu(I)-carbene Cu(I)-carbenelonger reaction clusters time 1010 (approximate onon carbon carbon nano-materials. nano-materials. 96% → 90%). The effect was ascribed to leaching of CuO in the water phase, estimated to occur at a pace of around 0.6 wt % per cycle. A lastEvenlast recentrecent in this entry entry case, in thein the the runs list list ofhad of GO-based toGO-based be carried materials ma forterials long for timefor CuAAC CuAAC (24–72 comes h comesat 40 from °C) from the and workthe with work of substantialDabiri of Dabiri et al. (Schemeet al.amounts (Scheme5)[ of122 catalyst5)]. [122]. In this (2 In mol this study, %–8 study, GO mol GO was %). was reactedIn spite reacted of with this, with ethylenediamine copper ethylenediamine concentration with with in the the the aim filtrate aim of of preparing from preparing the a 3Da 3Dreaction graphene graphene mixture hydrogel hydrogel was reportedly that, that, in in a atoo subsequent subsequent low for accurate step, step, was wasquantification. decorateddecorated withwith oxidizedoxidized CuNPs,CuNPs, from the Another instance of copper oxide nanoparticles on GO was described by Reddy et al. [116]. The reduction of Cu(NOCu(NO3)2,, to to give give 11.. In In a a series of two- andand three-componentsthree-components reactionsreactions inin EtOH-HEtOH-H22O preparation of the supported system was achieved through a published procedure [117], whose key (1:1), the catalyticcatalytic activity in CuAACCuAAC of thethe resultingresulting systemsystem resembledresembled thatthat ofof otherother carbon-basedcarbon-based materials noted above. In particular, relatively high loading and reaction temperature (5 mol % and 70 °C)◦C) respectively, had to be adopted for attaining good yields within 1–7 h (81%–99%). On the other hand, the 3D-graphene material displayed a better re recyclabilitycyclability than most of the analogous systems, as witnessed by minimal reduction of product yield at fixedfixed reaction time even after 10 consecutiveconsecutive cycles (99%(99% →→ 97%).97%).

SchemeScheme 5.5. Preparation ofof 3D-graphene/CuNPs3D-graphene/CuNPs nanocomposite 11..

2.2. Insoluble Synthetic Organic Polymers CuAAC catalytic systems on organic polymers, 12 and 13 (Scheme 6), were obtained recently by depositing nanoparticles of cuprous halides on a poly(styrene-co-maleic anhydride) imide (SMI) or polyaniline (PANI). The former support material, studied by Hashemi et al., was obtained by treating styrene-maleic anhydride copolymer with 4-aminopyridine under dehydrating conditions [123]. Subsequent refluxing with CuI nanoparticles, prepared by DMF precipitation of the cuprous salt from a MeCN solution, led 12, that was shown by SEM to contain an uniform dispersion of copper halide crystals within the fiber-like polymeric matrix. In a similar approach, 13 was obtained by Saadat et al. by refluxing PANI and CuI in EtOH, under an inert atmosphere [124]. The catalytic activity of the materials was evaluated in three-component CuAAC reactions of activated halides or methyl iodide (Scheme 2a). The reactions were typically carried out in boiling water, with 1 mol % of 12 or, respectively, 5 mol % of 13. Despite the potential solvolytic instability of the halide reactants under Molecules 2016, 21, 1174 8 of 43

2.2. Insoluble Synthetic Organic Polymers CuAAC catalytic systems on organic polymers, 12 and 13 (Scheme6), were obtained recently by depositing nanoparticles of cuprous halides on a poly(styrene-co-maleic anhydride) imide (SMI) or polyaniline (PANI). The former support material, studied by Hashemi et al., was obtained by treating styrene-maleic anhydride copolymer with 4-aminopyridine under dehydrating conditions [123]. Subsequent refluxing with CuI nanoparticles, prepared by DMF precipitation of the cuprous salt from a MeCN solution, led 12, that was shown by SEM to contain an uniform dispersion of copper halide crystals within the fiber-like polymeric matrix. In a similar approach, 13 was obtained by Saadat et al. by refluxing PANI and CuI in EtOH, under an inert atmosphere [124]. The catalytic activity of the materials was evaluated in three-component CuAAC reactions of activated halides or methylMolecules iodide2016, 21, (Scheme1174 2a). The reactions were typically carried out in boiling water, with 1 mol8 of % 41 of 12 or, respectively, 5 mol % of 13. Despite the potential solvolytic instability of the halide reactants underthese conditions, these conditions, fair to fairgood to yields good yieldswere report were reporteded in both in bothstudies studies (71%–92% (71%–92% in 15–145 in 15–145 min). min). The Thescarce scarce solubility solubility of the of therespective respective support support material material in inwater, water, as as well well as as in in most most organic organic solvents, allowed thethe recoveryrecovery and and reuse reuse of of the the catalytic catalytic systems. systems. Also Also from from this this point point of view,of view, the the findings findings of the of twothe two investigations investigations were were quite quite similar, similar, with with some some decrease decrease of product of product yield yield (approximate (approximate92% →92%83% → and83% 92%and →92%88%, → 88%, respectively) respectively) and a and moderate a moderate reduction reduction of metal of loading metal loading on the supporton the support (5% and (5% 3%, respectively)and 3%, respectively) after five after consecutive five consecutive runs. runs.

CuI, MeCN-DMF (0.35 mmol Cu g-1, SMI SMI/CuI (12) d = 53-101 nm) reflux, 5 h P n Ph O N O N H n CuI, EtOH (0.94 mmol Cu g-1, SMI PANI PANI PANI/CuI (13) d = 20-60 nm) N reflux, 12 h P Scheme 6. Preparation of CuI nanocrystals on SMI and PANI polymericpolymeric supports,supports, 1212 andand 1313..

Savva et al. investigated the use of electrospinning as a mean for obtaining Cu2O nanoparticles Savva et al. investigated the use of electrospinning as a mean for obtaining Cu2O nanoparticlesembedded into embedded membranes into membranesmade of cross-linked made of cross-linked poly(N-vinyl poly( Npyrrolidone)-vinyl pyrrolidone) (PVP) (PVP)[125]. [125The]. Thepreparation preparation route route (Scheme (Scheme 7a)7 a)involved involved hydrazin hydrazinee reduction reduction of of a amixture mixture of of linear PVPPVP andand Cu(OAc)2, followed by electrospinning of the resulting colloidal solution on a target collector and Cu(OAc)2, followed by electrospinning of the resulting colloidal solution on a target collector and final final curing at◦ 180 °C. With this procedure, initially formed Cu(0) clusters were probably oxidized to curing at 180 C. With this procedure, initially formed Cu(0) clusters were probably oxidized to Cu2O andCu2O a materialand a material14 was obtained14 was obtained that, contrarily that, contrarily to linear PVP, to linear resulted PVP, insoluble resulted in insoluble water. Interestingly, in water. theInterestingly, curing stage the did curing not causestage did dramatic not cause variations dramat ofic thevariations morphology of the ofmorphology the membrane, of the in membrane, particular forin particular what it concerns for what the it occurrenceconcerns the of occurrence cylindrical of polymer cylindrical fibrils polymer supporting fibrils a uniformsupporting dispersion a uniform of metaldispersion oxide of particles. metal Theoxide electrospun particles. compositeThe electrospun membrane composite14 was effective membrane in promoting 14 was effective the CuAAC in additionpromoting of benzylthe CuAAC azide to addition phenylacetylene of benzyl in 1,4-dioxaneazide to phenylacetylene and in the presence in 1,4-dioxane of an equivalent andamount in the presence of an equivalent amount of Et3N. However, a rather high metal loading (5 mol % Cu) was of Et3N. However, a rather high metal loading (5 mol % Cu) was used in these experiments in order toused obtain in these the triazole experiments product in inorder 87% to yield obtain after the 2 h triazole at 60 ◦C. product Moreover, in 87% reuse yield of the after material 2 h at in 60 three °C. consecutiveMoreover, reuse runs of indicated the material a gradual in three loss consecutive of catalytic runs activity indicated (87% a →gradual77% yield),loss of accompaniedcatalytic activity by aggregation(87% → 77%phenomena yield), accompanied of the polymer by aggregation fibers. phenomena of the polymer fibers. The use of poly(vinyl ) (PVA) for stabilizing Cu2O nanoparticles was explored by Hajipour et al. [97]. In this case, the preparation of the catalytic system (Scheme7b) involved the initial formation of a gel from PVA and CuSO4 in alkaline NaOH solution, followed by reduction with sodium ascorbate, aging, filtration, and washing. Drying in air afforded a reddish product 15, characterized by a broad UV band centered around 491 nm and an XRD pattern matching that of Cu2O. Interestingly, the choice of basic conditions (pH = 12) proved essential for the reduction to Cu(I) because the same step, carried out without the addition of NaOH, led to a material featuring the XRD diffractions of metallic copper. Screening of PVA-Cu2O in CuAAC involved reactions of preformed

Scheme 7. Preparation of PVP/Cu2O membrane 14 (a) and of PVA/Cu2O composite 15 (b).

The use of poly(vinyl alcohol) (PVA) for stabilizing Cu2O nanoparticles was explored by Hajipour et al. [97]. In this case, the preparation of the catalytic system (Scheme 7b) involved the initial formation of a gel from PVA and CuSO4 in alkaline NaOH solution, followed by reduction with sodium ascorbate, aging, filtration, and washing. Drying in air afforded a reddish product 15, characterized by a broad UV band centered around 491 nm and an XRD pattern matching that of Cu2O. Interestingly, the choice of basic conditions (pH = 12) proved essential for the reduction to Cu(I) because the same step, carried out without the addition of NaOH, led to a material featuring the XRD diffractions of metallic copper. Screening of PVA-Cu2O in CuAAC involved reactions of Molecules 2016, 21, 1174 8 of 41

these conditions, fair to good yields were reported in both studies (71%–92% in 15–145 min). The scarce solubility of the respective support material in water, as well as in most organic solvents, allowed the recovery and reuse of the catalytic systems. Also from this point of view, the findings of the two investigations were quite similar, with some decrease of product yield (approximate 92% → 83% and 92% → 88%, respectively) and a moderate reduction of metal loading on the support (5% and 3%, respectively) after five consecutive runs.

CuI, MeCN-DMF (0.35 mmol Cu g-1, SMI SMI/CuI (12) d = 53-101 nm) reflux, 5 h P n Ph O N O N H n CuI, EtOH (0.94 mmol Cu g-1, SMI PANI PANI PANI/CuI (13) d = 20-60 nm) N reflux, 12 h P Scheme 6. Preparation of CuI nanocrystals on SMI and PANI polymeric supports, 12 and 13.

Savva et al. investigated the use of electrospinning as a mean for obtaining Cu2O nanoparticles embedded into membranes made of cross-linked poly(N-vinyl pyrrolidone) (PVP) [125]. The preparation route (Scheme 7a) involved hydrazine reduction of a mixture of linear PVP and MoleculesCu(OAc)20162,,21 followed, 1174 by electrospinning of the resulting colloidal solution on a target collector and9 of 43 final curing at 180 °C. With this procedure, initially formed Cu(0) clusters were probably oxidized to Cu2O and a material 14 was obtained that, contrarily to linear PVP, resulted insoluble in water. aromatic azides (Scheme1), or benzyl azides formed in situ from the corresponding halides and NaN Interestingly, the curing stage did not cause dramatic variations of the morphology of the membrane, 3 (Scheme2a). In both cases the reactions were run in water with a low, yet unspecified, copper loading in particular for what it concerns the occurrence of cylindrical polymer fibrils supporting a uniform and in the presence of tetrabutylammonium bromide. Rather surprisingly, the latter proved beneficial dispersion of metal oxide particles. The electrospun composite membrane 14 was effective in evenpromoting in the former the CuAAC scenario, addition i.e., where of benzyl the action azide of ato typical phenylacetylene phase-transfer in 1,4-dioxane catalyst was and expected in the to bepresence marginal of due an toequivalent the lack amount of ionic reactants.of Et3N. However, Under the a rather said conditionshigh metal theloading CuAAC (5 mol runs % Cu) proceeded was smoothlyused in tothese give experiments the expected in triazoles order to in obtain reasonable the triazole yield (68%–95%product in in87% 1–9 yield h). Moreover, after 2 h at the 60 activity °C. of theMoreover, pristine reuse catalyst of the was material retained in three with theconsecutive insoluble runs material indicated recovered a gradual by decantationloss of catalytic and activity washing, as(87% confirmed → 77% by yield), essentially accompanied constant by results aggregation in the phenomena course of 4 reactionof the polymer cycles fibers. (95% → 94% yield).

Molecules 2016, 21, 1174 9 of 41 preformed aromatic azides (Scheme 1), or benzyl azides formed in situ from the corresponding halides and NaN3 (Scheme 2a). In both cases the reactions were run in water with a low, yet unspecified, copper loading and in the presence of tetrabutylammonium bromide. Rather surprisingly, the latter proved beneficial even in the former scenario, i.e., where the action of a typical phase-transfer catalyst was expected to be marginal due to the lack of ionic reactants. Under the said conditions the CuAAC runs proceeded smoothly to give the expected triazoles in reasonable yield Scheme 7. Preparation of PVP/Cu2O membrane 14 (a) and of PVA/Cu2O composite 15 (b). (68%–95%Scheme in 1–9 7. h).Preparation Moreover, of PVP/Cuthe activity2O membrane of the pristine14 (a) and catalyst of PVA/Cu was retained2O composite with15 the(b). insoluble material recovered by decantation and washing, as confirmed by essentially constant results in the The use of poly(vinyl alcohol) (PVA) for stabilizing Cu2O nanoparticles was explored by courseIn of an 4 unusual reaction approach,cycles (95% Patil → 94% et al. yield). immobilized the ascorbate reducing agent on a polystyrene Hajipour et al. [97]. In this case, the preparation of the catalytic system (Scheme 7b) involved the resinIn decorated an unusual with approach,N-methylimidazolium Patil et al. immobilize ionic fragmentsd the ascorbate [126]. reducing The material agent 16on wasa polystyrene obtained initial formation of a gel from PVA and CuSO4 in alkaline NaOH solution, followed by reduction (Scheme8) by reacting a Merrifield resin with N-methylimidazole, exchanging hydroxide ions for resinwith decorated sodium ascorbate, with N-methylimidazolium aging, filtration, and ionicwashing. fragments Drying in[126]. air aThefforded material a reddish 16 wasproduct obtained 15, the(Schemecharacterized chloride 8) by ones reacting by and a broad thena Merrifield treatingUV band resin the centered basic with formNaround-methylimidazole, of the491 materialnm and anwithexchanging XRD ascorbic pattern hydroxide acid. matching The ions supported that for of the reducing agent (16 mol %) was employed in three-components CuAAC reactions in water of aromatic chlorideCu2O. Interestingly,ones and then the treating choice ofthe basic basic conditions form of the(pH material= 12) proved with essentialascorbic foracid. the The reduction supported to diazoniumreducingCu(I) because agent tetrafluoroborates (16 the mol same %) step, was (Schemecarriedemployed out2c), inwithout implementedthree- componentsthe addition by making CuAACof NaOH, use reactions led of CuSOto a inmaterial4 water(4 mol offeaturing %)aromatic as the solublediazoniumthe XRD catalyst tetrafluoroboratesdiffractions precursor. of metallic While (Scheme thiscopper. choice2c), Screening implemented is expected of PVA-Cu by to leadmaking2O to in progressive CuAACuse of CuSO involved consumption4 (4 molreactions %) as of of the ascorbatesoluble catalyst co-catalyst, precursor. TEM-EDS While and this XPS choice analyses is expected of the resinto lead recovered to progressive at the endconsumption of CuAAC of runs the suggestedascorbate co-catalyst, the presence TEM-EDS of CuNPs and on theXPS material analyses (probably of the resin CuO, recovered approximate at the 0.52 end mmol of CuAAC·g−1). At runs the samesuggested time, the no presence metal was of CuNPs found on in the mate filtraterial by(probably AAS, thus CuO, offering approximate the possibility 0.52 mmol·g of− recycling1). At the thesame (in time, situ) no immobilized metal was found catalyst. in the This filtrate was by effected AAS, thus with offering reasonable the possibility albeit incomplete of recycling efficiency, the (in assitu) confirmed immobilized by thecatalyst. observation This was of effected significant with yieldreasonable values albeit through incomplete 6 consecutive efficiency, reaction as confirmed cycles (94%by the→ observation85%). of significant yield values through 6 consecutive reaction cycles (94% → 85%).

Me (1) NN N toluene, reflux, 24 h N Me Cl (2) KOH, water, 18 h OH O (3) Ascorbic acid H O water, 12 h O HO Merrifield resin OH 16 (2% DVB, 2-4 mmol Cl g-1)

Scheme 8. Preparation of resin-supported ascorbate 16.

2.3. Metal-Organic Frameworks Metal-organic frameworks (MOFs) (MOFs) represent an interesting class ofof hybridhybrid organic-inorganicorganic-inorganic 2 porous materials with tunabletunable propertiesproperties [[127].127]. TheThe preparationpreparation ofof CuCu2O nanoparticlesnanoparticles immobilizedimmobilized within the pores of (Zn(Himdc)(bipy)0.5) (Himdc = 4,5-imidazoledicarboxylate; bipy = 4,4′-bipyridine, Scheme 9) was achieved by Jayaramulu et al. through reduction with hydrazine hydrate of the CuSO4- impregnated MOF [128]. XRD, XPS, and TEM characterization of the resulting solid 17 showed the presence of Cu2O nanoparticles (mainly 2–3 nm in size and containing minor amounts of CuO), dispersed within the pores of the essentially intact Zn(II)-ligands framework. Two-components CuAAC catalytic runs (Scheme 1), in the presence of an equivalent amount of Et3N and 0.5 mol % of 17 in t-BuOH-H2O (2:1), afforded nearly quantitative yields after 7 h at 50 °C. The MOF-supported catalyst could be recovered by filtration, dissolution of the triazole product in CHCl3 and centrifugation, thus allowing the completion of three reaction cycles with reportedly unchanged activity.

Scheme 9. Preparation of Cu2O nanoparticles in 2D metal-organic framework, 17. Molecules 2016, 21, 1174 9 of 41 preformed aromatic azides (Scheme 1), or benzyl azides formed in situ from the corresponding halides and NaN3 (Scheme 2a). In both cases the reactions were run in water with a low, yet unspecified, copper loading and in the presence of tetrabutylammonium bromide. Rather surprisingly, the latter proved beneficial even in the former scenario, i.e., where the action of a typical phase-transfer catalyst was expected to be marginal due to the lack of ionic reactants. Under the said conditions the CuAAC runs proceeded smoothly to give the expected triazoles in reasonable yield (68%–95% in 1–9 h). Moreover, the activity of the pristine catalyst was retained with the insoluble material recovered by decantation and washing, as confirmed by essentially constant results in the course of 4 reaction cycles (95% → 94% yield). In an unusual approach, Patil et al. immobilized the ascorbate reducing agent on a polystyrene resin decorated with N-methylimidazolium ionic fragments [126]. The material 16 was obtained (Scheme 8) by reacting a Merrifield resin with N-methylimidazole, exchanging hydroxide ions for the chloride ones and then treating the basic form of the material with ascorbic acid. The supported reducing agent (16 mol %) was employed in three-components CuAAC reactions in water of aromatic diazonium tetrafluoroborates (Scheme 2c), implemented by making use of CuSO4 (4 mol %) as the soluble catalyst precursor. While this choice is expected to lead to progressive consumption of the ascorbate co-catalyst, TEM-EDS and XPS analyses of the resin recovered at the end of CuAAC runs suggested the presence of CuNPs on the material (probably CuO, approximate 0.52 mmol·g−1). At the same time, no metal was found in the filtrate by AAS, thus offering the possibility of recycling the (in situ) immobilized catalyst. This was effected with reasonable albeit incomplete efficiency, as confirmed by the observation of significant yield values through 6 consecutive reaction cycles (94% → 85%).

Me (1) NN N toluene, reflux, 24 h N Me Cl (2) KOH, water, 18 h OH O (3) Ascorbic acid H O water, 12 h O HO Merrifield resin OH 16 (2% DVB, 2-4 mmol Cl g-1) Scheme 8. Preparation of resin-supported ascorbate 16.

2.3. Metal-Organic Frameworks Molecules 2016, 21, 1174 10 of 43 Metal-organic frameworks (MOFs) represent an interesting class of hybrid organic-inorganic porous materials with tunable properties [127]. The preparation of Cu2O nanoparticles immobilized 0 withinwithin thethe porespores ofof (Zn(Himdc)(bipy)(Zn(Himdc)(bipy)0.50.5) (Himdc == 4,5-imidazoledicarboxylate;4,5-imidazoledicarboxylate; bipy == 4,44,4′-bipyridine, Scheme 99)) was achieved achieved by by Jayara Jayaramulumulu et etal. al.through through reduction reduction with withhydrazine hydrazine hydrate hydrate of the CuSO of the4- CuSOimpregnated4-impregnated MOF [128]. MOF XRD, [128]. XPS, XRD, and XPS, TEM and characterization TEM characterization of the of resulting the resulting solid solid 17 showed17 showed the thepresence presence of Cu of2 CuO 2nanoparticlesO nanoparticles (mainly (mainly 2–3 2–3 nm nm in insize size and and containing containing minor minor amounts amounts of of CuO), dispersed within the pores of the essentially intact Zn(II)-ligands framework. Two-components CuAAC catalytic runs (Scheme 11),), inin thethe presencepresence ofof anan equivalentequivalent amountamount ofof EtEt3NN and and 0.5 0.5 mol % of 17 inin ◦ t-BuOH-H2O (2:1), afforded nearly quantitative yields after 7 h at 50 °C.C. The MOF-supported catalyst could be recoveredrecovered byby filtration,filtration, dissolutiondissolution ofof thethe triazoletriazole productproduct inin CHClCHCl33 and centrifugation,centrifugation, thus allowing the completion of of three three reaction reaction cycles cycles with with reportedly reportedly unchanged unchanged activity. activity.

2 Molecules 2016, 21Scheme, 1174 9. Preparation of Cu2O nanoparticles in 2D metal-organic framework, 17.. 10 of 41

Considering also that TEM, XRD, and COCO22 adsorption measurements showed no significantsignificant changes with respect to the pristine material, these result led to the conclusion that pendant Himdc carboxylate groups in the MOF structure may have aa positivepositive rolerole inin stabilizingstabilizing CuCu22O nanoparticles and preventing their aggregation. Unfortunately, Unfortunately, the the lack of any information about the content of copper and MOF components in the crude triazoles (either Zn(II) or the organic ligands) makes it difficultdifficult to draw any conclusion about this interestinginteresting CuAAC system from the point of view of product contamination.

2.4. Polymers from Natural Sources With thethe specificspecific goal goal of of overcoming overcoming the the modest modest yields yields in thein the CuAAC CuAAC of some of some glycosyl glycosyl azides azides with withthe standard the standard CuSO 4CuSO/sodium4/sodium ascorbate ascorbate system, system, Yu et al.Yu endeavored et al. endeavored to prepare to CuNPsprepareon CuNPs cellulose on (Schemecellulose 10(Scheme), by reduction 10), by ofreduction Cu(NO3 )of2 with Cu(NO hydrazine3)2 within hydrazine the presence in the ofthe presence polymeric of the support polymeric [129]. supportDespite the[129]. fact Despite that distinction the fact that between distinction Cu(0) between and Cu(I) Cu(0) is not and always Cu(I) easyis not [130 always], the easy observation [130], the a XPSobservation Cu 2p3/2 a XPSpeak Cu at 932.682p3/2 peak eV inat the932.68 spectrum eV in the of thespectrum insoluble of the material insoluble18 was material taken 18 as was a proof taken of asthe a occurrenceproof of the of occurrence clusters containing of clusters metallic containing copper. metallic Evaluation copper. of Evaluation the activity of ofthe18 activityin the CuAAC of 18 in thereaction CuAAC of phenylacetylene reaction of phenylacetylene with acetylated withα-L -arabinopyranosylacetylated α-L-arabinopyranosyl azide displayed azide a good displayed activity ata goodr.t. in severalactivity organicat r.t. in solvents. several However,organic solvents. for the sake However, of better for eco-compatibility the sake of better water eco-compatibility was eventually waterselected was as theeventually medium selected of choice, as resulting the medium in an optimizedof choice, protocolresulting that in requiredan optimized the use protocol of 10 mol that % requiredof supported the use catalyst of 10 atmol 60 %◦C of for supported 12 h. Under catalyst these at conditions, 60 °C for 12 a rangeh. Under of protectedthese conditions, glycosyl a azidesrange wereof protected coupled glycosyl with different azides alkynes, were coupled to provide with the different corresponding alkynes, triazoles to provide in good the isolatedcorresponding yields (84%–94%).triazoles in good isolated yields (84%–94%).

Scheme 10. Preparation of Cu nanoparticles on cellulose, 18.

Because the cellulosic material and the triazole products were all poorly soluble in water, recovery of the catalyst required solvent extraction with AcOEt of the residue obtained by filtering the reaction mixture. Even if no apparent loss of supported system was noted at this stage, reuse of the material across five CuAAC cycles caused an evident decrease of product yield (93% → 84%). In consideration of the minute amounts of found copper into the filtrate (0.3–1.9 ppm), leaching phenomena were concluded to be irrelevant in this regard. On the contrary, the origin of the problem was tentatively related to oxidation phenomena, as suggested also by the observation of new peaks at 933.28 and 934.88 eV in the XPS spectrum of the spent catalyst, attributed to Cu(I) and Cu(II) species.

2.5. Oxides and Other Inorganic Supports Although details of the preparation and structure are not entirely clear, Agalave et al. reported the use of CuI on bare neutral alumina as a cost-effective supported CuAAC catalyst [131]. The material was used in the reactions of activated halides (Scheme 2a) or a few preformed azides (Scheme 1), in water or DMF-water (4:1) with microwave (MW) or ultrasound (US) irradiation. The former conditions (MW) led to the fastest conversion rate and furnished good yields in 6–13 min, even in the case of triazole products with relatively complex structure (70%–98%). Reuse of the recovered catalyst in the course of eight reaction cycles displayed a progressive decrease of efficiency (approximate 98% → 89% yield), accompanied by some reduction of the copper content of the material (4.2 wt % → 3.8 wt %). Molecules 2016, 21, 1174 11 of 43

Because the cellulosic material and the triazole products were all poorly soluble in water, recovery of the catalyst required solvent extraction with AcOEt of the residue obtained by filtering the reaction mixture. Even if no apparent loss of supported system was noted at this stage, reuse of the material across five CuAAC cycles caused an evident decrease of product yield (93% → 84%). In consideration of the minute amounts of found copper into the filtrate (0.3–1.9 ppm), leaching phenomena were concluded to be irrelevant in this regard. On the contrary, the origin of the problem was tentatively related to oxidation phenomena, as suggested also by the observation of new peaks at 933.28 and 934.88 eV in the XPS spectrum of the spent catalyst, attributed to Cu(I) and Cu(II) species.

2.5. Oxides and Other Inorganic Supports Although details of the preparation and structure are not entirely clear, Agalave et al. reported the use of CuI on bare neutral alumina as a cost-effective supported CuAAC catalyst [131]. The material was used in the reactions of activated halides (Scheme2a) or a few preformed azides (Scheme1), in water or DMF-water (4:1) with microwave (MW) or ultrasound (US) irradiation. The former conditions (MW) led to the fastest conversion rate and furnished good yields in 6–13 min, even in the case of triazole products with relatively complex structure (70%–98%). Reuse of the recovered catalyst in the course of eight reaction cycles displayed a progressive decrease of efficiency (approximate 98% → 89% yield), accompanied by some reduction of the copper content of the material (4.2 wt % → 3.8 wt %). KIT-5 mesoporous silica modified with aminopropyl groups was employed by Mirsafaei et al. for supporting CuI [83]. In spite of the fact that the aminated support was simply stirred at r.t. in a solution of CuI in MeCN or DMF, XRD measurements identified the presence of crystalline CuI (Marshite structure, estimated size 12–40 nm) in the resulting materials. The usefulness of the supported catalyst in CuAAC was assessed in the three-component process with activated alkyl halides (Scheme2a). Good yields were generally obtained in refluxing water, in some cases after very short reaction time (69%–95% in 15–150 min). In addition, the recovered material could be used in 6 consecutive cycles with just a minor decrease of product yield (approximate 96% → 91%) and an unspecified small variation of the copper content. Reduction of Fehling solution with glucose in boiling water, in the presence of various insoluble materials (silica gel, hydroxyapatite, cellulose, basic alumina), was used by Gupta et al. for preparing supported Cu2O nanoparticles [132]. Amongst the systems examined, that based on silica gel showed maximum activity in the three-component reaction (Scheme2a) between phenylacetylene, benzyl chloride, and . The reaction was carried out with a relatively high catalyst loading (5 mol %), preferentially in water at r.t. Under these conditions very good yields (91%–97%) were obtained in reasonable time (2–8 h), also on switching to the use of less reactive alkyl halides (e.g., n-butyl chloride). Reuse of the catalyst resulted in only slight reduction of product yield in the course of 5 cycles (96% → 92%). Albadi et al. employed a CuO/CeO2 nanocomposite (approximate 5 wt % Cu) for performing three-components reactions with activated bromides (Scheme2a) and Amberlite-supported azide [ 133]. The latter was selected with the intent of reducing the environmental impact of the process and to avoid handling toxic NaN3, at least in the CuAAC step. Optimization of the conditions revealed that the rate of CuAAC was maximum in refluxing ethanol, where different triazole products were obtained in good yield within 45–120 min (88%–92%). Interestingly, the CuO-CeO2 nanocomposite and the resin were recovered together by filtration and the latter was restored in the azide form by stirring with aqueous NaN3. With this procedure, the attainment of nearly unchanged yields in the course of five reaction cycles (91% → 88%) required a slight increase of the reaction time, from 65 min to 75 min. The same group prepared CuO/ZnO nanocomposites by co-precipitation of the metal nitrates with aqueous NaHCO3 [134]. The use of the material in three-component CuAAC reactions of benzyl halides (Scheme2a) provided best results in boiling water and with a high loading of the catalyst Molecules 2016, 21, 1174 12 of 43

(89%–92% yield in 15–65 min with approximate 17 mol % Cu). Also in this case, reuse of the recovered solid led to an evident decrease of catalytic activity after just five consecutive reaction cycles (92% yield in 20 min → 88% yield in 32 min). Very recently, Rad et al. described the CuAAC preparation of β-hydroxyalkyltriazoles, containing carbazolemethyl side chains, by the use of copper-doped silica cuprous sulfate [135]. Contrarily to previous work by the same group [136], no recycling of the catalyst was reported in this example of application to the synthesis of bioactive compounds.

2.6. Magnetically Recoverable Systems The use of nano-sized super-paramagnetic supports offers the opportunity of catalyst recovery by the use of an external magnet. In principle, this technique can be more advantageous than filtration or centrifugation, even at scale, thus justifying the interest towards the approach in last decade [137,138]. Hence, irrespective of the fact that many of these materials embed additional organic or inorganic components, recent advances with nano-structured copper catalysts that can benefit from such a specificity recovery mechanism are discusses separately in the present section. Magnetic Cu-Ni nano-alloy particles were obtained by Biswas et al. through reduction of nickel acetate and copper acetate with hydrazine [139]. The preparation (Scheme 11a) was carried out in the presence of PEG or poly(4-vinylphenol) (PVPh) as a polymer stabilizer, to give well dispersible organic-inorganic hybrid materials 19. TEM and XPS analyses showed the presence of spherical alloy nanoparticles containing a Cu(I) surface layer and assembled in chain-like structures through the interaction of their magnetic dipoles. Benchmark runs (Scheme1) between benzyl azide and phenylacetylene were carried out at r.t. in water or DMF, with an amount of nano-alloy corresponding to about 2 mol % of copper. Under these conditions, the PEG-containing catalyst 19 was found to be equally effective in both reaction media. By contrast, the PVPh-stabilized one proved significantly more active in DMF than in water, a difference attributed to the collapsed state of the less polar PVPh coating in the latter solvent. In any case, with the proper choice of reaction conditions either catalytic system provided acceptable results in CuAAC reactions involving other low-molecular weight reactants (56%–82% yield), a propargylated imidazolium ionic liquid, or azide-terminated substrates containing a tripeptide or a poly(methyl methacrylate) chain. Recovery of the catalyst by magnetic separation allowed the use of 19 (PEG) in three consecutive benchmark runs, albeit with reduction of the triazole yield (96% → 87%). Because the XPS analysis of the recovered material showed some increase of Cu(I) peaks but not of those of Cu(II), this trend does not appear to be related to severe oxidation of the nano-alloy surface. On the contrary, it might be connected with particle aggregation phenomena, evidenced by TEM analysis of the spent catalyst. A tris-metallic system, entailing Cu(0) nanoparticles on glutamate-coated NiFe2O4 (Scheme 11b), was prepared by Lu et al. by sequentially loading the super-paramagnetic core nano-sheets with the amino acid ligand and Cu(OAc)2, followed by reduction with N2H4 and NaBH4 [140]. The resulting material 20 was examined as a catalyst in multi-component CuAAC reactions in water, involving activated halides, epoxides, or aromatic boronic acids (Scheme2a,b,d, respectively). In the presence of the composite catalyst (1 mol %–5 mol % Cu) the reaction proceeded in relatively short times at r.t. (1.5–8.5 h), allowing the preparation of a rather large library of triazole products in fair to excellent yields (50%–95%). Recovery with an external magnet and washing made it possible to reuse the supported catalyst in ten successive cycles, with moderate decrease of the product yield (95% → 88%). Molecules 2016, 21, 1174 12 of 41 corresponding to about 2 mol % of copper. Under these conditions, the PEG-containing catalyst 19 was found to be equally effective in both reaction media. By contrast, the PVPh-stabilized one proved significantly more active in DMF than in water, a difference attributed to the collapsed state of the less polar PVPh coating in the latter solvent.In any case, with the proper choice of reaction conditions either catalytic system provided acceptable results in CuAAC reactions involving other low-molecular weight reactants (56%–82% yield), a propargylated imidazolium ionic liquid, or azide-terminated substrates containing a tripeptide or a poly(methyl methacrylate) chain. Recovery of the catalyst by magnetic separation allowed the use of 19 (PEG) in three consecutive benchmark runs, albeit with reduction of the triazole yield (96% → 87%). Because the XPS analysis of the recovered material showed some increase of Cu(I) peaks but not of those of Cu(II), this trend does not appear to be related to severe oxidation of the nano-alloy surface. On the contrary, it might be connected with particle aggregation phenomena, evidenced by TEM analysis of the spent catalyst. A tris-metallic system, entailing Cu(0) nanoparticles on glutamate-coated NiFe2O4 (Scheme 11b), was prepared by Lu et al. by sequentially loading the super-paramagnetic core nano-sheets with the amino acid ligand and Cu(OAc)2, followed by reduction with N2H4 and NaBH4 [140]. The resulting material 20 was examined as a catalyst in multi-component CuAAC reactions in water, involving activated halides, epoxides, or aromatic boronic acids (Scheme 2a,b,d, respectively). In the presence of the composite catalyst (1 mol %–5 mol % Cu) the reaction proceeded in relatively short times at r.t. (1.5–8.5 h), allowing the preparation of a rather large library of triazole products in fair to excellent

Moleculesyields (50%–95%).2016, 21, 1174 Recovery with an external magnet and washing made it possible to reuse13 ofthe 43 supported catalyst in ten successive cycles, with moderate decrease of the product yield (95% → 88%).

Scheme 11. Preparation of CuNPs on super-parama super-paramagneticgnetic supports with PEG or PVPh (a);), L-glutamic acid (b);), chitosan ((c);), andand EDACellEDACell ((d)) stabilizingstabilizing agents.agents.

CuAAC reactions promoted by Cu(0) nanoparticles on chitosan (CS)-magnetite have been described by Chetia et al. [141]. The nanocomposite was prepared by a three-step process (Scheme 11c), that began with the NaOH induced co-precipitation of CS, Fe(II), and Fe(III) from an AcOH solution. Characterization of the resulting material 21 by an array of techniques led to the conclusion that copper was present in the crystalline elemental form, as 10 nm spherical nanoparticles. Despite the fact that these dimensions do not appear much different from those estimated for the Fe2O3-CS support (10–15 nm), a uniform dispersion of copper on the surface of the nanocomposite was inferred at the SEM resolution level. Two-components CuAAC runs (Scheme1) were preferentially carried out in CH2Cl2, with 1.5 mol % of the catalyst, to afford good to excellent yields in 12 h at r.t. (77%–96%). A high yield was recorded also in the reaction of dimethyl acetylenedicarboxylate with phenyl azide (96% in 12 h), from which it was concluded that 21 was effective even for internal alkynes. In this respect it should be noted, however, that acetylenedicarboxylate are known to undergo the thermal Huisgen 1,3-dipolar cycloaddition reaction at rate not dissimilar to that demonstrated in the study under exam, or even faster [142]. On this ground, the catalytic role of the nanocomposite material in the specific reaction of such an internal acetylene appears therefore far less than obvious. Magnetic separation of the catalyst beads allowed their recycling with just a moderate reduction of efficiency along four consecutive runs (96% → 91% yield). The occurrence of aggregation phenomena, as a possible cause of performance loss, and of catalytic activity in solution, due to leached specie, Molecules 2016, 21, 1174 14 of 43 were examined and ruled out by TEM microscopy and through a standard “filtration experiment” (Maitlis0 test) [143], respectively. An organic-inorganic hybrid material (Scheme 11d), consisting in a layer of ethylenediamine- functionalized cellulose (EDACell) adsorbed onto silica gel-coated Fe3O4 particles, was recently employed by Bhardwaj et al. as a novel support for CuAAC catalytic systems [144]. Reduction with NaBH4 of the material loaded with CuCl2 gave a dark solid 22 that, according to XRD and electron microscopy, contained metallic copper clusters uniformly dispersed on the surface of around one order of magnitude larger core-shell magnetic nanoparticles. The activity of the supported system was probed in the CuAAC reaction between acetylenes and aromatic azides, with the latter formed in situ by substitution with NaN3 on the product of diazotisation of the corresponding in HCl-H2O (1:1) (Scheme2c). An initial optimization stage demonstrated good performance at r.t. with as little as 0.25 mol % of the copper catalyst. Therefore, the same conditions were applied to the CuAAC of different substrates, to afford uniformly good results in relatively short reaction time (92%–95% yield in 3.5–5 h). Despite the use of a strongly acidic reaction medium, filtration tests did not reveal any significant catalytic activity in the solution. In addition, the copper content of the solid recovered by magnetic separation proved almost identical to that of the pristine material and its recycling led to almost unchanged results in the course of six consecutive runs (96% → 93% yield). In addition to hybrid (organic-inorganic) magnetic catalytic systems above, some progress with purely inorganic materials were reported also. These examples, mentioned here for the sake of completeness, include the use of commercially available copper ferrite (CuFe2O4) and Fe3O4@TiO2/Cu2O nanocomposites [145,146].

2.7. Polymer-Stabilized Soluble Systems and Quasi-Homogeneous CuNPs Leaf extracts from Otostegia persica and Ginkgo biloba were recently examined by Nasrollahzadeh et al. as green reducing agents in the preparation of unsupported CuNPs [147,148]. These systems showed reasonable catalytic activity and possibility of reuse in three-component CuAAC reactions. Similarly to other quasi-homogeneous nanostructured materials reported in the last two years, i.e., lanthanum-loaded CuO nanoparticles [149], porous copper [99], copper salts reduced in ethylene glycol [101], and Cu2O nanocubes [96], these systems do not appear however to involve any additional polymeric component. Therefore, according to the scope of this review they will not be discussed in further detail herein. On the contrary, Chahdoura et al. prepared polymer-stabilized Cu2O nanoparticles, by dihydrogen reductionMolecules 2016 of, 21 copper, 1174 acetate in glycerol in the presence of PVP (Scheme 12a) [95]. As confirmed14 of by 41 TEM, XRD and IR analyses, the use of glycerol as the solvent, H2 as the reducing agent, and PVP as theand stabilizerPVP as the turned stabilizer out toturned be all out important to be all forimportant obtaining for oxidation-stable obtaining oxidation-stable Cu2O clusters Cu2O devoid clusters of Cu(0)devoid or of Cu(II) Cu(0) phases. or Cu(II) phases.

Scheme 12. Preparation of soluble and qu quasi-homogeneousasi-homogeneous CuAAC catalysts 23 (a) and 24 ((b).).

The synthesized nanoparticles 23 proved moderately active in two- and three-components CuAAC reactions (Scheme 1 and Scheme 2a). The catalytic runs were carried out with 2.5 mol % Cu2O at 100 °C for 2 h to give an array of different triazoles in high yield (91%–98%) and with complete 1,4-regioselectivity. In this regard it is worth noting that, even if the thermal reaction proceeded appreciably in neat glycerol at 100 °C (40% yield in 2 h), as expected both regioisomeric products 1 and 2 (see Scheme 1) formed in substantial amounts (4:1 ratio) in the absence of the copper catalyst. Combination with Ullmann chemistry was also feasible and provided a tandem process for preparing arylaminoethyl-functionalized triazoles (Scheme 13). The separation of the products in standard CuAAC runs was effected by extraction with CH2Cl2 or pentane of the catalyst-containing glycerol layer. Afterwards, the glycerol phase was heated under vacuum for removing the volatiles and employed in a new experiment. With this procedure ten cycles of the reaction between benzyl azide and phenylacetylene were carried out, obtaining the corresponding triazole product in nearly constant yield (94%–97%).

Scheme 13. Tandem CuAAC-Ullmann three-component coupling promoted by 23.

Polyoxometalates (POMs) and heteropolyacids (HPAs) are ionic compounds containing cations and large polyanion clusters made, e.g., by the condensation of MOx polyhedra [150,151]. Besides having catalytic activity on their own, these materials find use as supports for other catalytic systems and for the stabilization of metal nanoparticles. An example in this latter sense was reported recently by Amini et al. (Scheme 12b), who prepared Cu2O/CuO nanoparticles on a molybdenum POM by treating a suspension of (NH4)12(Mo36(NO)4O108(H2O)16) in AcOEt with Cu(NO3)2 [152]. With this procedure, the occurrence of the Cu(I) compound in the resulting material 24 was supposed to derive from direct reduction of the Cu(II) salt at the POM surface. Three-components CuAAC runs of activate halides (Scheme 2a) were typically performed in water, where the resulting nanocomposite was soluble. In the event, this permitted the recovery of the catalytic system in the aqueous phase, by filtering off the insoluble triazole product at the end of the experiment. Despite the rather high catalyst loading and reaction temperature adopted in these runs (5 mol % and 70 °C, respectively), Molecules 2016, 21, 1174 14 of 41

and PVP as the stabilizer turned out to be all important for obtaining oxidation-stable Cu2O clusters devoid of Cu(0) or Cu(II) phases.

Molecules 2016, 21, 1174 15 of 43 Scheme 12. Preparation of soluble and quasi-homogeneous CuAAC catalysts 23 (a) and 24 (b).

The synthesized nanoparticles 23 proved moderately active in two-two- andand three-componentsthree-components CuAAC reactions reactions (Scheme (Schemes 1 and1 and Scheme2a). The 2a). catalyticThe catalytic runs runs were were carried carried out out with with 2.5 2.5 molmol % Cu 2O2 Oat at100 100 °C◦ forC for 2 h 2 hto to give give an an array array of of different different triazoles triazoles in in high high yield (91%–98%) and with completecomplete 1,4-regioselectivity.1,4-regioselectivity. In In this regard it is worth notingnoting that, even if the thermalthermal reactionreaction proceededproceeded appreciably in neat glycerol at 100 ◦°CC (40% yield in 2 h), as expectedexpected both regioisomeric products 1 and 2 (see(see SchemeScheme1 1))formed formed inin substantialsubstantial amountsamounts (4:1(4:1 ratio)ratio) inin thethe absenceabsence ofof thethe coppercopper catalyst.catalyst. Combination withwith Ullmann chemistry waswas also feasiblefeasible and provided a tandem process for preparing arylaminoethyl-functionalized triazoles (Scheme 13).13). The The separation separation of of the products in standardstandard CuAAC runs waswas effectedeffected byby extractionextraction withwith CHCH22Cl22 or pentane of thethe catalyst-containingcatalyst-containing glycerol layer.layer. Afterwards, Afterwards, the the glycerol glycerol phase phase was was heated under vacuum for removing the volatilesvolatiles andand employed in a new experiment. With this procedure ten cycles of the reaction between benzyl azide and phenylacetylenephenylacetylene were were carried carried out, out, obtaining obtaining the correspondingthe corresponding triazole triazole product product in nearly in constant nearly yieldconstant (94%–97%). yield (94%–97%).

Scheme 13. Tandem CuAAC-Ullmann three-componentthree-component couplingcoupling promotedpromoted byby 2323..

Polyoxometalates (POMs) and heteropolyacids (HPAs) are ionicionic compoundscompounds containing cations and large large polyanion polyanion clusters clusters made, made, e.g., e.g., by the by co thendensation condensation of MOx of polyhe MOxdra polyhedra [150,151]. [150 Besides,151]. Besideshaving catalytic having catalytic activity activityon their onown, their these own, materi theseals materials find use findas supports use as supports for other for catalytic other catalyticsystems systemsand for the and stabilization for the stabilization of metal ofnanoparticles. metal nanoparticles. An example An examplein this latter in this sense latter was sense reported was reportedrecently by Amini et al. (Scheme 12b), who prepared Cu2O/CuO nanoparticles on a molybdenum POM by recently by Amini et al. (Scheme 12b), who prepared Cu2O/CuO nanoparticles on a molybdenum treating a suspension of (NH4)12(Mo36(NO)4O108(H2O)16) in AcOEt with Cu(NO3)2 [152]. With this POM by treating a suspension of (NH4)12(Mo36(NO)4O108(H2O)16) in AcOEt with Cu(NO3)2 [152]. Withprocedure, this procedure, the occurrence the occurrence of the Cu(I) of thecompound Cu(I) compound in the resulting in the resultingmaterial 24 material was supposed24 was supposed to derive tofrom derive direct from reduction direct reduction of the Cu(II) of the Cu(II)salt at saltthe at POM the POM surface. surface. Three-components Three-components CuAAC CuAAC runs runs of ofactivate activate halides halides (Scheme (Scheme 2a)2a) were were typically typically perfor performedmed in in water, water, where the resulting nanocompositenanocomposite waswas soluble. In In the the event, event, this this permitted permitted the the recovery recovery of of the the catalytic catalytic system system in the in the aqueou aqueouss phase, phase, by byfiltering filtering off offthe the insoluble insoluble triazole triazole product product atat th thee end end of of the the experiment. experiment. Despite Despite the the rather high catalyst loading and reaction temperature adopted in these runs (5 mol % and 70 ◦°C,C, respectively), recycling of the POM solution led, however, to rapid degradation of catalytic performance already after a few reaction cycles (approximate 88% → 44% yield in three runs).

3. Discrete Cu(I/II) Complexes Well-defined Cu(I) salts and complexes with nitrogen, phosphorous, oxygen and carbon-based ligands have played a prominent role in the development of new effective systems for CuAAC [64,153]. Because properly designed ligands, firmly anchored onto an insoluble support, might prevent metal ions to leach from the material, it is not surprising that immobilized catalytic systems of this kind, as well as analogous Cu(II) pre-catalysts, were actively investigated [88,89].

3.1. Cross-Linked Synthetic Organic Polymer Supports After the introduction in 2006 of CuI on Amberlyst A-21 by Girard et al. [154], this supported Cu(I) system has been successfully employed as a recoverable catalyst in CuAAC reactions carried out under batch or continuous-flow conditions (for a discussion of previous work, see refs. [88,89]). Occasional observations of C-5 iodinated triazole by-products in the cycloaddition process catalyzed Molecules 2016, 21, 1174 15 of 41

recycling of the POM solution led, however, to rapid degradation of catalytic performance already after a few reaction cycles (approximate 88% → 44% yield in three runs).

3. Discrete Cu(I/II) Complexes Well-defined Cu(I) salts and complexes with nitrogen, phosphorous, oxygen and carbon-based ligands have played a prominent role in the development of new effective systems for CuAAC [64,153]. Because properly designed ligands, firmly anchored onto an insoluble support, might prevent metal ions to leach from the material, it is not surprising that immobilized catalytic systems of this kind, as well as analogous Cu(II) pre-catalysts, were actively investigated [88,89].

3.1. Cross-Linked Synthetic Organic Polymer Supports

MoleculesAfter2016 the, 21 ,introduction 1174 in 2006 of CuI on Amberlyst A-21 by Girard et al. [154], this supported16 of 43 Cu(I) system has been successfully employed as a recoverable catalyst in CuAAC reactions carried out under batch or continuous-flow conditions (for a discussion of previous work, see refs. [88,89]). byOccasional A-21/CuI observations led the same of C-5 group iodinated to investigate triazole by-products the possible in causes the cycloaddition of such a side-reaction process catalyzed [155]. Afterby A-21/CuI examining led variousthe same factors, group potentialto investigate mistakes the po weressible identified causes inof thesuch preparation a side-reaction of the [155]. supported After catalystexamining and various in the conduct factors, ofpotential CuAAC mistakes runs, which were result identified in the obtainmentin the preparation of substantial of theamounts supported of iodinatedcatalyst and triazoles in the conduct (up to 12 of mol CuAAC %). In runs, turn, which this allowed result in tothe establish obtainment optimized of substantial conditions, amounts whose of adoptioniodinatedis triazoles expected (up to to reduce 12 mol the %). formation In turn, ofthis by-products allowed to below establish the 0.5optimized mol %–1 conditions, mol % level. whose adoptionA ionically is expected immobilized to reduce Nthe-heterocyclic formation of carbene by-products (NHC)-Cu(I) below the catalyst 0.5 mol25 %–1(Scheme mol % level.14a) was preparedA ionically by Velazquez immobilized et al. byN- suspendingheterocyclic thecarbene gel-type, (NHC)-Cu(I) quaternary catalyst ammonium 25 (Scheme resin Amberlyst 14a) was IRA-402prepared in by an Velazquez aqueous solutionet al. by ofsuspending the metal th complexe gel-type, [67]. quaternary After washing ammonium with water, resin theAmberlyst loaded resinIRA-402 (2 molin an % aqueous of Cu) solution was tested of the in metal three-component complex [67]. CuAAC After washing reaction with between water, benzyl the loaded bromide, resin sodium(2 mol % azide, of Cu) and was phenylacetylene tested in three-component in water (Scheme CuAAC2a). reaction Possibly between due to be poornzyl bromide, solubility sodium of the reactantsazide, and in phenylacetylene water, and thence in wate hinderedr (Scheme access 2a). to Possibly the catalytic due to sites, poor mechanical solubility of stirring the reactants resulting in ineffectivewater, and thence under hindered these conditions. access to the The catalytic problem sites, was mechanical circumvented stirring by resulting resorting ineffective to ultrasound under irradiation,these conditions. which The permitted problem to was attain circumvented full conversion by inresorting five hours to ultrasound at r.t. Remarkably, irradiation, the which same conditionspermitted to worked attain finefull conversion also for the in rarely five investigatedhours at r.t. Remarkably, three-component the same reaction conditions involving worked acetylene fine asalso the for dipolarophile the rarely investigated partner. Recycling three-component of the resin reaction was studied involving in the acetylene former process as the dipolarophile and involved extractionpartner. Recycling of the product of the resin with CHwas2 Clstudied2, removal in the of former the water process phase and by involved syringe, extraction and subsequent of the additionproduct with of fresh CH reactants2Cl2, removal and solvent.of the water By carrying phase by out syringe, all the stepsand subsequent under an argon addition atmosphere, of fresh fourreactants consecutive and solvent. runs By could carrying be performed, out all the steps albeit under with an argon appreciable atmosphere, reduction four ofconsecutive product yield runs (99%could→ be75%). performed, albeit with an appreciable reduction of product yield (99% → 75%).

SchemeScheme 14.14. Preparation ofof NHC-Cu(I/II)NHC-Cu(I/II) complexes complexes on insoluble organic supports, 25 (a) and 26 (b).

A further attempt to reuse the supported complex was reported to lead to a dramatic, yet unspecified, further decrease. Although some details of the measurements are not entirely clear, XRF analysis suggested that leaching of Cu(I) species into the solution might be the cause of the problem. Another instance of carbene-stabilized CuAAC catalyst on a resin support was reported very recently by Jia et al. [156]. The first step of the preparation route (Scheme 14b) consisted in the covalent immobilization of 1,3-dibenzylbenzimidazolium chloride into a hyper-crosslinked matrix, obtained by “knitting” the ligand precursor with , 1,2-dichloroethane, and methylal under Friedel-Crafts conditions. Loading the resulting, highly porous insoluble material with different amounts of CuCl and t-BuONa led to the corresponding supported metal-carbene complexes 26. Despite the fact that XPS analysis revealed the presence of Cu(II), instead of Cu(I), all the resins could Molecules 2016, 21, 1174 16 of 41

A further attempt to reuse the supported complex was reported to lead to a dramatic, yet unspecified, further decrease. Although some details of the measurements are not entirely clear, XRF analysis suggested that leaching of Cu(I) species into the solution might be the cause of the problem. Another instance of carbene-stabilized CuAAC catalyst on a resin support was reported very recently by Jia et al. [156]. The first step of the preparation route (Scheme 14b) consisted in the covalent immobilization of 1,3-dibenzylbenzimidazolium chloride into a hyper-crosslinked matrix,

Moleculesobtained2016 ,by21 ,“knitting” 1174 the ligand precursor with benzene, 1,2-dichloroethane, and methylal under17 of 43 Friedel-Crafts conditions. Loading the resulting, highly porous insoluble material with different amounts of CuCl and t-BuONa led to the corresponding supported metal-carbene complexes 26. catalyzeDespite the the three-components fact that XPS analysis CuAAC revealed reaction the presen of benzylce of Cu(II), halides instead in EtOH of Cu(I), (Scheme all the2a). resins Best could results werecatalyze provided the three-components by the material withCuAAC the reaction largest metalof benzyl content halides that, in EtOH at the (Scheme relatively 2a). low Best loading results of 0.45were mol provided % Cu, afforded by the material the expected with the triazole largest products metal content in good that, to at excellent the relatively yields low within loading 8 h of at 0.45 80 ◦ C (61%–99%).mol % Cu, Separation afforded the of theexpected resin bytriazole centrifugation products in made good it possibleto excellent to useyields the within supported 8 h at catalyst 80 °C in six(61%–99%). consecutive Separation cycles with of the essentially resin by centrifugation unchanged results made (98%it possible→ 96% to yield).use the supported catalyst in sixCommercial consecutive cycles poly(4-vinylpyridine- with essentially unchangedco-divinylbenzene) results (98% was → employed 96% yield). by Zarchi and Nazem for Commercial poly(4-vinylpyridine-co-divinylbenzene) was employed by Zarchi and Nazem for preparing the CuAAC pre-catalyst 27 (Figure3), through absorption of aqueous CuSO 4 on the gel-type preparing the CuAAC pre-catalyst 27 (Figure 3), through absorption of aqueous CuSO4 on the resin [157]. After in situ reduction of the blue polymer with sodium ascorbate, the material was gel-type resin [157]. After in situ reduction of the blue polymer with sodium ascorbate, the material tested as a catalyst in three-component CuAAC of halides (Scheme2a). Following an initial solvent was tested as a catalyst in three-component CuAAC of halides (Scheme 2a). Following an initial screening, the reactions were performed in biphasic t-BuOH-H2O (1:1) medium to give various triazole solvent screening, the reactions were performed in biphasic t-BuOH-H2O (1:1) medium to give products in fair to excellent isolated yields and short reaction time (69%–96% in 30–135 min). In this various triazole products in fair to excellent isolated◦ yields and short reaction time (69%–96% in respect30–135 it min). must In be this noted, respect however, it must that be noted, heating howe to 70ver,C that was heating required to 70 and, °C morewas required important, and, a more higher thanimportant, stoichiometric a higher catalyst than stoichiometric amounts was catalyst applied amounts (225 molwas %applied Cu, on (225 the mol basis % Cu, of publishedon the basis data). of Evenpublished though data). the polymeric Even though material the polymeric could be material used in could six reaction be used cycles in six withreaction slight cycles reduction with slight of the triazolereduction yield of (91% the triazole→ 87%), yield its catalytic (91% → performance 87%), its catalytic appears performance therefore somewhatappears therefore less impressive somewhat than forless many impressive other recoverable than for many CuAAC other systems recoverable reported CuAAC to date.systems reported to date.

FigureFigure 3. 3. CuAACCuAAC catalysts catalysts and pre-catalysts and pre-catalysts 27–30, on insoluble27–30, organic on insoluble supports organicfrom commercial supports resins. from commercial resins. Following their seminal paper on CuAAC with copper catalysts on DIAION resins [158,159], more recently Kitamura et al. investigated the use of the highly porous styrene-divinylbenzene (DVB) Following their seminal paper on CuAAC with copper catalysts on DIAION resins [158,159], material 28, under solventless conditions [160]. Two-component catalytic runs (Scheme 1) were more recently Kitamura et al. investigated the use of the highly porous styrene-divinylbenzene (DVB) carried out at r.t. under Ar, with 1 mol % of the catalyst and the addition of substoichiometric material 28, under solventless conditions [160]. Two-component catalytic runs (Scheme1) were carried amounts of Et3N to the neat reactants. Under these conditions, CuAAC between different azides and out at r.t. under Ar, with 1 mol % of the catalyst and the addition of substoichiometric amounts of Et N alkynes led to largely variable product yields after 4 h (47%–100%). The observation that worst results3 towere the neat obtained reactants. with dipolarophiles Under these conditions, devoid of Lewis-basic CuAAC between heteroatoms different (N, O) azides in the and proximity alkynes of ledthe to largelyC-C triple variable bond, product led the yields Authors after 4to h conclude (47%–100%). that Theneighboring-group observation that participation worst results may were play obtained an with dipolarophiles devoid of Lewis-basic heteroatoms (N, O) in the proximity of the C-C triple bond, led the Authors to conclude that neighboring-group participation may play an important role in the system under exam. Due to the fact that many triazoles are solid, isolation of the product required dilution with water and AcOEt before removal of the polymeric material by filtration. At variance with previous results with 28 in toluene [159], reuse of the resin under neat conditions showed a marked decrease of activity over four cycles (100% → 27% triazole yield). As expected, given the lack of strongly coordinating groups in HP-20, the origin of the problem was traced back to metal leaching which was indeed found to occur to a significant extent (19%) even in a single run. Moreover, assay of the separated liquid layers from product isolation (vide supra) revealed more than twelve-fold higher metal concentration in the AcOEt phase than in the aqueous one. Although copper contamination in Molecules 2016, 21, 1174 18 of 43 the crude triazoles was not explicitly reported, an estimation of around 400 ppm (dry weight basis) can be made on the basis of published data. A Cu(I) chelate catalyst 29, immobilized on polystyrene resin, was described by Movassagh and Rezaei [161]. The supported complex was obtained by alkylating the diazacrown macrocyclic ether Kryptofix® 22 with a Merrifield resin and then charging the resulting polymeric material with CuI in refluxing EtOH. Perhaps because of limited solubility of the copper salt in EtOH or scarce compatibility of the polystyrene backbone with the protic medium, the metal loading attained in the last step was considerably lower than the cryptand content of the resin. Nevertheless, 29 displayed appreciable activity in two- and three-components CuAAC reactions, especially when water was used as the reaction medium. Under air and at 0.3 mol % catalyst loading, several azides were added to acetylenic substrates (Scheme1) to provide the corresponding triazole products in good to excellent yield after 10 h at r.t. (78%–99%). Analogous three-component CuAAC runs (Scheme2a) with alkyl chlorides, bromides, or iodides and 0.6 mol % of supported complex were slower (56%–99% yield in 15–21 h at r.t.). Given also the structure of some of the halides used in the screening (e.g., cyclohexyl bromide and 1-adamantyl bromide), these variations are likely to reflect more the difficulty of the latter to be converted into the corresponding azide intermediate than actual differences in catalyst performance under alternative reaction conditions. Recovery of the supported system by filtration, washing, and drying with an air stream made it possible four consecutive reaction cycles, with a drop of product yield more evident under three-component conditions (99% → 71%) than under two-components ones (approximate 99% → 87%). In a multi-step solid-phase synthesis approach, Tavassoli et al. pursued the preparation on Merrifield resin of a dicationic ligand provided with 1,2-dithioether chelating site [162]. Stirring of the material with Cu(OTf)2 in MeOH led to the corresponding Cu(II) complex 30, characterized inter alia by cyclic voltammetry on glassy carbon electrode. Notwithstanding the presence of iodide in the material, addition of sodium ascorbate turned out to be essential for obtaining a catalytically active system for CuAAC. ◦ In the presence of the reducing agent and with 0.2 mol % of 30 in PEG400 at 65 C, quite fast reaction kinetics (87%–99% yield in 10–25 min) were observed in three-components CuAAC runs with mono-functional activated bromides (Scheme2a). By contrast, somewhat reduced yields were recorded in the reaction of bis(bromomethyl)benzene starting materials, even after longer reaction time (68%–88% in 45–60 min). Despite the observation of some copper leaching in the first run (<2%), the supported system displayed a reasonable recyclability, with just a modest drop of product yield after seven consecutive cycles (approximate 99% → 94%). A 1,10-phenanthroline-CuI catalytic system on Merrifield resin, 31, was reported by Wu et al. for the click-polymerization of di-functional azide and alkyne reagents (Scheme 15)[163]. Similarly to previous work from the same group [79], the solubility in THF of the resulting linear polymers allowed the separation of the supported catalyst and the obtainment of polytriazole materials containing relatively low amounts of copper (190–410 ppm). At variance with the precedent study, however, in this case the process was found to proceed only in the presence of air and no recycling of the supported catalyst was attempted. Molecules 2016, 21, 1174 19 of 43 Molecules 2016, 21, 1174 18 of 41

Scheme 15. Click-polymerization of di-functional monomers in the presence of 31..

In additionaddition to thethe systemssystems above,above, obtainedobtained fromfrom commerciallycommercially availableavailable resins, examples were described also of materialsmaterials preparedprepared byby radicalradical copolymerizationcopolymerization ofof functionalfunctional monomers.monomers. For the purpose of increasing the loading capacity of GO and its effectiveness in retaining copper ions, Pourjavadi et al.al. resorted resorted to to the the entrapment entrapment of of the carbonaceous support into a cross-linkedcross-linked poly(vinyl imidazole) matrix (Pim) [[164].164]. With this aim,aim, NN--vinylimidazolevinylimidazole and the correspondingcorresponding 1,4-bis-(imidazolium)butane di-functional monomer were radically polymerized in solution, in the presence of GO GO as as a a filler filler (Scheme (Scheme 16a). 16a). Interest Interestingly,ingly, while while SEM SEM examination examination of Pim of Pim devoid devoid of GO of GOshowed showed a smooth a smooth surface, surface, the the nanocomposite nanocomposite was was found found to to possess possess aa corrugated corrugated morphology, morphology, attributed to the embedded GO sheets. Soaking the material in aqueous CuSO4 led to load a attributed to the embedded GO sheets. Soaking the material in aqueousaqueous CuSOCuSO4 led to load a considerable amount of metal salt, corresponding to about one half of the imidazoleimidazole units content estimated forfor the the material. material. A preliminaryA preliminary optimization optimization stage stage for the for three-component the three-component CuAAC CuAAC reaction reaction of phenylacetylene, benzyl bromide, and NaN3 suggested the use of 1 mol % of the supported ofreaction phenylacetylene, of phenylacetylene, benzyl bromide, benzyl bromide, and NaN and3 suggested NaN3 suggested the use the of 1 use mol of % 1 ofmol the % supportedof the supported Cu(II) complexCu(II) complex32 and 32 10 and mol 10 % mol of sodium % of sodium ascorbate, ascorbate, in water in atwater 50 ◦ C.at 50 °C.

Scheme 16. Preparation of supported Cu(I/II) complex 32 (a) and 33 (b) onto resins obtained by radical Scheme 16. Preparation of supported Cu(I/II) complex complex 32 ((a)) and and 3333 ((bb)) onto onto resins resins obtained obtained by radical copolymerization and plausible structures of Pim and P(im/IL)(X). copolymerization and plausible structuresstructures ofof PimPim andand P(im/IL)(X).P(im/IL)(X). Molecules 2016, 21, 1174 20 of 43

When the same experimental set-up was applied to the CuAAC of other terminal alkynes with benzyl or alkyl chlorides or bromides (Scheme2a), good yields were uniformly recorded in 0.5–3.5 h (80%–96%). Remarkably, the reaction was found to proceed even with as little as 0.002 mol % of catalysts, but in this case a significantly longer reaction time was required for completion (20 h). Examination of leaching-related issues in the study under exam entailed a standard filtration test and the quantification of copper in the filtrate by ICP-OES. As desirable for a highly stable supported system, no evidence for catalytic activity in solution was gained by the former experiment, while in the latter the metal concentration was found to be below the detection limit. Therefore, the moderate reduction in product yield and TOF, observed in the course of eight recycle runs (approximate 99% → 92% and 195 → 140 h−1, respectively), was tentatively ascribed to catalyst loss during washing and recovery procedures. The radical copolymerization of N-vinylimidazole with 3-methacrylamidopropyl trimethyl ammonium chloride and N,N0-methylenebisacrylamide (Scheme 16b) was employed by Pourjavadi et al. for preparing the cross-linked P[im/IL][X] material, provided with imidazole units for copper complexation and ionic trimethylammonium groups for tuning the catalytic properties by variation of the counter- X [165]. In fact, before charging with CuSO4, the resin was subjected to ion-exchange for the purpose of replacing chloride with other anions. Even though the result might look counterintuitive, because of the presence of a large excess of azide ions, when the different Cu(II)-loaded resins 33 were employed in three-component CuAAC runs (Scheme2a) the activity of the supported systems was found to depend on the nature of the counter-ion in the order: Cl− > AcO− − − − > Br > BF4 > NO3 . Therefore, the chloride form 33 (X = Cl) was selected for being examined in more detail. This resulted in an optimized procedure that, with the use of 0.1 mol % of the supported ◦ system and 10 mol % of sodium ascorbate in t-BuOH-H2O (1:3) at 55 C, provided high yields of triazole products in 1.5–6 h (85%–99%). Remarkably, when the catalyst amount was lowered to 0.0013 mol % (130 mol ppm) a respectable 91% yield was still obtained after 18 h (TOF = 3889 h−1). Moreover, under standard conditions the reuse of the material recovered by centrifugation allowed to perform 12 reaction cycles, without any appreciable reduction of product yield and turnover frequency. A few resins and other insoluble polymers for the immobilization of CuAAC catalytic systems were obtained also by condensation or oxidative routes. For instance, an original approach to the preparation of a polymer-supported Cu(I) systems led Ul Islam et al. to realize polymer formation and copper immobilization at once, by addition of CuSO4 in DMF to 2-aminobenzoic acid in water, under open air (Scheme 17a) [166]. At SEM magnification, the resulting green precipitate 34 appeared to consist of robust fibers, devoid of metal particles down to the TEM resolution level. Therefore, the inference was made that the material was a complex between poly(2-aminobenzoic acid) (pABA), from the oxidative polymerization of the amino acid precursor, and Cu(I), from the partial reduction of the copper salt. The conclusion was strengthened by Raman, XPS and XRD analyses, with the latter additionally showing the crystalline nature of the organic polymer. Despite the low surface area (7.8 m2·g−1), the solid proved active in the benchmark addition of benzyl azide to phenylacetylene, reportedly carried out with 0.01 mol % Cu in solvents of different polarity. As revealed by kinetic measurements, the addition of Et3N (1 equiv. with respect to the reactants) was essential in order to improve the reaction rate and to avoid the occurrence of an initial induction period. Because H2O-Et3N led to best results, this medium was selected in the subsequent investigation of substrate scope, that led to the attainment of good to excellent yields at r.t. (84%–98% in 3–7 h) under both two-components (Scheme1) and three-component reaction conditions (Scheme2a). Although limited details of the procedure are provided, filtration of the reaction mixture and extraction of the triazole product with EtOAc allowed the recovery of the supported catalyst and its reuse. Molecules 2016, 21, 1174 21 of 43 Molecules 2016, 21, 1174 20 of 41

SchemeScheme 17. 17.Preparation Preparation of of supported supported Cu(I/II) Cu(I/II) complexes 3434 (a(a),), 3535 (b(),b ),and and 3636 (c)( ontoc) onto resins resins obtained obtained by oxidation or condensation routes and plausible structures of SNW and p[C4R-NH2]. by oxidation or condensation routes and plausible structures of SNW and p[C4R-NH2]. This cause to some reduction of product yield across five cycles of a benchmark reaction This cause to some reduction of product yield across five cycles of a benchmark reaction (98% → 83%), explained in terms of catalyst losses during the washing stage. In this context, it is → (98%worth83% of note), explained that, while in terms ICP-MS of catalystanalysis lossesruled duringout significant the washing metal stage.leaching In thisin the context, filtrate, it TEM is worth of noteexamination that, while of ICP-MSthe catalyst analysis after ruledthe first out cycle significant showed metal the formation leaching of in therather filtrate, large TEMCuNPs examination (10–40 of thenm). catalyst Because after the thespecific first activity cycle showed of the latter the formation is essentially of ratherunknown, large it CuNPscannot be (10–40 excluded nm). that Because some the specifickind activityof sintering, of the e.g., latter by is clus essentiallytering of unknown, Cu(I) species it cannot or over-reduction, be excluded thatmight some contribute kind of to sintering, the e.g.,observed by clustering deterioration of Cu(I) of species catalyst or performance. over-reduction, might contribute to the observed deterioration of catalystThe performance. condensation of melamine with terephthalaldehyde allowed Taskin et al. to prepare a microporousThe condensation Schiff-base of melaminenetwork polymer with terephthalaldehyde (SNW) as a rigid allowedand insoluble Taskin yellow et al. topowder prepare a microporous(Scheme 17b) Schiff-base[167]. Solid-state network CP-MASS, polymer 13C-NMR (SNW) and as FT-IR a rigid characterization and insoluble of yellowthe material powder (Schemeidentified 17b) the [167 presence]. Solid-state of aminal CP-MASS, units, as13 C-NMRwell as residual and FT-IR functional characterization groups of ofthe the starting material identifiedcompounds. the presence This evidence of aminal prompted units, asthe well Authors as residual to depict functional the structure groups of the of network the starting as containing compounds. the diaminomethyl structural motif (-CH(NH-)2) instead of the expected Schiff base (-CH=N-) one. This evidence prompted the Authors to depict the structure of the network as containing the Prolonged stirring with CuBr in MeCN afforded the corresponding Cu(I) loaded material 35 that, diaminomethyl structural motif (-CH(NH-) ) instead of the expected Schiff base (-CH=N-) one. similarly to the bare support, was found to possess2 a rather large micropore surface area (306 m2·g−1 Prolonged stirring with CuBr in MeCN afforded the corresponding Cu(I) loaded material 35 that, and 548 m2·g−1, respectively). Testing of the immobilized catalytic system in two-components CuAAC 2· −1 similarlyreactions to the(Scheme bare support,1), at unspecified was found loading, to possess evidence a ratherd a relatively large micropore fast process surface in MeCN area at (306r.t., with m g 2 −1 andformation 548 m ·g of ,the respectively). expected triazoles Testing in of fair the to immobilized good yields (61%–98% catalytic system in 90–300 in two-componentsmin). This proved CuAACtrue reactionseven for (Scheme a substrate,1), at like unspecified propargyl loading, acrylate, evidenced that can face a relatively selectivity fast problems process in in the MeCN Huisgen at r.t., withcycloaddition formation of reaction the expected [168]. Recycling triazoles inof fairthe tomate goodrial yieldsrecovered (61%–98% by filtration in 90–300 displayed min). sustained This proved truecatalytic even for activity a substrate, in the course like propargyl of 7 runs acrylate,(98% → 94% that yield), can face while selectivity AAS analysis problems of the infiltrate the Huisgenfrom cycloadditionthe reaction reactionmixture could [168]. not Recycling detect any of copper the material down to recovered the ppb level. by filtration displayed sustained catalyticA activity more complex in the course system of was 7 runs reported (98% by→ Mouradzadegun94% yield), while and AAS Mostafavi, analysis who of immobilized the filtrate from CuI the reactionon a 3D-network mixture could polymer not detect made any by polycondensati copper down toon theof calix ppb level.[4] resorcinarene and formaldehyde (SchemeA more 17c) complex [169]. With system this was aim, reported the resin bywas Mouradzadegun initially modified and by the Mostafavi, introduction who of immobilized aminopropylCuI on achains 3D-network and then polymer loaded with made a solution by polycondensation of the cuprous salt of in calix DMF [4 ]to resorcinarene give 36. The system and formaldehyde was tested in the three-component CuAAC reaction of halides in water (Scheme 2a). Even though the catalyst (5 (Scheme 17c) [169]. With this aim, the resin was initially modified by the introduction of aminopropyl mol %) displayed reasonable activity at room temperature, reflux conditions were ultimately selected chains and then loaded with a solution of the cuprous salt in DMF to give 36. The system was tested in the three-component CuAAC reaction of halides in water (Scheme2a). Even though the catalyst Molecules 2016, 21, 1174 22 of 43

Molecules 2016, 21, 1174 21 of 41 (5 mol %) displayed reasonable activity at room temperature, reflux conditions were ultimately selected asas they they could could provide provide good good yields yields (80%–97%) (80%–97%) withinwithin 5–30 min. Recovery Recovery of of the the resin resin by by filtration filtration and and solventsolvent washing washing permitted permitted to to confirm confirm its its potentialpotential reuse, with with just just a a slight slight reduction reduction of of product product yield yield in thein the course course of of 5 cycles5 cycles (97% (97%→ →94%). 94%). AtAt thethe same time, AAS AAS analysis analysis of of the the filtrate filtrate evidenced evidenced a not a not specifiedspecified “trace “trace amount” amount” of of copper copper ions. ions. After introducing PEG-modified melanin as a platform for multimodality imaging [170], Sun et After introducing PEG-modified melanin as a platform for multimodality imaging [170], Sun et al. al. explored its use as a nanosized support for CuAAC catalytic systems [171]. The preparation of the explored its use as a nanosized support for CuAAC catalytic systems [171]. The preparation of the material (Scheme 18) began with the dissolution of synthetic melanine granules into NaOH, followed material (Scheme 18) began with the dissolution of synthetic melanine granules into NaOH, followed by US-assisted re-precipitation of the polymer on lowering the pH. After this step, aimed to by US-assisted re-precipitation of the polymer on lowering the pH. After this step, aimed to disentangle disentangle the macromolecular chains, the resulting water-insoluble melanine nanoparticles were the macromolecular chains, the resulting water-insoluble melanine nanoparticles were subjected to subjected to chemical modification with NH2-PEG5000-NH2 [170]. This second stage afforded chemicalnanoparticles modification 37 (M-dots) with that, NH2 -PEGprobably5000 -NHthanks2 [170 to ].their This surface second charge stage ( afforded−2.2 mV zeta nanoparticles potential), 37 (M-dots)resulted that, well probably dispersible thanks in water to their but surface could be charge recovered (−2.2 by mV centrifugal zeta potential), separation resulted through well dispersiblea 30 kDa in watercutoff filter. but could be recovered by centrifugal separation through a 30 kDa cutoff filter.

SchemeScheme 18. 18. PreparationPreparation of the of theM-dots/Cu(I) M-dots/Cu(I) nanoparticle nanoparticless and likely and structure likely of structure M-dots (Note: of M-dots The (Note:formula The formulashown for shown the latter for the is latterthe dihydroxyind is the dihydroxyindoleole tautomer tautomer of the ofdihydroindolequinone the dihydroindolequinone one depicted in the original publication [171]). one depicted in the original publication [171]).

After loading with an aqueous solution of CuSO4 and reducing with sodium ascorbate, the same After loading with an aqueous solution of CuSO and reducing with sodium ascorbate, the same technique was applied for the purification of the4 corresponding supported Cu(I) complex 38. technique was applied for the purification of the corresponding supported Cu(I) complex 38. Characterization of the material by ICP-MS revealed that, on the average, each M-dot particle was Characterizationloaded with 50 ± of 2 thecopper material centers, by whose ICP-MS +I revealedoxidation that,state onwas the confirmed average, by each XPS. M-dot Specific particle tests on was loadedthe M-dots/Cu(I) with 50 ± 2 system copper evidenced centers, whose just a modest +I oxidation metal stateleaching was in confirmed phosphate by PBS XPS. buffer Specific at pH tests = 7.4on theand M-dots/Cu(I) no systemagainst evidencedtwo cellular just lines. a modest In addition, metal leachingM-dots displayed in phosphate the ability PBS buffer to quench at pH the = 7.4 andproduction no toxicity of againsthydroxyl two radicals cellular in the lines. Cu(II)-ascorbate In addition, M-dotsreactive displayedsystem, thus the circumventing ability to quench one of the productionthe main ofissues hydroxyl when radicalsthis chemistry in the is Cu(II)-ascorbate applied for bio-conjugation reactive system, purposes. thus circumventingThe appealing features one of the mainof 38 issues prompted when thisits study chemistry in CuAAC is applied reactions for bio-conjugation between low molecular purposes. weight The appealing reactants features(Scheme of1) 38 promptedand for itsthe studyclick-derivatisation in CuAAC reactions of biomolecules. between lowIn the molecular former scenario, weightreactants very good (Scheme product1) yields and for the(90%–95%) click-derivatisation were obtained of biomolecules. in 30 min at r.t., In by the stirring former the scenario, azide and very alkyne good reactants product yieldsin PBS (90%–95%)buffer in werethe obtained presence inof 300.1 minmol at% r.t.,of the by copper stirring catalyst. the azide Simi andlar, alkynealbeit slightly reactants wors ine PBS results buffer (67%–90% in the presence yield) of 0.1were mol obtained % of the in copper the corresponding catalyst. Similar, three-compon albeit slightlyent process worse resultswith halides (67%–90% in PBS-DMSO yield) were (Scheme obtained in the2a). correspondingReusability of three-componentthe catalytic system process was with studied halides in inthe PBS-DMSO reaction of (Scheme phenylacetylene2a). Reusability and a of thetetra(ethylene catalytic system glycol)-derived was studied azide. in the With reaction this of choice, phenylacetylene 38 could be andseparated a tetra(ethylene by centrifugal glycol)-derived filtration azide.from With the solution this choice, containing38 could the be triazole separated produc by centrifugalt, without filtrationleaving behind from the measurable solution containingamounts of the triazolecopper. product, The subsequent without direct leaving reus behinde of the measurable recovered catalyst, amounts i.e., of without copper. adding The subsequent any reducing direct agent, reuse afford then reasonably constant results in the course of seven reaction cycles (88% → 82% yield). of the recovered catalyst, i.e., without adding any reducing agent, afford then reasonably constant In a second set of applications, 38 was used for click-modifying biotin and AE105 or RGDyK results in the course of seven reaction cycles (88% → 82% yield). polypeptide derivatives, provided with either alkyne or azide side chains. Moreover, the same In a second set of applications, 38 was used for click-modifying biotin and AE105 or RGDyK protocol could be applied to the fluorescent tagging of a 3’-alkyne DNA strand with the cyanine polypeptide derivatives, provided with either alkyne or azide side chains. Moreover, the same protocol 5.5-azide , in this case using a 10 kDa cut-off centrifugal filter for separating the polynucleotide could be applied to the fluorescent tagging of a 3’-alkyne DNA strand with the cyanine 5.5-azide product from 38. In a final noteworthy example, the in situ imaging of the integrin αVβ3 receptor in dye,human in this glioblastoma case using aU87MG 10 kDa cells cut-off was centrifugalrealized. In filter this forcase, separating the procedure the polynucleotideinvolved preliminary product Molecules 2016, 21, 1174 23 of 43 from 38. In a final noteworthy example, the in situ imaging of the integrin α β receptor in human Molecules 2016, 21, 1174 V 3 22 of 41 glioblastoma U87MG cells was realized. In this case, the procedure involved preliminary labelling labellingthe receptor the sitesreceptor with sites RGD-alkyne, with RGD-alkyne, followed followed by exposure by exposure of the whole of the cells whole to Cyanine cells to 5.5-azideCyanine dye5.5- azideand 38 dye. As and for the 38. other As for biomolecules the other biomolecules mentioned above, mentione the possibilityd above, ofthe using possibility the melanine-based of using the melanine-basedCu(I) catalytic system, Cu(I) catalytic without thesystem, need without of any added the need ascorbate, of any added was undoubtedly ascorbate, was a major undoubtedly advantage a majorin order advantage to prevent in unwantedorder to prevent side reactions unwanted in the side CuAAC reactions process. in the CuAAC process. As anticipated anticipated in in the the Introduction, Introduction, the thenecessity necessity of handling of handling potentially potentially explosive explosive azides azidesunder safeunder conditions safe conditions prompted prompted several several studies studies on continuous-flow on continuous-flow CuAAC CuAAC [31]. [In31 ].this In thiscontext, context, the combinationthe combination of flow-chemistry of flow-chemistry with with an anotherother enabling enabling technology technology [172], [172 ],viz viz.. the the use use of of supported catalytic systems, stands stands as as one one of the most promising trends of current efforts towards the improvement of of the the reaction. reaction. Accordingl Accordingly,y, several several examples examples of in of continuo in continuo CuAAC CuAAC reactions reactions have appearedhave appeared in the inliterature, the literature, most of most which of make which us makee of copper use of tubular copper tubularreactors reactorsor supported or supported systems insystems meso-sized in meso-sized fluidic devices fluidic [32]. devices Given [the32]. intere Givenst of the fast interest CuAAC of reactions fast CuAAC on the reactions pico-mole on scale the pico-moleas a tool for, scale e.g., as aidentifying tool for, e.g.,enzyme identifying inhibitors enzyme [173,174], inhibitors Li et [al.173 explored,174], Li etthe al. preparation explored theof preparationglass-poly(dimethylsiloxane) of glass-poly(dimethylsiloxane) (PDMS) chip (PDMS) micro-reactors chip micro-reactors containing containing immobilized tris(triazolylmethyl)-amine-Cu(I) units units 39 (Scheme39 (Scheme 19) [175].19)[ The175]. step The by stepstep progress by step of progress the fabrication of the sequencefabrication was sequence verified by was XPS verified analyses by on XPS test wafers, analyses while on radiochemical test wafers, while assay with radiochemical 64CuSO4/sodium assay 64 withascorbateCuSO allowed4/sodium to quantify ascorbate the allowed capacity to of quantify the device the capacityin retaining of the Cu(I) device (1136 in retaining± 272 nmol Cu(I) or −2 (811136 ± 20± nmol·cm272 nmol−2).or Testing 81 ± 20 of nmolthe microfluidic·cm ). Testing reactor of thein two-components microfluidic reactor CuAAC in two-components (Scheme 1) was performedCuAAC (Scheme in a semi-batch1) was performed fashion, in by a semi-batchfilling the fashion,channels by with filling the the reactants channels in with ammonium the reactants acetate in ◦ bufferammonium and then acetate allowing buffer the and reaction then allowing to proceed the reaction for some to proceedtime (15–30 for somemin) timeat 37 (15–30°C under min) stopped- at 37 C flowunder conditions. stopped-flow Application conditions. of the Application procedure of to the the procedure CuAAC coupling to the CuAAC between coupling the azide-modified between the fluorescentazide-modified dye fluorescentFlu568-N3 and dye Flu568-Npropargylamine3 and propargylamine led to product ledyields to product that, asyields expected, that, increased as expected, at largerincreased incubation at larger times incubation (e.g., 83% times after (e.g., 50 min 83% vs. after 55% 50 after min 15 vs. min). 55% Interestingly, after 15 min). the protocol Interestingly, was effectivethe protocol for wasperforming effective also for performingthe click reaction also the between click reaction the azide-containing between the azide-containing cyclic penta-peptide cyclic penta-peptidecyclo(RGDfK)-N cyclo(RGDfK)-N3 and the functionalized3 and the functionalized dye Flu568-acetylene, dye Flu568-acetylene, with better results with better in the results flow device in the thanflow deviceunder analogous than under batch analogous conditions batch conditions(75% yield (75%vs. 54% yield yield vs. 54%with yield 60 mol with % 60of molcatalyst). % of catalyst).Control experimentsControl experiments showed showedgood reproducibility good reproducibility between betweendifferent differentreactors and reactors confirmed and confirmed that the catalytic that the activitycatalytic of activity non-specifically of non-specifically bound Cu(I), bound as found Cu(I), in as bare found chips, in bare was chips, just a was fraction just aof fraction that observed of that inobserved the ligand-functionalized in the ligand-functionalized devices. devices. The latter The lattercould could be used be used 4–6 4–6 times times before before an an appreciable appreciable reduction of product yield ensued. After that, full “regeneration” could be achieved by reloading the channels with CuSO4/sodium ascorbate. ascorbate. Arguably, Arguably, while while this this observation observation points points to to a a good stability of the supported ligand units, it evidences also possible leaching phenomena, whose extent was not quantified,quantified, in the product-containingproduct-containing liquidliquid phase.phase.

H O N O H (1) H2O2-aq.HCl N N O 3 N N 3 (2) N N (MeO)3Si O OH O H 70°C, 2 h Si O N N N Cu(I) O N OH O O 3 (3) L, aq. borax, 47°C OH OH 39 (4) CuSO , sodium ascorbate Glass or PDMS 4

H O O H N N N 3 3 N N N N

N N NH2 L N O 3 Scheme 19.19. Immobilization of tris(triazolylmethyl)aminetris(triazolylmethyl)amine ligand/Cu(I) inside inside a a glass-PDMS chip reactor 39.

3.2. Polymeric Organic Supports From Natural Sources As noted already in Section 2.6, chitosan, the biodegradable polymer obtained by deacetylation of chitin, is still attracting much interest as catalyst support in view of its low cost, inoffensive nature, Molecules 2016, 21, 1174 24 of 43

3.2. Polymeric Organic Supports from Natural Sources As noted already in Section 2.6, chitosan, the biodegradable polymer obtained by deacetylation of chitin, is still attracting much interest as catalyst support in view of its low cost, inoffensive nature, and prompt adsorption of metal ions by surface hydroxy and amino groups. After early contributions by Chtchigrovsky et al. [176], the use in CuAAC of CS-Cu(I/II) complexes was examined recently by Nasir Baig et al. and by Anil Kumar et al. [177,178]. In both studies the supported polymeric catalysts were obtained by suspending CS in the solution of a proper Cu(I/II) salt, followed by filtration or centrifugation, washing, and drying of the insoluble material. Characterization of the solid indicated an appreciable copper content (5.1 wt % by ICP-AES), but no signals pertinent to crystalline forms were observed by XRD. The former group tested CS-CuSO4, at low catalyst loading (0.4 mol % of Cu) in water, in CuAAC between alkyl azides and aliphatic or aromatic alkynes (Scheme1). On the contrary, the latter focused on the three-component CuAAC reaction between aromatic boronic acids, sodium azide, and aromatic alkynes (Scheme2d). Also in this case water proved to be the solvent of choice, but the experiments involved the use of considerably larger amounts of catalyst (typically 10 mol % of CS-CuSO4). Under the said conditions good to excellent yields (71%–99%) were attained in both studies in 4–12 h at r.t. The CS-supported catalyst could be recovered by decantation and reused, albeit with variable degrees of success depending upon the specific reaction: With preformed azides, essentially quantitative yields were obtained in five initial runs and constant, yet reduced values (28%), were recorded in five additional reaction cycles carried out at five-fold larger S/C ratio. On the contrary, with boronic acids an appreciable reduction of yield was observed in the initial 5 cycles (90% → 79%), which appears to mirror quite closely the progressively larger losses of insoluble material along the reaction series (approximate 18% of the initial amount after the 5th reaction cycle). Cuttlebone, the rigid structural component of the cuttlefish body, is an hybrid material composed of calcium carbonate (aragonite form), proteins, and β-chitin [179]. In view of the complexing/reducing properties of the latter component, Ghodsinia et al. explored the use of cuttlebone as a support for CuAAC catalytic systems [180]. Because XPS analysis of the solid obtained by treating powdered cuttlebone with CuCl2 in water confirmed the presence of copper in the Cu(I)/Cu(II) mixed oxidation state, the material was tested directly in the three-components CuAAC reaction of benzyl bromide and phenylacetylene. Strangely enough, bare cuttlebone displayed some catalytic activity itself but, as expected, the reaction rate in the presence of metal-loaded material proved significantly higher. Best results were attained by using 8.5 mol % of the supported copper catalyst in water at 40 ◦C, conditions under which the CuAAC multi-component reaction of other reactive bromides led to good triazole yields (72%–95%) within 5–80 min. Recovery by filtration and washing with different solvents allowed the reuse of the catalytic material in seven reaction cycles. This led to observe some decrease of substrate conversion and product yield (100% → 90% and 95% → 85%, respectively) and the reduction of the metal loading on the cuttlebone support (1.77 mmol·g−1 → 1.54 mmol·g−1). In spite of this, the measured amount of leached copper was found to be relatively modest, with reported levels in selected isolated triazole products ranging between 37 ppm and 46 ppm.

3.3. Linear Organic Polymer Supports In the course of their investigation of new Cu(II) complexes with ferrocene-containing Schiff-base ligands, Liu et al. developed a molecularly-enlarged CuAAC pre-catalyst 40 anchored to linear poly(methyl methacrylate) (PMMA) [181]. The material was obtained by coupling PMMA to the pre-formed complex by trans-esterification (Scheme 20a) and, thanks to its poor solubility in EtOH, was employed as a heterogeneous catalyst in CuAAC runs in this solvent. Molecules 2016, 21, 1174 25 of 43 Molecules 2016, 21, 1174 24 of 41

(a) OH Me Me

5 1 Fc = Fe (1) t-BuOK, THF CO Me 2 O O reflux, overnight N O Me Cu + n (2) Concentration N O CO2Me Me Fc PMMA N O (Mw 35 000) Cu N O

Me Fc 40 (1 mmol Cu g-1)

(b) Bn Bn N N N (1) CuSO4, N degassed H O O N 2 O N Me O Me O n N Bn (2) Sodium ascorbate n N N N Bn N N N N N N N N Cu(I) 41 Bn Bn

Scheme 20.20. Preparation of the molecularlymolecularly enlarged Cu(II) pre-catalyst 40 ((a)) andand thethe water-solublewater-soluble Cu(I) complex 41 ((b).).

Two-component reactions reactions (Scheme (Scheme 1),1), for for 24 24 h hat atr.t. r.t. with with 2 mol 2 % mol of 40 % reduced of 40 reduced with sodium with sodiumascorbate, ascorbate, led to lednearly to nearlyconstant constant results results in th ine thecourse course of ofthree three consecutive consecutive reaction reaction cyclescycles (approximate(approximate 88%88% or or 95% 95% yields, yields, depending depending on the on specific the specific alkyne alkyne substrate). substrate). Moreover, Moreover, efforts directed efforts todirected address to theaddress issue the of issue metal of leaching metal leaching by TEM by (detection TEM (detection of metal of nanoparticles)metal nanoparticles) and 1 H-NMRand 1H- (complexation-inducedNMR (complexation-induced shift by shift Cu(I/II) by Cu(I/II) salts) didsalts) not did provide not provide any clue any about clue theabout occurrence the occurrence of such of a phenomenon.such a phenomenon. No attempt No attempt was reported, was reported, however, however, for quantifying for quantifying the copper the content copper by content a technique, by a e.g.,technique, ICP-AES, e.g., better ICP-AES, fit for better accurate fit for determinations accurate determinations at the ppm at level. the ppm level. In aa veryvery recentrecent example,example, Wang etet al.al. ex examinedamined the use of the water soluble complex 4141 [78].[78]. Striking features of this system were the possibility to effectively catalyze CuAAC reactions in water down to 1010 molmol ppmppm loadingloading levellevel (with(with TONTON andand TOFTOF valuesvalues ofof 86,00086,000 and and 3600 3600 h h−−11, respectively) and its suitability for the click modification modification of dendrimers and substrates of potential pharmaceutical interestinterest (typically(typically at 50–50050–500 molmol ppmppm loading).loading). Because the PEG-containingPEG-containing complex 41 was expected to be be poorly poorly soluble soluble in incold cold diethyl diethyl ether, ether, such such solvent solvent was employed was employed for recovering for recovering the triazole the product triazole productfrom the fromreaction the reactionmixture while mixture leaving while the leaving cataly thest in catalyst the aqueous in the phase. aqueous Although phase. the Although procedure the procedureallowed the allowed use of the the catalyst use of the solution catalyst in solution6 consecut inive 6 consecutive reaction cycles, reaction a signif cycles,icant a significantdecrease of decrease product ofyield product was observed yield was (95% observed → 53%). (95% The→ problem53%). The was problem attributed was to attributed the unavoidable to the unavoidableloss of copper loss ions, of copperdue to the ions, strong due tocomplexing the strong ability complexing of the he abilityterocyclic of the nucleus heterocyclic of the nucleustriazole ofproduct. the triazole product.

3.4. Inorganic Supports In addition addition to to the the many many examples examples published published in th ine past the pastyears years [88,89], [88 a, 89few], new a few supported new supported Cu(I/II) Cu(I/II)complexes complexes have been have disclosed been disclosedrecently, which recently, contai whichn low contain molecular low molecularweight organic weight ligands organic covalently ligands covalentlyanchored onto anchored (or within) onto a (or siliceous within) support a siliceous (Figure support 4). Because (Figure these4). Becausematerials these do not materials contain doany notpolymeric contain component, any polymeric but the component, oxidic support but itself, the oxidic they will support be mentioned itself, they only will briefly be mentionedhere. only briefly here. Molecules 2016, 21, 1174 26 of 43 Molecules 2016, 21, 1174 25 of 41

Figure 4. Cu(I/II) complexes with organic ligands covalently immobilized on insoluble Figure 4. Cu(I/II) complexes with organic ligands covalently immobilized on insoluble inorganic supports. inorganic supports. Silica gel decorated with a sulfur-containing ligand was developed by Tavassoli et al. as a new Silica gel decorated with a sulfur-containing ligand was developed by Tavassoli et al. as a new support material for Cu(I/II) [182]. In situ reduction with sodium ascorbate of the complex obtained support material for Cu(I/II) [182]. In situ reduction with sodium ascorbate of the complex obtained by stirring the modified silica with CuCl2 or Cu(OTf)2 afforded the corresponding CuAAC catalyst by stirring the modified silica with CuCl or Cu(OTf) afforded the corresponding CuAAC catalyst 42. 42. Under optimized conditions, which2 included inter2 alia the use of 0.05–0.1 mol % of the triflate Under optimized conditions, which included inter alia the use of 0.05–0.1 mol % of the triflate catalyst at catalyst at r.t. in PEG400–H2O (1:1), fair to nearly quantitative yields (72%–99%) were obtained in r.t. in PEG –H O (1:1), fair to nearly quantitative yields (72%–99%) were obtained in three-component three-component400 2 CuAAC reactions (Scheme 2a), after a reaction time comprised between 15 min and CuAAC reactions (Scheme2a), after a reaction time comprised between 15 min and 1 h. In the most 1 h. In the most favorable case, this translated into a remarkable TOF value of 7920 h−1. Unfortunately, favorable case, this translated into a remarkable TOF value of 7920 h−1. Unfortunately, reuse of the reuse of the supported system in a series of six benchmark CuAAC runs caused some reduction of supported system in a series of six benchmark CuAAC runs caused some reduction of product yield product yield (approximate 5%). (approximateCompared 5%). to the previous example, the MCM-41 supported Cu(I)-NHC complex 43, described 43 by GarcésCompared et al. to[183], the previousand especially example, the theCu(I)-acetylacetonate MCM-41 supported on Cu(I)-NHC HMS silica complex 44, studied, described by Lai et byal. 44 Garcés[184], displayed et al. [183 ],lower and especiallycatalytic activity the Cu(I)-acetylacetonate in two- or three-components on HMS silica CuAAC, studied reactions by (Scheme Lai et al. [1184 and], displayedScheme 2a). lower In the catalytic case of activitythe latter in system, two- or however, three-components the material CuAAC could be reactions used four (Schemes times in1 anda model2a). Inreaction, the case with of theessentially latter system, identical however, results the(99% material → 98% couldyield). be used four times in a model reaction, → with essentiallyWhile most identical of the reported results (99% approaches98% yield).rely on surface functionalization of pre-formed oxide supports,While Naeimi most of et theal. resorted reported to approaches the sol-gel relyprocess on surfacefor immobilizing functionalization a copper of complex pre-formed containing oxide supports,trimethoxysilane Naeimi groups et al. resorted in a templated to the sol-gel organosilica process matrix for immobilizing [185]. Contrarily a copper to most complex other containing studies in trimethoxysilanethe field, testing groups of the in cataly a templatedtic properties organosilica of the matrix material [185 ].45 Contrarily was performed to most otherby adopting studies ina theBox-Behnken field, testing factorial of the catalytic design properties of experiments of the material in order45 was to performed optimize byan adopting ultrasound-promoted a Box-Behnken factorialthree-component design of experimentsCuAAC reaction in order in towater optimize with anstyrene ultrasound-promoted oxide (Scheme 2b). three-component The approach CuAAC led to reactionidentify inthe water best conditions with styrene in oxidethe use (Scheme of 0.33 2molb). The% of approach the supported led to catalyst, identify under the best irradiation conditions at in40 thekHz use for of7 min. 0.33 molBy adopting % of the the supported same experimental catalyst, under set-up, irradiation different at epoxides 40 kHz could for 7 min. be converted By adopting into thethe samecorresponding experimental triazole set-up, products different in fair epoxides to excellent could yield be converted (74%–99%, into TOF the correspondingup to 2926 h−1). triazoleIn spite −1 productsof the mechanical in fair to stress excellent put on yield the (74%–99%,siliceous materi TOFal up by to sonication, 2926 h ). the In spitesupported of the system mechanical maintained stress putintact on its the activity siliceous in materialsix consecutive by sonication, runs (98% the → supported 98% yield) system and no maintained copper was intact reportedly its activity detected in six → consecutivein the filtrate runs by AAS. (98% 98% yield) and no copper was reportedly detected in the filtrate by AAS. 3.5. Magnetically Recoverable Systems 3.5. Magnetically Recoverable Systems Similarly to materials containing copper and copper oxide clusters on super-paramagnetic Similarly to materials containing copper and copper oxide clusters on super-paramagnetic supports (Section 2.6), the last few years saw progresses also for what it concerns magnetically supports (Section 2.6), the last few years saw progresses also for what it concerns magnetically recoverable systems containing Cu(I/II) species on a polymeric organic layer (Scheme 21). Advances in recoverable systems containing Cu(I/II) species on a polymeric organic layer (Scheme 21). Advances this direction were reported, for instance, by Pourjavadi et al. [186]. With an approach in some respects in this direction were reported, for instance, by Pourjavadi et al. [186]. With an approach in some respects analogous to that already discussed for the GO-based material 32 (Section 3.1), N- Molecules 2016, 21, 1174 27 of 43 Molecules 2016, 21, 1174 26 of 41 vinylimidazole,analogous to that N- alreadyethyl-N′ discussed-vinylimidazolium for the GO-based tetrafluoroborate, material and32 (Section a dicationic 3.1), cross-linkingN-vinylimidazole, agent wereN-ethyl- subjectedN0-vinylimidazolium to radical copolymerization. tetrafluoroborate, In this and case a dicationic the process cross-linking was carried agent out in were the subjectedpresence ofto core-shell radical copolymerization. Fe3O4-silica gel nanoparticles In this case thebearing process surface was methacrylate carried out in groups, the presence in order of core-shellto endow theFe3 Opolymeric4-silica gel material nanoparticles (55 wt bearing% by TGA) surface with methacrylate a covalently groups, embedded in order magnetic to endow core. the Charging polymeric of thematerial resin (55with wt CuSO % by4 TGA)in the withfinal astep covalently led to the embedded supported magnetic catalyst core.precursor Charging 46. The of theactivity resin of with the materialCuSO4 in was the finaltested step in ledthe tothree-components the supported catalyst CuAAC precursor reaction46 of. Thebenzyl activity bromide, of the with material sodium was ascorbatetested in theas the three-components reducing agent. CuAACCompromise reaction cond ofitions benzyl for bromide, minimizing with both sodium catalyst ascorbate loading as and the reactionreducing time agent. were Compromise determined conditions to be the foruse minimizing of 0.75 mol both% of catalystsupported loading copper and complex reaction in time water were at 50determined °C. With tothis be choice, the use different of 0.75 mol chlorides % of supported or bromides copper and complexterminal inalkynes, water ateither 50 ◦ C.aliphatic With this or aromaticchoice, different (Scheme chlorides 2a), could or be bromides effectively and coupled terminal in alkynes, 2–4 h (80%–97% either aliphatic yield). orFiltration aromatic of (Schemethe mixture2a), wascould confirmed be effectively to halt coupled completely in 2–4 the h (80%–97%reaction progress yield). Filtrationand ICP-AES of the assay mixture of the was filtrate confirmed did not to detecthalt completely any significant the reaction concentration progress of and copper. ICP-AES Still, assaya moderate of the reduction filtrate did of not turnover detect anyfrequency significant was recordedconcentration in the of course copper. of Still, 6 recycle a moderate runs of reduction the benchmark of turnover reaction, frequency which wasforced recorded to increase in the the course time fromof 6 recycle 150 min runs to of170 the min benchmark in order reaction,to maintain which the forcedproduct to increaseyield in the timerange from 90%–95%. 150 min As to in 170 other min cases,in order the to trend maintain was therelated product to mechanical yield in the losses range of 90%–95%. the supported As in system other cases, during the the trend separation was related and washingto mechanical steps. losses of the supported system during the separation and washing steps. A similarsimilar approach approach was was followed followed by Zohrehby Zohreh et al. foret theal. preparationfor the preparation of magnetically of magnetically recoverable recoverablenanoparticles nanoparticles consisting of aconsisting Fe3O4 core of embed a Fe3 intoO4 core silica gelembed and cross-linkedinto silica gel poly(methyl and cross-linked acrylate) (PMA)poly(methyl shell layersacrylate) [187 (PMA)]. shell layers [187].

Scheme 21. PreparationPreparation of of supported supported Cu(II) Cu(II) salts salts 46–48 onto organic cross-linked polymers with super-paramagnetic core.

Aminolysis of the groups of the latterlatter withwith N,NN,N-dimethylethylenediamine-dimethylethylenediamine allowed the installation ofof chelating chelating units, units, exploited exploited in thein lastthe steplast forstep adsorbing for adsorbing CuSO4 CuSOfrom an4 from aqueous an aqueous solution. Whensolution. tested When in three-componentstested in three-components CuAAC reactionsCuAAC reactions (Scheme2 (Schemea), the resulting 2a), the supportedresulting supported complex complex47 afforded 47 afforded best results best in results water in at water 50 ◦C, at at 50 0.3 °C, mol at 0.3 % loadingmol % loading and in theand presencein the presence of an excess of an excessof sodium of sodium ascorbate. ascorbate. Under Under these conditions,these conditio differentns, different triazole triazole products products were smoothly were smoothly formed formedfrom the from corresponding the corresponding alkyne andalkyne alkyl and chloride, alkyl ch bromideloride, bromide or tosylate or (75%–97%tosylate (75%–97% yield in 1.5–4yield h).in While1.5–4 h). no While ICP-OES no ICP-OES detectable detectable metal was metal found was in found the liquid in the phases liquid from phases seven from consecutive seven consecutive reaction reactionruns, analysis runs, analysis of the magnetic of the magnetic material material recovered recovered in the last in the cycle last indicated cycle indicated a slight a reductionslight reduction of the of the copper content with respect to the original system (0.54 vs. 0.57 mmol·g−1). In addition, some mass loss of the nanoparticles as a whole was recorded. As suggested, this fact may represent the Molecules 2016, 21, 1174 28 of 43 copper content with respect to the original system (0.54 vs. 0.57 mmol·g−1). In addition, some mass loss of the nanoparticles as a whole was recorded. As suggested, this fact may represent the likely explanation of the progressively longer reaction time required for attaining constant conversion in consecutive CuAAC runs. Still, it cannot be excluded that metal leaching might play a role in the problem, as seemingly supported by the fact that TOF values corrected for mass loss underwent also some decrease on passing from the first to the last reaction cycle (160 h−1 → 142 h−1). Coating of Fe3O4-silica gel core-shell magnetic nanoparticles with a cross-linked organic polymeric layer was tackled also by Pourjavadi et al. [188]. In this case, the macromolecular material was obtained by copolymerization of acrylamide and N,N0-methylenebisacrylamide, in the presence of starch and support nanoparticles bearing methacrylate groups on the surface. Loading with CuCl2 afforded the insoluble catalyst precursor 48, which was examined in three-components CuAAC reactions of halides (Scheme2a). With sodium ascorbate as the reducing agent, the use of 0.5 mol % of the system in water required to warm the reaction mixture to 50 ◦C for obtaining the triazole products in good yield after a short reaction time (82%–99% in 1–5 h). A standard ‘filtration experiment0 and ICP-OES determination of copper in the separated reaction mixture excluded significant amounts of metal in the solution. At the same time, the reuse of recovered magnetic nanoparticles revealed a reasonable durability of the catalyst. Indeed, while a step drop of average turnover frequency was observed on passing from the 5th to the 6th reaction cycle (TOF approximate 400 h−1 → 300 h−1), no further reduction of turnover rate was recorded in the next five runs. Because FT-IR and ICP-OES data for the recovered catalyst were not very dissimilar from those of the original material, the trend was attributed to mechanical losses during the isolation step. At the borderline between low molecular weight ligands and high-polymeric ones, functional dendrimers have proved to be very effective in the development of recoverable catalytic systems [189], including those for CuAAC [77]. Very recently, Bahrami and Arabi described the preparation of a triazine-based, 2nd generation dendrimer-Cu(II) complex on ferromagnetic nanoparticles 49 (Figure5) and its use in three-component CuAAC reactions [190]. The material was obtained by initially coating the Fe3O4 nanoparticles with an aminopropylsilica layer and then reacting the surface functional groups with trichlorotriazine and ethylenediamine, in a two-round iterative fashion. Although these solid-phase steps were found not to be complete, the final material showed an appreciable adsorbing capacity towards Cu(OAc)2 and eventually provided the supported Cu(II) complex as a dark-green solid. Examination of the powder by various techniques (SEM, XRD, and TEM) revealed the presence of well dispersed particles, uniform in shape and size (35 nm average diameter) and consisting of a Fe3O4 core coated by a thinner silica shell. The catalytic activity of 49 was optimized in the reaction between benzyl chloride, sodium azide, and phenylacetylene, rather unusually carried out in the presence of an equivalent amount of Na2CO3. In spite of the relatively low catalyst loading (mostly 0.3 mol % of Cu), nearly quantitative yields were recorded in 10–15 min at r.t. in EtOH-H2O (1:1). The same conditions were therefore adopted for the CuAAC of other alkynes and halides (Scheme2a), to give the corresponding triazoles with excellent yield in no more than 40 min (90%–99%). Surprisingly, this held true not only in the case of very reactive halides (benzyl, allyl, and α-halocarbonyl chlorides and bromides) but even for a reactant, like hexyl bromide, which is expected to undergo the halogen/azide exchange at much slower rate. Recycling of the nanoparticles by magnetic decantation showed some slight reduction of activity along six consecutive runs in the aforementioned benchmark relation (99% → 93% yield). Such a trend was tentatively assigned to “the normal loss the catalyst during the work-up stage”, but no clue was provided about the possible relevance of missing nanoparticles for the problem of product contamination. Molecules 2016, 21, 1174 29 of 43 Molecules 2016, 21, 1174 28 of 41

Figure 5.5. Cu(I/II)Cu(I/II) complexes complexes 4949––5353, ,containing containing organic organic ligands ligands immobilized on magneticallymagnetically recoverable supports.supports.

Also for this this class class of of recoverabl recoverablee CuAAC CuAAC catalytic catalytic systems, systems, exampl exampleses were were reported reported recently recently of ofmaterials materials embedding embedding discrete discrete organic organic ligands ligands (Figur (Figuree 5). Considering5). Considering that thatcyclodextrins cyclodextrins (CDs) (CDs) have havefound found use in use CuAAC in CuAAC reactions, reactions, with with probable probable roles roles ranging ranging from from phase-transfer phase-transfer agents agents [191], [191 to], toligands ligands for for Cu(II) Cu(II) or or Cu(I) Cu(I) [192,193], [192,193 ],Mahdavi Mahdavi et et al. al. used used a asurface surface silanization silanization approach approach for for binding β-CD units to super-paramagnetic super-paramagnetic iron nanoparticles [194]. [194]. Treatment Treatment of the resulting white material with CuClCuCl underunder alkaline alkaline conditions conditions afforded afforded a darka dark powder powder50 that,50 that, although although hard hard to assess to assess for what for itwhat concerns it concerns oxidation oxidation state, aggregation state, aggregation degree, anddegree, location and oflocation Cu centers, of Cu displayed centers, satisfactory displayed catalyticsatisfactory activity catalytic in a four-componentsactivity in a four-compone reaction involvingnts reaction a CuAAC involving click a CuAAC step (Scheme click step22). Reuse(Scheme of the22). magnetically-recoveredReuse of the magnetically-recovered nanoparticles nanoparticle led to nearlys constantled to nearly yields constant in the course yields of in 5 the cycles course and of a − cumulative5 cycles and TON a cumulative of 8300 after TON 10 of runs 8300 (average after 10 TOFruns =(average 347 h 1 TOF). A ‘filtration= 347 h−1). experiment’,A ‘filtration experiment’, in which the supportedin which the catalyst supported was stirred catalyst with was EtOH–H stirred 2withO for EtOH–H 24 h revealed2O for a 24 very h revealed low metal a concentrationvery low metal in theconcentration liquid phase in (<1the ppm liquid by ICP-AES)phase (<1 that,ppm expectedly, by ICP-AES) did notthat, lead expectedly, to any appreciable did not lead conversion to any whenappreciable standard conversion reactants when of the standard process above reactants were of added the process to the solution. above were Nonetheless, added to the the fact solution. that in someNonetheless, documented the fact cases that copper in some leaching documented was significantly cases copper larger leaching in the presencewas significantly of CuAAC larger substrates in the andpresence products, of CuAAC than in substrates the reaction and solvent products, alone than [75 in], makesthe reaction it difficult solvent to evaluate alone [75], the makes relevance it difficult of the experimentto evaluate forthe the relevance problem ofofmetal the experiment release under fo actualr the four-componentproblem of metal reaction release conditions. under actual four-component reaction conditions. Molecules 2016, 21, 1174 30 of 43 Molecules 2016, 21, 1174 29 of 41

Scheme 22. Four-component condensation-click process promoted by 50..

Given thethe strong strong tendency tendency of triazolesof triazoles to bind to bind copper, copper, the same thestructural same structural motif has motif been has exploited been inexploited the past in for the retaining past for Cu(I/II) retaining onto Cu(I/II) an insoluble onto an support insoluble bearing support tris-triazole bearing tris-triazole units, e.g., of units, the TBTA e.g., typeof the [195 TBTA]. More type recently, [195]. More Moghaddam recently, etMoghaddam al. examined et the al. useexamined for the the same use purpose for the ofsame mono-triazoles purpose of providedmono-triazoles with an provided ancillary with coordination an ancillary site coordination [196,197]. Grafting site [196,197]. of ligand Grafting units was of realizedligand units either was by reactionrealized ofeither surface-anchored by reaction functionalof surface-anchored groups with afunctional preformed groups triazole with derivative, a preformed or by generating triazole thederivative, heterocycle or by nucleus generating in a three-componentsthe heterocycle nucleus CuAAC in step.a three-comp In the latteronents case CuAAC the resulting step. In material the latter51 wascase obtainedthe resulting already material charged 51 withwas obtained Cu(I). Instead, already in thecharged former with case Cu(I). the supported Instead, in Cu(II) the former complex case52 wasthe supported prepared byCu(II) stirring complex the magnetic 52 was prepared nanoparticles by stirring with CuClthe magnetic2 in water. nanoparticles At 0.5 mol % with loading CuCl and2 in inwater. the presenceAt 0.5 mol of sodium% loading ascorbate, and in the both presence systems of were sodium active ascorbate, in three-component both systems CuAAC were reactionsactive in inthree-component water with alkyl CuAAC halides reactions or tosylates in water (Scheme with2a) alky andl halides afforded or the tosylates corresponding (Scheme triazoles2a) and afforded in high yield,the corresponding after 2–8 h at triazoles 55 ◦C (85%–98%). in high yield, Recycling after 2–8 of the h at materials 55 °C (85%–98%). proved feasible, Recycling with of slight the reductionmaterials ofproved product feasible, yield (approximatewith slight reduction 5%) in the courseof prod ofuct 10 yield consecutive (approximate runs. 5%) in the course of 10 0 consecutiveSimilarly, runs. 2,2 -bis(imidazole) on core-shell Fe3O4-SiO2 nanomagnetite particles was obtained by TajbakhshSimilarly, et2,2 al.′-bis(imidazole) through reaction on core-shell of the ligand Fe3O4 with-SiO2 thenanomagnetite chloropropyl-modified particles was support obtained [198 by]. LoadingTajbakhsh with et differental. through metal reaction salts led of tothe the ligand corresponding with thecomplexes, chloropropyl-modified among which support that prepared [198]. fromLoading CuI with (53) showeddifferent the metal highest salts activity led to inthe three-component corresponding complexes, CuAAC reactions among (Schemewhich that2a). prepared With the usefrom of CuI 0.85 (53 mol) showed % of this the catalyst highest at activity r.t., in waterin three-co or EtOH–Hmponent2O CuAAC (1:1), various reactions chlorides, (Scheme bromides 2a). With or tosylatesthe use of were 0.85 transformedmol % of this effectively catalyst at in r.t., the in corresponding water or EtOH–H triazole2O (1:1), within various 0.5–3.5 chlorides, h (88%–99% bromides yield). Reuseor tosylates of the were magnetically transformed recovered effectively material in demonstratedthe corresponding good triazole preservation within of 0.5–3.5 its catalytic h (88%–99% activity, withyield). a Reuse measurable of the dropmagnetically of product recovered yield only material in the demonstrated 5th cycle (99% good→ preser93%)vation (and the of its attainment catalytic ofactivity, a still with respectable a measurable 96% yield drop in theof pr 6thoduct run, yield carried only out in with the somewhat5th cycle (99% extended → 93%) reaction (and time: the 30attainment min → 40 of mina still). Norespectable textural 96% changes yield in in the the recovered6th run, carried solid wereout with noticed somewhat by electron extended microscopy, reaction buttime: copper 30 min was → detected 40 min). in No minute textural amounts changes (0.08% in ofthe the recovered initial quantity) solid were in the noticed product by phase electron after themicroscopy, 5th run. but On copper this ground, was detected reloading in minute of the amounts magnetic (0.08% material of the with initial CuI quantity) was effected, in the to product give a “regenerated”phase after the system 5th run. with On thethis same ground, activity reloading of the of original the magnetic one. material with CuI was effected, to give a “regenerated” system with the same activity of the original one. 4. Cu-Exchanged Clays and Other Inorganic Materials 4. Cu-ExchangedAlthough purely Clays inorganic and Other materials Inorganic fall outside Materials the main focus of the present review, for the sake of completenessAlthough purely recent inorganic advances materials on the topic fall are outside only brieflythe main summarized focus of the in thispresent section. review, for the sake ZMS-5of completeness zeolite exchanged recent advances with Cu(II)on the andtopic Co(II) are only was briefly used summarized by Safa and in Mousazadeh this section. in the three-componentZMS-5 zeolite CuAAC exchanged reaction with of Cu(II) benzyl and bromides Co(II) andwas propargylused by Safa alcohol, and carriedMousazadeh out in in water the underthree-component thermal or CuAAC US-promoted reaction conditions of benzyl [ 199bromid]. Thees mostand propargyl interesting alcohol, findings carried of the out study in water were theunder observation thermal or that US-promoted the mixed Cu/Coconditions system [199]. was The more most effective interesting than findings an analogous of the study ZMS-5 were zeolite the exchangedobservation with that Cu(II) the mixed alone andCu/Co the system fact that, was under more sonication, effective the than reaction an analogous time could ZMS-5 be shortened zeolite fromexchanged several with hours Cu(II) to 5 alone min. and The the possibility fact that, was unde alsor sonication, mentioned the of reaction reusing thetime catalyst could be eighth shortened times withoutfrom several significant hours lossto 5 ofmin. activity. The possibility However, was no specific also mentioned data was provided,of reusingneither the catalyst in this eighth respect times nor forwithout what significant it concerns loss potential of activity. leaching However, issues. no specific data was provided, neither in this respect nor forA comparativewhat it concerns evaluation potential of differentleaching catalystsissues. for the CuAAC reaction between dipropargylated alloxanA andcomparative various benzylevaluation azides of was different undertaken catalysts by Dubey for etthe al. [200CuAAC]. Apart reaction for the naturebetween of thedipropargylated reactants, the alloxan study strictly and various mirrored benzyl in methods azides was and undertaken conclusions by those Dubey of Mohammedet al. [200]. Apart et al. for the nature of the reactants, the study strictly mirrored in methods and conclusions those of Molecules 2016, 21, 1174 31 of 43 three-components CuAAC reactions involving aromatic boronic acids (Scheme2d) [ 201]. Among the systems included in the screening, a Cu(II)-exchanged clay proved superior to other Cu(I/II) catalysts examined in the work. Recovery and recycling of the catalyst was possible, but some decrease of the product yield was observed in the course of five reaction cycles with a fixed reaction time of 3 h (96% → 81%). In their continuing interest in flow-chemistry, Ötvös et al. examined a Cu(II)-Fe(III) layered double hydroxide (LDH) as an heterogeneous catalyst for in continuo two-components CuAAC reactions [202]. When the material was used in a stainless-steel reactor provided with a back-pressure regulator set ◦ to 100 bar, optimal results (77%–98% yield) were obtained in CH2Cl2 at 100 C with contact time as short as 100 s. With this experimental set-up, the system could be kept working for 10 h without any evident decrease in activity and provided the expected triazole product with a final TON around 5 and a residual copper content of 45.3 ppm. Although the resting state of the catalyst was found to be Cu(II), its activity in CuAAC was explained by reasoning that under the vigorous reaction conditions cupric ions might undergo in situ reduction (e.g., by dehydrogenative homocoupling of the alkyne substrate), to generate Cu(I) active sites as defects in the LDH lattice. González-Olvera et al. carried out a comparison of the catalytic properties in CuAAC of a Cu-Al LDH, with those of the Cu(Al)O mixed oxide obtained by high temperature calcination of the former [203]. The mixed oxide was found to be more active and better fit for recycling than the LDH, especially when calcination was used before each new run in order to get rid of any organic material deposited on its surface. Both materials displayed some tendency to leach copper in the solution, albeit to an extent significantly larger for LDH than for the mixed oxide (0.4% and 4%, respectively). The phenomenon, attributed to the capability of sodium ascorbate to chelate metal ions, translated into an appreciable catalytic activity in the filtrate. This let the Authors to conclude that, at variance with most of the supported CuAAC catalysts reported in related studies, homogeneous and heterogeneous type of catalysis coexisted in their system. Another instance of a copper-exchanged clay material, in this case natural montmorillonite, was described recently by Mekhzoum et al. [204]. Rather surprisingly in view of the very low solubility of CuI in water (approximate 4.2 × 10−4 M at 18–20 ◦C) [205], the material was reportedly prepared by vigorous stirring of the clay in a saturated aqueous solution of the copper salt. The activity of the system was probed in the two-components CuAAC reactions (Scheme1), performed in water at r.t. and with about 2 mol % of supported catalyst (88%–98% yield in 2 h). Reuse of the material recovered by filtration proved also feasible, albeit with a slight decrease of product yield in five consecutive cycles (97% → 92%). Finally, the entrapment of Cu(II) in a silica matrix by sol-gel process allowed Diz et al. to prepare spherical nanoparticles (<100 nm in size) containing variable amounts of the metal (0.05 wt %–9.4 wt %)[206]. Stirring with an aqueous solution of sodium ascorbate led to complete fading of the pale-blue color of the solid and afforded an EPR silent material with reasonable activity in two- and three-components CuAAC reactions in DMF or t-BuOH-H2O (3:1) (Schemes1 and2 a: 80%–98% yield in 3–6 h at r.t., at 5 mol % loading and with three equiv. of added N,N-diisopropylethylamine). Recyclability of the catalytic system was verified in two series of 10 consecutive runs (93% → 87% or 89% → 87% yield), while the nature of catalysis was confirmed to be heterogeneous by running not only a standard “filtration experiment”, but also a “three-phase test” with a benzylic azide derivative anchored to Wang resin. Remarkably, when the filtrates from two CuAAC runs were subjected to copper quantification by ICP-MS, a very low metal content was found (approximate 0.1–0.2 ppb). Even if the figures for dry triazole products are at least one order of magnitude larger, it seems therefore that copper contamination by the system under exam is one of the lowest reported to date for any recoverable CuAAC catalyst. Molecules 2016, 21, 1174 32 of 43

5. Conclusions With a cost ranking among the lowest for transition metals employed in organic synthesis, it might be argued that recovery and recycling of the copper catalyst used in CuAAC is not of prime importance for the economics of the process. Still, the difficulty of removing the metal from highly functionalized products or polymeric materials and the specific problems raised by biomolecules, prompted the introduction of new and more effective protocols in the past years. Almost invariably, this resulted in the use of relatively expensive soluble ligands that in addition could not solve completely the issue of product contamination. Especially in the perspective of synthesizing triazole compounds supposed to undergo biological screening, or whose functional properties (e.g., fluorescence) are adversely affected by copper contamination, this state of facts justifies the efforts currently devoted to the quest for improved CuAAC catalytic systems. As shown also by the cases discussed in the present review, the proposed solutions range from very simple materials to very complex ones. In the case of the former, once the separation issue is granted and a large enough turnover is achieved, the possibility of reusing the catalyst is probably a useful, but not strictly essential feature of the system. On the contrary, in the case of catalyst comprising expensive components the attainment of extensive recycling (presumably much beyond what disclosed in the examples reported to date) appears to be an additional mandatory requirement, at least in view of their possible use at scale [207]. In this context it is worth of note that, although the need or reducing copper contamination is generally acknowledged in the introductory section of most of the published works, little care is paid in a surprisingly large number of papers to provide reliable data on this aspect. In perspective, with the introduction of additional components in the catalytic system that might be even more toxic (e.g., Ni) or more difficult to spot than copper (e.g., organic contaminants from partially soluble polymeric components in the material), this situation is at risk of taking the research in the field, very far from its stated target. As noted in the review of Haldon et al., “almost any copper source that delivers catalytically active Cu(I) species in the reaction mixture can be employed as a pre-catalyst in the CuAAC reaction” [88]. Although the same conclusions can be drawn also for the recoverable systems discussed in the present paper, different materials display nonetheless a broad spectrum of activity: Some work at low loading and temperatures close to 25 ◦C, in the very spirit of click-chemistry, other require high-boiling solvents at reflux temperature. While this allows certainly some kind of ranking between the systems that keep being published, also from this point of view a punctual comparison is severely hampered in some cases by the lack of relevant data like, e.g., catalyst loading. Considering the degree of ingenuity demonstrated in many of the examples reported to date, the unquestionable success with some of the disclosed systems, and the relevance for the development of greener synthetic processes, further developments in the field of recoverable catalyst for CuAAC are expected. Hopefully, these advancements will strive to take the issues above into greater account and make an effort to adhere more strictly to recommended best practices for benchmarking new catalysts [208].

Acknowledgments: Financial support by the Università di Pisa (PRA_2016_46 “Studio di sistemi confinati: verso un approccio multiscale”) and by MIUR (FIRB Project RBFR10BF5V “Multifunctional hybrid materials for the development of sustainable catalytic processes”). Conflicts of Interest: The author declares no conflict of interest.

Abbreviations The following abbreviations are used in this manuscript: AAS Atomic absorption spectroscopy AES Atomic emission spectroscopy Bipy 4,40-Bipyridine CD Cyclodextrin Molecules 2016, 21, 1174 33 of 43

CNT carbon nano-tubes CP-MASS Cross-polarization magic angle spinning spectroscopy CRGO Chemically-reduced graphene oxide CS Chitosan CuAAC Copper-catalyzed azide-alkyne cycloaddition CuNPs Copper nanoparticles DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide DVB divinylbenzene EDACell Ethylenediamine-modified cellulose EDS Energy-dispersive (X-ray) spectroscopy FT-IR Fourier-transform infra-red spectroscopy GO Graphene oxide Himdc 4,5-Imidazoledicarboxylate HPA Heteropolyacid ICP Inductively-coupled plasma LDH Layered double hydroxide M-dots Melanine nanoparticles MOF Metal-organic framework MS Mass spectrometry MW Microwave, molecular weight NHC N-Heterocyclic carbene OES Optical emission spectroscopy pABA Poly(2-aminobenzoic acid) PANI Polyaniline PIB Poly(isobutylene) PEG Poly(ethylene glycol), poly(ethylene oxide) Pim Poly(vinyl imidazole) p[C4R-NH2] amine-modified calix[4]resorcinarene-formaldehyde resin P[im/IL] Imidazole-ionic liquid copolymer PMMA Poly(methyl methacrylate) POM Polyoxometalate ppm, ppb parts per milion, parts per bilion PTFE Poly(tetrafluoroethylene) PVA Poly(vinyl alcohol) PVP Poly(N-vinyl pyrrolidone) PVPh Poly(4-vinylphenol) r.t. Room temperature SEM Scanning electron microscopy SMI Poly(styrene-co-maleic anhydride) imide SNW Schiff-base network polymer TBTA Tris[(1-benzyl-1,2,3-triazole-4-yl)methyl]amine TEM Transmission electron microscopy TGA Thermogravimetric analysis THF Tetrahydrofurane TOF Turnover frequency TON Turnover number UV Ultraviolet spectroscopy XPS X-ray photoelectron spectroscopy XRD X-ray (powder) diffraction analysis XRF X-ray fluorescence analysis

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