Solid-Supported Palladium Catalysts in Sonogashira Reactions: Recent Developments Reactions: Recent Developments Diego A

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catalysts Review ReviewSolid-Supported Palladium Catalysts in Sonogashira Solid-Supported Palladium Catalysts in Sonogashira Reactions: Recent Developments Reactions: Recent Developments Diego A. Alonso, Alejandro Baeza, Rafael Chinchilla *, Cecilia Gómez, Gabriela Guillena, IsidroDiego M. A. AlonsoPastor *ID and, Alejandro Diego J. BaezaRamónID , Rafael Chinchilla * ID , Cecilia Gómez, Gabriela Guillena, Isidro M. Pastor * ID and Diego J. Ramón ID Department of Organic Chemistry and Institute of Organic Synthesis (ISO), Faculty of Sciences, University of Alicante,Department PO ofBox Organic 99, 03080 Chemistry Alicante, and Spain Institute; [email protected] of Organic Synthesis (D.A.A.); (ISO), [email protected] Faculty of Sciences, (A.B.); University of Alicante,[email protected] PO Box (C.G.); 99, 03080 [email protected] Alicante, Spain; [email protected] (G.G.); [email protected] (D.A.A.); (D.J.R.) [email protected] (A.B.); *[email protected] Correspondence: (C.G.); [email protected] [email protected] (R.C.); [email protected] (G.G.); [email protected] (I.M.P); Tel.: (D.J.R.) +34-965-903-822 (R.C.) * Correspondence: [email protected] (R.C.); [email protected] (I.M.P); Tel.: +34-965-903-822 (R.C.) Received: 19 April 2018; Accepted: 9 May 2018; Published: 11 May 2018 Abstract:Received: 19The April Sonogashira 2018; Accepted: cross 9 May-coupling 2018; Published: reaction 11 is May the 2018 most frequently employed synthetic procedure for the preparation of arylated alkynes, which are important conjugated compounds with Abstract: The Sonogashira cross-coupling reaction is the most frequently employed synthetic multiple applications. Despite of their rather high price, this reaction is usually catalyzed by procedure for the preparation of arylated alkynes, which are important conjugated compounds palladium species, making the recovery and reuse of the catalyst an interesting topic, mainly for with multiple applications. Despite of their rather high price, this reaction is usually catalyzed by industrial purposes. Easy recycle can be achieved anchoring the palladium catalyst to a separable palladium species, making the recovery and reuse of the catalyst an interesting topic, mainly for support. This review shows recent developments in the use of palladium species anchored to industrial purposes. Easy recycle can be achieved anchoring the palladium catalyst to a separable different solid supports as recoverable catalysts for Sonogashira cross-coupling reactions. support. This review shows recent developments in the use of palladium species anchored to different solid supports as recoverable catalysts for Sonogashira cross-coupling reactions. Keywords: palladium; catalysis; Sonogashira reaction; supported reagents; cross-coupling reactions

Keywords: palladium; catalysis; Sonogashira reaction; supported reagents; cross-coupling reactions

1. Introduction

1. IntroductionThe palladium-catalyzed Csp2-Csp coupling reaction between aryl or alkenyl halides or triflates and terminalThe palladium-catalyzed alkynes is the most Csp important2-Csp coupling method reaction to prepare between arylalkynes aryl or alkenyl and conjugated halides or enynes, triﬂates whichand terminal are precursors alkynes is for the naturalmost important products, method pharmaceuticals, to prepare arylalkynes and molecular and conjugated organic materials enynes, which(Scheme are 1) [1]. precursors The pioneering for natural works products, of Heck [2] pharmaceuticals, and Cassar [3] in and 1975, molecular using phosphine organic-palladium materials (Schemecatalysts1 at)[ temperatures1]. The pioneering up to 100 works °C, ofwere Heck improved [2] and in Cassar the same [3] in year 1975, by using Sonogashira phosphine-palladium and Hagihara, reportingcatalysts at that temperatures the addition up of to a 100 catalytic◦C, were amount improved of copper(I) in the same accelerates year by the Sonogashira reaction, thus and Hagihara,enabling toreporting achieve thatthe a thelkynylation addition ofat aroom catalytic temperature amount of[4]. copper(I) Therefore, accelerates the Sonogashira the reaction,–Hagihara thus enablingprotocol (moreto achieve often the simply alkynylation known at as room Sonogashira temperature reaction) [4]. Therefore, became the the most Sonogashira–Hagihara popular procedure protocol for the (morealkynylation often simply of aryl known or alkenyl as Sonogashira halides [1,5,6 reaction)]. It is interestingbecame the to most note popular that ma procedureny of the for recent the developmentsalkynylation of about aryl new or alkenyl catalytic halides systems [1 able,5,6]. to Itcarry is interesting out this reaction to note are that intended many to of be the “copper recent- freedevelopments” processes, about to avoid new catalytic undesirable systems Glaser able-type to alkyne carry out homocoupling this reaction [7] are and intended to diminish to be “copper-free”environmental processes, contamination, to avoid these undesirable processes Glaser-type however alkyne still homocoupling being termed [ 7] as and “Sonogashira to diminish reactionsenvironmental”. contamination, these processes however still being termed as “Sonogashira reactions”.

Scheme 1. The general Sonogashira cross cross-coupling-coupling reaction reaction..

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From an economical, as well as an environmental, point of view, recovering and reusing the expensive palladium catalystcatalyst results particularly particularly interesting. interesting. The The obvious way of recovering the catalyst would be anchoring the catalytic species to a solid support, which would allow its easy separation after after the the reaction reaction completion completion just by just simple by simple ﬁltration, filtration, this topic this being topic considered being considered nowadays anowadays fast-moving a fast research-moving ﬁeld research [8–12]. field The present[8–12]. The review present shows review recent shows developments recent developments in the Sonogashira in the reactionSonogashira carried reaction out by carried using out solid-supported by using solid palladium-supported catalysts palladium and catalysts reported and from reported 2012 till from the beginning2012 till the of beginning 2018 [13]. Theof 2018 review [13]. has The been review divided has considering been divided the considering different types the ofdifferent supports types for the of palladiumsupports for species. the palladium It is necessary species. to note It is that, necessary although to note in many that, cases although the real in catalystmany cases is unknown, the real palladiumcatalyst is (0)unknown, nanoparticles palladium (PdNPs) (0) nanoparticles are generally considered(PdNPs) are to generally be the active considered catalytic species,to be the most active of thecatalyt palladiumic species, complexes most of the being palladium just precursors. complexes being just precursors.

2. Organic Polymer-SupportedPolymer-Supported Palladium Catalysts Organic polymers have been the oldest recoverable supports for palladium species acting as catalyst in Sonogashira reactions, and still manymany new palladium-containingpalladium-containing organic polymers able to catalyze this cross-couplingcross-coupling reactionreaction appear.appear. ItIt isis interesting toto note that almost all these new catalysts can perform the reaction inin aa copper-freecopper-free fashionfashion (Scheme(Scheme2 2).).

Scheme 2.2. A generalgeneral copper-freecopper-free Sonogashira cross-couplingcross-coupling reaction between an aryl halide and a terminal alkyne.alkyne.

Polystyrene-divinylbenzene resin beads have been the most frequently employed organic Polystyrene-divinylbenzene resin beads have been the most frequently employed organic supports supports for anchoring palladium complexes. Thus, PdNPs supported on a crosslinked polystyrene for anchoring palladium complexes. Thus, PdNPs supported on a crosslinked polystyrene 1 (Figure1) 1 (Figure 1) were used as catalyst in the copper-free Sonogashira coupling of phenylacetylene with were used as catalyst in the copper-free Sonogashira coupling of phenylacetylene with aryl iodides, aryl iodides, bromides and chlorides (Scheme 2), the addition of tetra-n-butylammonium bromide bromides and chlorides (Scheme2), the addition of tetra- n-butylammonium bromide (TBAB) as (TBAB) as nanoparticle stabilizer being necessary in the case of aryl chlorides [14]. The catalyst was nanoparticle stabilizer being necessary in the case of aryl chlorides [14]. The catalyst was recovered by recovered by filtration and reused up to five times in the model reaction between iodobenzene and filtration and reused up to five times in the model reaction between iodobenzene and phenylacetylene phenylacetylene obtaining recycling yields ranging from 88% to 72%. Other case is the obtaining recycling yields ranging from 88% to 72%. Other case is the phenyldithiocarbazate Pd(II) phenyldithiocarbazate Pd(II) complex 2 (Figure 1), which catalyzes the copper-free coupling of aryl complex 2 (Figure1), which catalyzes the copper-free coupling of aryl iodides and bromides, in pyridine iodides and bromides, in pyridine as base and at room temperature under neat conditions (Scheme as base and at room temperature under neat conditions (Scheme2)[ 15]. The supported catalyst 2) [15]. The supported catalyst has been reused up to five times in the reaction between iodobenzene has been reused up to five times in the reaction between iodobenzene and phenylacetylene almost and phenylacetylene almost keeping the same yield (from 99% to 95%). In addition, no additional keeping the same yield (from 99% to 95%). In addition, no additional solvent has been used when solvent has been used when the 1,2,4-triazine-functionalized polystyrene resin-supported Pd(II) the 1,2,4-triazine-functionalized polystyrene resin-supported Pd(II) complex 3 (Figure1) has been complex 3 (Figure 1) has been employed as catalyst using triethylamine or piperidine as base, the aryl employed as catalyst using triethylamine or piperidine as base, the aryl chloride derivatives affording chloride derivatives affording lower detected yields and almost no decreasing in the final yield being lower detected yields and almost no decreasing in the final yield being detected after reusing it five detected after reusing it five times [16]. In addition, the polystyrene-Pd(II)-furfural complex 4 (Figure times [16]. In addition, the polystyrene-Pd(II)-furfural complex 4 (Figure1) has presented catalytic 1) has presented catalytic activity in the C-C bond forming reactions, such as the Sonogashira activity in the C-C bond forming reactions, such as the Sonogashira coupling of aryl iodides, bromides coupling of aryl iodides, bromides and even chlorides with phenylacetylene, although chlorobenzene and even chlorides with phenylacetylene, although chlorobenzene showed low conversion and showed low conversion and activated aryl chlorides gave moderate yields working at higher activated aryl chlorides gave moderate yields working at higher temperatures in longer reaction temperatures in longer reaction times [17]. The recyclability of this catalyst was studied, but in a times [17]. The recyclability of this catalyst was studied, but in a Suzuki cross-coupling reaction, Suzuki cross-coupling reaction, keeping its reactivity after five runs. keeping its reactivity after five runs. Biphosphinite PCP-pincer palladium complex 5 (Figure 2), based on Merrifield resin, was Biphosphinite PCP-pincer palladium complex 5 (Figure2), based on Merrifield resin, was prepared prepared and characterized [18]. This supported species has been employed as catalyst in the cross- and characterized [18]. This supported species has been employed as catalyst in the cross-coupling of coupling of aryl iodides, bromides and chlorides with phenylacetylene, the addition TBAB additive aryl iodides, bromides and chlorides with phenylacetylene, the addition TBAB additive being necessary being necessary in the case of aryl chlorides. The recyclability of the catalyst was not checked in the in the case of aryl chlorides. The recyclability of the catalyst was not checked in the Sonogashira Sonogashira process but in a Heck reaction, showing the necessity of increasing the reaction time to process but in a Heck reaction, showing the necessity of increasing the reaction time to achieve similar achieve similar final yields after ten runs. In addition, a recent example of the use of a supported Pd- final yields after ten runs. In addition, a recent example of the use of a supported Pd-NHC complex NHC complex as catalyst is the Merrifield resin-anchored species 6, obtained from the corresponding supported imidazolium chlorides by treatment with palladium(II) acetate (Figure 2) [19]. This

Catalysts 2018, 8, 202 3 of 39 as catalyst is the Merrifield resin-anchored species 6, obtained from the corresponding supported imidazolium chlorides by treatment with palladium(II) acetate (Figure2)[ 19]. This catalyst has been used in theCatalyst copper-s 2018, 8 and, x FOR solvent-free PEER REVIEW coupling of different aryl bromides and two aryl chlorides3 of 38 with terminal acetylenes,catalyst has thesebeen used last in halides the copper affording- and solvent low- yields.free coupling The recyclabilityof different aryl of bromides the catalyst and two was assayed in the couplingaryl chlorides of bromobenzene with terminal acetylenes, with phenylacetylene these last halides for affording five consecutive low yields. The runs, recyclability observing of a certain decrease inthe the catalyst final was yield assayed (from in 95%the coupling to 75%). of bromobenzene It is interesting with tophenylacetylene note that a relatedfor five consecutive supported catalyst with a shorterruns, spacerobserving has a certain also been decreas preparede in the final showing yield (from a lower 95% to performance, 75%). It is interesting indicating to note thethat importancea related supported catalyst with a shorter spacer has also been prepared showing a lower of achievingperformance, accessibility indicating to active the importance catalytic sites.of achieving Moreover, accessibility the aminocarbene to active catalytic palladium sites. Moreover, complex with polystyrenethe support aminocarbene7 has palladium been used complex as catalyst with polystyrene in the typical support copper-cocatalyzed 7 has been used as catalyst Sonogashira in the coupling of aryl iodidestypical and copper bromides-cocatalyzed with Sonogashira monosubstituted coupling of aryl alkynes iodides and (Figure bromides2)[ with20]. monosubstituted Recycling experiments were conducted,alkynes (Figure and it 2) was [20]. possible Recycling to experiments reuse the were catalyst conducted, up to and eight it was times, possible although to reuse considerable the catalyst up to eight times, although considerable palladium leaching minimized by the addition of palladiumtriphenylphosphine leaching minimized was observed. by the addition of triphenylphosphine was observed.

Figure 1. Polystyrene-supported palladium catalysts for the Sonogashira reaction. Conditions, Figure 1. substratePolystyrene-supported scope and yield range palladium(Scheme 2). catalysts for the Sonogashira reaction. Conditions, substrate scope and yield range (Scheme2). The synthetic absorbent resin DIAION HP20 (a styrene-divinylbenzene copolymer) has been used to support palladium(II) acetate, using this material as catalyst for the coupling or aryl iodides The syntheticand terminal absorbent alkynes employing resin DIAION sodium phosphate HP20 (aas base styrene-divinylbenzene and isopropanol as solvent copolymer) at 80 °C [21]. has been used to supportThe use palladium(II)of a 10% of this Pd/HP20 acetate, catalyst, using resulted this material more effective as catalyst for the cross for-coupling the coupling reaction or than aryl iodides and terminalusing alkynes 10% Pd/C, employing only ultratra sodiumce amounts phosphate of palladium as leaching baseand being isopropanol detected. Similarly, as solvent the activity at 80 ◦C[21]. The use ofof a Pd/C 10% ofin the this Sonogashira Pd/HP20 reaction catalyst, has resulted been compared more effectivewith palladium for the catalysts cross-coupling immobilized reactionon than amphipathic monolithic polystyrene-divinylbenzene polymers bearing strong acidic cation exchange using 10%sulfonic Pd/C, acid only moieties ultratrace or basic amounts anion exchange of palladium functions [22]. leaching These anchored being detected. palladium Similarly, species have the activity of Pd/C inbeen the used Sonogashira as catalyst in reactionthe coupling has or beenaryl iodides compared and terminal with alkynes palladium under the catalysts same conditions immobilized on amphipathicthan monolithic above, performing polystyrene-divinylbenzene better than Pd/C. No palladium polymers leaching was bearing observed. strong acidic cation exchange sulfonic acid moieties or basic anion exchange functions [22]. These anchored palladium species have been used as catalyst in the coupling or aryl iodides and terminal alkynes under the same conditions than above, performing better than Pd/C. No palladium leaching was observed. Catalysts 2018, 8, x FOR PEER REVIEW 4 of 38

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Figure 2. Polystyrene-supported palladium catalysts for the Sonogashira reaction. Conditions, Figure 2. Polystyrene-supported palladium catalysts for the Sonogashira reaction. Conditions, Figure 2. substratePolystyrene scope -andsupported yield range palladium (Scheme 2). catalysts for the Sonogashira reaction. Conditions, substrate scope and yield range (Scheme2). substrate scope and yield range (Scheme 2). The use of water as solvent adds an “environmentally-friendly” tag when a catalytic methodology is developed [23], and its combination with recoverable catalysts from polystyrene The useresults use of of waterparticularly water as solvent asinteresting solvent adds for an addseconomic “environmentally-friendly” an and “environmentally industrial purposes.- friendly tagThus, when polystyrene” atag catalytic when-anchored methodology a catalytic methodologyis developedPd(II) [23 is pyridine ], developed and itscomplex combination [23], 8 (Figure and withits3) has combination recoverablebeen used as withcatalyst catalysts recoverable in the from copper polystyrene - catalystsfree coupling results from of aryl polystyrene particularly resultsinteresting particularlyiodides, for economic bromides interesting and and chlorides industrial for economic with purposes. some terminaland Thus, industrial alkynes, polystyrene-anchored in purposes.water and at Thus,room temperature, Pd(II) polystyrene pyridine the- anchored complex chloride derivatives affording just moderate yields. The catalyst was recovered by filtration and 8 (Figure3) has been used as catalyst in the copper-free coupling of aryl iodides, bromides and Pd(II) pyridinereused complexup to five times8 (Figure in the 3)reaction has beenbetween used iodobenzene as catalyst and inphenylacetylene, the copper -showingfree coupling only of aryl iodides,chlorides bromidesslight with decrease some and terminal in chlorides the detected alkynes, with final some yield in water(from terminal 98 and% to alkynes, at93%) room [24]. inWat temperature, waterer has alsoand been at the room used chloride as temperature, solvent derivatives the chloridaffordinge derivativeswhen just moderate the 4- amino affording- yields.5-methyl just-3 The- thio moderate-1,2,4 catalyst-triazole yields. was-functionalized recovered The catalyst polystyrene by filtrationwas recovered resin- andanchored reused by Pd(II) filtration up to andfive reusedtimes in up thecomplex to reactionfive 9 timeshas between been in thethe supported iodobenzenereaction catalystsbetween and in phenylacetylene,iodobenzene the coupling of aryland iodidesshowingphenylacetylene, and only bromides slight showing with decrease only in terminal alkynes (Figure 3) [25]. The catalyst was recycled for five runs in the coupling between the detected final yield (from 98% to 93%) [24]. Water has also been used as solvent when the slight decreaseiodobenzene in the anddetected phenylacetylene, final yield observing (from 98 a % decrease to 93%) in [24]. the final Wat yielder has from also 99 %been to 90%. used In as solvent when4-amino-5-methyl-3-thio-1,2,4-triazole-functionalized the addition, 4-amino the-5 dithizone-methyl--functionalized3-thio-1,2,4- supportedtriazole- functionalizedPd(II) polystyrene complex 10 resin-anchoredhas polystyrene proved effective resin Pd(II) as- anchoredcatalys complext Pd(II)9 has complexbeen the 9 supportedin has the copper been- catalystsfree the Sonogashira supported in the reaction coupling catalysts between ofin aryl aryl the iodides coupling iodides and andbromides of aryl bromides and iodides terminal with and acetylenes, terminal bromides alkynes with terminal(Figure3 )[ alkynesusing25]. piperidine The(Figure catalyst as base 3) [25]. in waswater The recycledas solvent catalyst at for room was five temperature recycled runs infor (Figure the five coupling3) runs[26]. The in recycled between the coupling catalyst iodobenzene between was reused for five runs observing almost no loss of effectivity. iodobenzeneand phenylacetylene, and phenylacetylene, observing a observing decrease in a decrease the final in yield the from final yield 99% to from 90%. 99%In to addition, 90%. In addition,the dithizone-functionalized the dithizone-functionalized supported supported Pd(II) complex Pd(II) complex10 has proved10 has proved effective effective as catalyst as catalys in thet incopper-free the copper Sonogashira-free Sonogashira reaction reaction between between aryl iodides aryl iodides and bromides and bromides and terminal and terminal acetylenes, acetylenes, using usingpiperidine piperidine as base as in base water in water as solvent as solvent at room at room temperature temperature (Figure (Figure3)[ 26 3)]. [26]. The recycledThe recycled catalyst catalyst was wasreused reused for five for runsfive runs observing observing almost almost no loss no ofloss effectivity. of effectivity.

Figure 3. Polystyrene-supported catalysts for the Sonogashira reaction in water. Conditions, substrate scope and yield range (Scheme 2).

Figure 3. PolystyrenePolystyrene-supported-supported catalysts for the the Sonogashira Sonogashira reaction reaction in water water.. Conditions, Conditions, substrate scope and yield range (Scheme 22).).

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The polystyrene-supportedpolystyrene-supported thiopseudourea Pd(II) complex 11 has also beenbeen applied as catalyst in the the Sonogashira Sonogashira coupling coupling between between aryl aryl iodides iodides and and terminal terminal acetylenes, acetylenes, using using triethylamine triethylamine as baseas base in water in water as solvent, as solvent, although although resulted resulted unable unable to perform to perform the reaction the reaction with aryl with bromides aryl bromides (Figure (Figure4) [27]. 4Another)[ 27]. supported Another supported thiopseudourea thiopseudourea Pd(II) species Pd(II) 12 specieshas also12 beenhas employed also been as employed catalysts asin thecatalysts cross- incoupling the cross-coupling of aryl iodides of and aryl bromides iodides and with bromides terminal with alkynes terminal (Figure alkynes 4) [28]. (Figure The coupling4)[ 28]. Theof aryl coupling iodides of aryl could iodides be performedcould be performed with triethylamine with triethylamine as base as base in water in water as as solvent solvent at at room ttemperatureemperature withwith aa catalystcatalyst loadingloading ofof 0.5 0.5 mol%, mol% whereas, whereas the the use use of of aryl aryl bromides bromides required required the the use use of oftetramethylguanidine tetramethylguanidine (TMG) (TMG) as base as base in water in water at 70 ◦atC with70 °C a with catalyst a catalyst loading loading of 1 mol%. of After1 mol% filtration,. After filtration,the catalyst the was catalyst recovered was recovered and reused and ten reused times, ten showing times, showing a certain a certain decrease decrease in the in reactivity the reactivity after afterthe sixth the sixth run. run. Moreover, Moreover, the tetrazole-supportedthe tetrazole-supported complex complex13 catalyzes13 catalyzes the the Sonogashira Sonogashira process process of ofaryl aryl iodides iodides and and bromides bromides in in water water as as solvent, solvent, using using triethylamine triethylamine asas basebase andand TBAB as additive, the catalys catalystt being recovered and reused up to five five times times in in the the reaction reaction between between 4 4-methyliodobenzene-methyliodobenzene and phenylacetylene with decreasing decreasing in in the the observed observed final final yield yield from from 94 94%% to to 89% 89% (Figure (Figure 44))[ [29].29]. Furthermore, a poly(styrene-co-maleicpoly(styrene-co-maleic anhydride) modifiedmodified with 2-aminothiazole2-aminothiazole moieties has been reported forfor thethe immobilizationimmobilization of of palladium(II) palladium(II) dichloride, dichloride, the the resulting resulting material material14 14being being suitable suitable as ascatalyst catalyst for for the the coupling coupling of aryl of aryl iodides, iodides, bromides bromides and chlorobenzeneand chlorobenzene with terminalwith terminal acetylenes, acetylenes, using pyridineusing pyridine as base as and base in and the in absence the absence of solvent of solvent (Figure (Figure4)[ 30 4)]. [30]. The catalystThe catalyst was recycledwas recycled up to up five to fivetimes, times, showing showing almost almost no decreasing no decreasing activity, activity, as well as well as low as palladiumlow palladium leaching. leaching.

Figure 4. Polystyrene-andPolystyrene-and co-polymericco-polymeric styrene styrene-supported-supported catalysts for the Sonogashira reaction in water.water. Conditions, substrate scope and yield rangerange (Scheme(Scheme2 2).).

Although less frequently, other organic polymers have recently been used as supports for Although less frequently, other organic polymers have recently been used as supports for palladium species destined to catalyze cross-coupling reactions such as the Sonogashira process. palladium species destined to catalyze cross-coupling reactions such as the Sonogashira process. Thus, a Schiff-base-derived porous polydivinylbenzene (PDVB) has been used for the creation of the palladium complex 15, which has been used as catalyst in the coupling of aryl iodides and bromides with phenylacetylene [31] (Figure 5). It has been determined that Pd(II) species in 15 are stable and

Catalysts 2018, 8, 202 6 of 39

Thus, a Schiff-base-derived porous polydivinylbenzene (PDVB) has been used for the creation of the palladiumCatalysts 2018 complex, 8, x FOR PEER15, which REVIEW has been used as catalyst in the coupling of aryl iodides and bromides6 of 38 with phenylacetylene [31] (Figure5). It has been determined that Pd(II) species in 15 are stable and almost leaching-free,leaching-free, which which is is responsible responsible for for the the recyclability, recyclability, the catalystthe catalyst being being reused reused up to up five to times five withtimes a with small a decreasesmall decrease in the yield in the (from yield 96% (from to 92%). 96% to In addition,92%). In addition, polyvinyl polyvinyl chloride (PVC)-supported chloride (PVC)- palladiumsupported speciespalladium have species alsobeen have reported also been as reported catalyst in as the catalyst Sonogashira in the Sonogashira reaction, as exemplified reaction, as exemplifiedin the phenyldithiocarbazate-functionalized in the phenyldithiocarbazate-functionalized PVC resin-anchored PVC resin Pd(II)-anchored complex Pd(II16, which) complex catalyzes 16, whichthe coupling catalyzes of aryl the iodides,coupling bromides of aryl iodides, and even bromides chlorides and with even terminal chlorides alkynes with under terminal solvent-free alkynes underconditions, solvent the-free chlorides conditions, giving the low chlorides to moderate giving yields low [to32 moderate] (Figure5 ).yields Recycling [32] (Figure of the catalyst5). Recycling after ofthe the coupling catalyst of after iodobenzene the coupling and phenylacetyleneof iodobenzene and (five phenylacetylene times) showed only(five atimes) slight showed decrease only of the a slightobserved decrease yield (fromof the 98%observed to 93%). yield Similar (from solvent-free 98% to 93%). reaction Similar conditions solvent-free and reaction aryl halides conditions have been and arylemployed halides when have thebeen PVC employed resin-supported when the triazinePVC resin Pd(II)-supported complex triazine17 has Pd(II) been usedcomplex as catalyst 17 has been [33], usedthe resulting as catalyst yields [33], being the resulting slightly better yields than being in theslightly former better case than showing in the similar former recyclability. case showing Moreover, similar recyclability.PVC has been Moreover, used for thePVC supporting has been used of PdNPs, for the andsupporting this material of PdNPs, has been and this employed material to has catalyze been employedthe coupling to catalyze of aryl iodides the coupling and phenylacetylene of aryl iodides and in water phenylacetylene as solvent, in although water as the solvent, presence although of six theequivalents presence of ofN six-methyl-2-pyrrolidone equivalents of N-methyl (NMP)-2-pyrrolidone was required (NMP) [34] (Figure was required5). Five reaction[34] (Figure cycles 5). were Five reactioncarried outcycles reusing were thecarried catalyst, out reusing the yield the diminishing catalyst, the fromyield 93%diminishing to 88% infrom the 93 reaction% to 88% between in the reactioniodobenzene between and iodobenzene phenylacetylene. and phenylacetylene.

Figure 5. Organic polymer-supportedpolymer-supported palladium catalysts for the Sonogashira reaction.reaction. Conditions, substrate scope and yield range (Scheme2 2).).

The radical polymerization of N-isopropylacrylamide (NIPAM) and potassium 4- The radical polymerization of N-isopropylacrylamide (NIPAM) and potassium 4-acryloxyoyl) acryloxyoyl)pyridine-2,6-dicarboxylate (PAP), crosslinked with N,N′-methylenediacrylamide, gave rise pyridine-2,6-dicarboxylate (PAP), crosslinked with N,N0-methylenediacrylamide, gave rise to a to a pH-responsive hydrogel (PNIPAM-co-PPAP) which has been used for the immobilization of pH-responsive hydrogel (PNIPAM-co-PPAP) which has been used for the immobilization of palladium(II) (18) (Figure 6) [35], a material that catalyzed the cross-coupling reaction of aryl iodides palladium(II) (18) (Figure6) [ 35], a material that catalyzed the cross-coupling reaction of aryl iodides and bromides with phenylacetylene in water as solvent. Its recyclability was being assayed in the and bromides with phenylacetylene in water as solvent. Its recyclability was being assayed in the coupling of iodobenzene and phenylacetylene, observing a decrease in the yield after six reaction cycles coupling of iodobenzene and phenylacetylene, observing a decrease in the yield after six reaction (from 91% to 85%), attributed to the aggregation of the formed PdNPs revealed by microscopy observations. Water has also been the employed solvent in the Sonogashira reaction when using as catalyst PdNPs immobilized on a melamine-based microporous network polymer [36]. Using this catalyst, differently substituted aryl iodides have been coupled to monoarylated acetylenes, the reaction being carried out using pyrrolidine as base, in water as solvent at 70 °C in 2 h. The recyclability was

Catalysts 2018, 8, 202 7 of 39 cycles (from 91% to 85%), attributed to the aggregation of the formed PdNPs revealed by microscopy observations. Water has also been the employed solvent in the Sonogashira reaction when using as catalyst PdNPs immobilized on a melamine-based microporous network polymer [36]. Using this

Catalystcatalyst,s 2018 differently, 8, x FOR PEER substituted REVIEW aryl iodides have been coupled to monoarylated acetylenes, the reaction7 of 38 being carried out using pyrrolidine as base, in water as solvent at 70 ◦C in 2 h. The recyclability was determined using the model coupling of iodobenzene and phenylacetylene, five consecutive runs bein beingg performed with very low decrease in in the the observed observed final final yield yield (from (from 98 98%% to to 94%). 94%).

Figure 6. 6. ImmobilizedImmobilized palladium palladium on onPNIPAM PNIPAM-co-PPAP-co-PPAP hydrogel hydrogel as catalyst as catalyst in the in Sonogashira the Sonogashira cross- couplingcross-coupling reaction reaction.. Conditions, Conditions, substrate substrate scope scopeand yield and range yield range(Scheme (Scheme 2). 2).

The treatment of commercially available polymethyl methacrylate (PMMA) microspheres with The treatment of commercially available polymethyl methacrylate (PMMA) microspheres with palladium(II) dichloride and formaldehyde generated supported Pd(0)-PMMA, which has been used palladium(II) dichloride and formaldehyde generated supported Pd(0)-PMMA, which has been used as catalyst (0.5 mol%) for the copper-free Sonogashira reaction of aryl iodides, bromides and chlorides as catalyst (0.5 mol%) for the copper-free Sonogashira reaction of aryl iodides, bromides and chlorides with terminal acetylenes, the aryl chlorides affording very low yields [37]. Triethylamine was used with terminal acetylenes, the aryl chlorides affording very low yields [37]. Triethylamine was used as base and water as solvent at 80 °C, the recovered catalyst having consistent performance for five as base and water as solvent at 80 ◦C, the recovered catalyst having consistent performance for cycles with very low palladium leaching rate. In addition, a porous organic polymer (POP) has been five cycles with very low palladium leaching rate. In addition, a porous organic polymer (POP) obtained by a copper-catalyzed click reaction between tetra(4-azidophenyl)methane and 1,4- has been obtained by a copper-catalyzed click reaction between tetra(4-azidophenyl)methane and diethynylbenzene (two equivalents), and the resulting material with high thermal stability and large 1,4-diethynylbenzene (two equivalents), and the resulting material with high thermal stability and surface area, has been employed for supporting PdNPs [38]. These anchored PdNPs catalyze the large surface area, has been employed for supporting PdNPs [38]. These anchored PdNPs catalyze Sonogashira coupling (0.14 mol%) of aryl iodides and terminal alkynes, using sodium hydroxide as the Sonogashira coupling (0.14 mol%) of aryl iodides and terminal alkynes, using sodium hydroxide base and methanol at 80 °C as solvent. The recyclability of the catalyst was determined using the as base and methanol at 80 ◦C as solvent. The recyclability of the catalyst was determined using the coupling of iodobenzene and phenylacetylene as model, a certain decrease in its performance being coupling of iodobenzene and phenylacetylene as model, a certain decrease in its performance being observed after five runs (from 99% to 72%). Moreover, PdNPs have been immobilized on preoxidated observed after five runs (from 99% to 72%). Moreover, PdNPs have been immobilized on preoxidated polyacrylonitrile fiber mats (prePAN), and this Pd-prePAN material has been employed (2 mol%) to polyacrylonitrile fiber mats (prePAN), and this Pd-prePAN material has been employed (2 mol%) to catalyze the coupling of aryl iodides and phenylacetylene [39]. The coupling was carried out in the catalyze the coupling of aryl iodides and phenylacetylene [39]. The coupling was carried out in the presence of potassium acetate as base in dimethyl sulfoxide (DMSO) as solvent at 110 °C, and the presence of potassium acetate as base in dimethyl sulfoxide (DMSO) as solvent at 110 ◦C, and the recyclability of the supported catalyst was assayed in a Heck coupling, revealing the remarkable recyclability of the supported catalyst was assayed in a Heck coupling, revealing the remarkable stability of the fiber structure. Furthermore, CuPd bimetallic solvated metal atoms have been stability of the fiber structure. Furthermore, CuPd bimetallic solvated metal atoms have been supported supported on a poly-4-vinylpyridine (PVP) resin, showing higher catalytic activity in the Sonogashira on a poly-4-vinylpyridine (PVP) resin, showing higher catalytic activity in the Sonogashira reaction reaction between 4-iodotoluene and phenylacetylene, in the presence of TBAB as additive and in between 4-iodotoluene and phenylacetylene, in the presence of TBAB as additive and in water as water as solvent at 95 °C, than the monometallic Cu and Pd systems as well as their physical mixture solvent at 95 ◦C, than the monometallic Cu and Pd systems as well as their physical mixture [40]. [40]. Naturally occurring organic polymers are usually biodegradable solids, cheap, available and Naturally occurring organic polymers are usually biodegradable solids, cheap, available and abundant, being a good alternative to unnatural organic polymeric materials for the immobilization abundant, being a good alternative to unnatural organic polymeric materials for the immobilization of palladium species destined to catalytic purposes [41,42]. Thus, several polysaccharides have of palladium species destined to catalytic purposes [41,42]. Thus, several polysaccharides have been employed for supporting PdNPs, the resulting materials being used as recoverable catalysts in Sonogashira reactions. This is the case of agarose (19) (Figure 7), which has been functionalized with phosphinite groups for the stabilization of palladium/copper bimetallic nanoparticles [43]. The resulting PdCu@Phos. Agarose can catalyze the coupling of aryl iodides and bromides, bearing electron-donating and withdrawing groups, with terminal acetylenes, using triethylendiamine (DABCO) as base and dimethylacetamide (DMA) as solvent at 30–50 °C. This Pd/Cu supported catalyst has been reused three times with low metal leaching. In addition, unfunctionalized agarose

Catalysts 2018, 8, 202 8 of 39 been employed for supporting PdNPs, the resulting materials being used as recoverable catalysts in Sonogashira reactions. This is the case of agarose (19) (Figure7), which has been functionalized with phosphinite groups for the stabilization of palladium/copper bimetallic nanoparticles [43]. The resulting PdCu@Phos. Agarose can catalyze the coupling of aryl iodides and bromides, bearing electron-donating and withdrawing groups, with terminal acetylenes, using triethylendiamine (DABCO) as base and dimethylacetamide (DMA) as solvent at 30–50 ◦C. This Pd/Cu supported catalystCatalyst hass 2018 been, 8, x reused FOR PEER three REVIEW times with low metal leaching. In addition, unfunctionalized8 of agarose 38 has also been used to support PdNPs, catalyzing the cross-coupling of aryl iodides, bromides and has also been used to support PdNPs, catalyzing the cross-coupling of aryl iodides, bromides and chlorides with phenylacetylene in good yields, using potassium acetate as base and polyethylene chlorides with phenylacetylene in good yields, using potassium acetate as base and polyethylene glycol (PEG) as solvent at 90 ◦C[44]. Recycling experiments were conducted on a Heck reaction in ﬁve glycol (PEG) as solvent at 90 °C [44]. Recycling experiments were conducted on a Heck reaction in runs,five observing runs, observing a sharp a decrease sharp decrease in the in activity the activity after after the fourth.the fourth.

Figure 7. Polysaccharides used for supporting PdNPs catalyzing the Sonogashira cross-coupling Figure 7. Polysaccharides used for supporting PdNPs catalyzing the Sonogashira reaction. cross-coupling reaction. Cellulose (20) (Figure 7) has also been functionalized with ethylenediamine, the resulting Cellulosematerial (EDAC) (20) (Figurebeing used7) hasto support also been PdNPs, functionalized suitable to heterogeneously with ethylenediamine, catalyze the Sonogashira the resulting materialreaction (EDAC) [45]. being Thus, used this to PdNPs@EDAC support PdNPs, can suitable cross-couple to heterogeneously aryl iodides catalyze and bromides the Sonogashira with reactionphenylacetylene [45]. Thus, in wate thisr at PdNPs@EDAC 100 °C, the presence can of cross-couplecopper(I) iodide aryl as cocatalyst iodides being and necessary. bromides Its with recyclability was checked in four consecutive couplings of iodobenzene and phenylacetylene, phenylacetylene in water at 100 ◦C, the presence of copper(I) iodide as cocatalyst being necessary. observing a very low decrease of the final yield (from 98% to 95%). In addition, PdNPs have also Its recyclability was checked in four consecutive couplings of iodobenzene and phenylacetylene, being immobilized on xylan-type hemicellulose 21 (Figure 7), a waste product from biorefineries and observingpulp anda very paper low industries, decrease of catalyzing the final (1 yield mol%) (from the 98% cross to-coupling 95%). In of addition, iodides andPdNPs bromides have also with being immobilizedterminal alkynes on xylan-type [46]. The hemicellulose process has been21 car(Figureried out7), using a waste triethylamine product from as base, biorefineries in acetonitrile and as pulp and papersolvent industries, at 90 °C and catalyzing the catalyst (1 mol%)was reused the cross-coupling six times in the of reaction iodides between and bromides 4-iodoanisole with terminaland alkynesphenylacetylene, [46]. The process affording has beenyields carried from 96 out% to using 87%. triethylamine as base, in acetonitrile as solvent at 90 ◦C andPectin the catalyst (22) (Figure was reused8) has also six been times used in thefor supp reactionorting between PdNPs [47]. 4-iodoanisole The immobilized and phenylacetylene, palladium affordingcatalyzes yields the from Sonogashira 96% to reaction 87%. of aryl iodides, bromides and chlorides with phenylacetylene, the Pectinprocess ( 22taking) (Figure place8 using) has potassium also been acetate used for as supportingbase in N,N-dimethylformamide PdNPs [ 47]. The immobilized (DMF) as solvent palladium at 100 °C. The reaction of iodobenzene and phenylacetylene was used as model for recycling catalyzes the Sonogashira reaction of aryl iodides, bromides and chlorides with phenylacetylene, experiments, observing a certain decrease in the catalytic activity after three runs. Moreover, PdNPs the process taking place using potassium acetate as base in N,N-dimethylformamide (DMF) as embedded◦ in chitosan microspheres differently modified, catalyze the coupling of aryl iodides and solventbromides at 100 withC. The terminal reaction alkynes, of iodobenzene the reaction being and phenylacetylene carried out in ethanol/water was used asas modelsolvent formixture recycling experiments,[48]. No palladium observing leaching a certain was decrease observed in when the catalyticrecycling activityexperiments after were three conducted, runs. Moreover, the catalyst PdNPs embeddedkeeping in totally chitosan its reactivity microspheres after six differently runs. modified, catalyze the coupling of aryl iodides and bromidesOther with terminalbiopolymers alkynes, have thealso reaction been used being recently carried for outthe inimmobilization ethanol/water of aspalladium solvent mixturespecies. [48]. No palladiumThus, wool leaching has been was used observed to incorporate when palladium(II) recycling experiments acetate into wereits structure, conducted, forming the catalysta supported keeping totallycomplex its reactivity able to catalyze after six the runs. cross-coupling reaction of pyrimidin-2-yl 4-tolylsulfonates with terminal alkynes, as shown in Scheme 3 [49]. The addition of a copper(I) cocatalyst such as copper(I) thiophenecarboxylate (CuTC) is necessary, as well as the presence of a diphosphine such as 1,3- bis(diphenylphosphino)propane (dppp). Recycling experiments were conducted, but using a Suzuki coupling, observing a low decrease in the activity after ten runs and not significant palladium leaching. Moreover, even DNA has been used recently as a biopolymeric support for PdNPs, able to

Catalysts 2018, 8, x FOR PEER REVIEW 9 of 38

catalyze (0.5 mol%) the Sonogashira reaction between aryl iodides and aromatic and aliphatic terminal acetylenes [50]. The reaction is carried out in methanol as solvent at 65 °C, using cesium carbonate as base. After recovering the catalyst by centrifugation, recycling experiments carried out in the coupling of iodobenzene and phenylacetylene shown that the supported PdNPs could be Catalystsreused2018, 8 up, 202 to five times with some decrease in the performance in the fifth run, minor inactive9 of 39 palladium leaching being observed.

Catalysts 2018, 8, x FOR PEER REVIEW 9 of 38 catalyze (0.5 mol%) the Sonogashira reaction between aryl iodides and aromatic and aliphatic terminal acetylenes [50]. The reaction is carried out in methanol as solvent at 65 °C, using cesium carbonate as base. After recovering the catalyst by centrifugation, recycling experiments carried out in the coupling of iodobenzene and phenylacetylene shown that the supported PdNPs could be reused up to five times with some decrease in the performance in the fifth run, minor inactive palladium leaching being observed. FigureFigure 8. The8. The polysaccharide polysaccharide pectin pectin used used for forsupporting supporting PdNPs PdNPs and catalyze and catalyzethe Sonogashira the Sonogashira cross- cross-couplingcoupling reaction. reaction.

Other biopolymers have also been used recently for the immobilization of palladium species. Thus, wool has been used to incorporate palladium(II) acetate into its structure, forming a supported complex able to catalyze the cross-coupling reaction of pyrimidin-2-yl 4-tolylsulfonates with terminal alkynes, as shown in Scheme3[ 49]. The addition of a copper(I) cocatalyst such as copper(I) thiophenecarboxylate (CuTC) is necessary, as well as the presence of a diphosphine such as 1,3-bis(diphenylphosphino)propane (dppp). Recycling experiments were conducted, but using a Suzuki coupling, observing a low decrease in the activity after ten runs and not significant palladium leaching. Moreover,Scheme 3. Coupling even DNA of pyrimidin has been-2-yl usedtosylates recently with ter asminal a biopolymeric alkynes catalyzed support by wool- forPd(OAc) PdNPs,2. able to catalyze (0.5 mol%) the Sonogashira reaction between aryl iodides and aromatic and aliphatic terminal 3. Carbon-Based Material-Supported Palladium Catalysts acetylenes [50]. The reaction is carried out in methanol as solvent at 65 ◦C, using cesium carbonate as base. AfterThe recovering Sonogashira the coupling catalyst by between centrifugation, terminal alkynes recycling and experiments aromatic halides carried has out been in the studied coupling of iodobenzeneusing different and palladium phenylacetylene species, mainly shown PdNPs, that theimmobilized supported on PdNPscarbona couldceous materials be reused such up as to five timesFigurecarbon with 8. somenanotubes, The p decreaseolysaccharide graphene in the- pectinderived performance used materials for supporting in[51] the and fifth PdNPscarbon run, anditself. minor catalyze In general, inactive the Sonogashira good palladium activity cross leachingand- recyclability have been observed when employing supported PdNPs, especially when activated beingcoupling observed. reaction. electrophiles, such as aryl iodides and bromides are coupled with aromatic terminal alkynes. For instance, PdNPs supported in mesoporous carbon afforded good yields (90–100%) in the Sonogashira coupling of aryl iodides and bromides with arylacetylenes using water as solvent at 60 °C [52]. Although the catalytic system has shown good recyclability with aryl iodides (up to five runs), no reactivity has been detected with aryl chlorides. In addition, the reaction conditions involve the use of copper as cocatalysts and triphenylphosphine as ligand, which reduce the interest of this catalytic system. Moreover, PdNPs supported on other carbon-derived materials, such as partially reduced graphene oxide (PdNPs@PRGO, 23) [53], reduced graphene oxide (PdNPs@RGO, 24) [54], graphene oxide (PdNPs@GO, 25) [54,55], and nanoporous carbon hollow tubes (PdNPs@CHT, 26) [56] have generally shown good activity in the Sonogashira reaction of aryl halides (Figure 9).

Scheme 3. Coupling of pyrimidin pyrimidin-2-yl-2-yl tosylates with ter terminalminal alkynes catalyzed by wool-Pd(OAc)wool-Pd(OAc)2..

3. Carbon Carbon-Based -Based Material Material-Supported-Supported Palladium Catalysts The Sonogashira Sonogashira coupling coupling between between terminal terminal alkynes alkynes and and aromatic aromatic halides halides has been has studiedbeen studied using usingdifferent different palladium palladium species, species, mainly mainly PdNPs, PdNPs, immobilized immobilized on carbonaceous on carbona materialsceous materials such as such carbon as carbonnanotubes, nanotubes, graphene-derived graphene- materialsderived materials [51] and carbon[51] and itself. carbon In general, itself. In good general, activity good and activity recyclability and recyclabilityhave been observed have been when observed employing when supported employing PdNPs, supported especially PdNPs, when especially activated when electrophiles, activated electrophiles,such as aryl iodides such as and aryl bromides iodides areand coupled bromides with are aromatic coupled terminal with aromatic alkynes. terminal For instance, alkynes. PdNPs For instance,supported PdNPs in mesoporous supported carbonin mesoporous afforded carbon good afforded yields (90–100%) good yields in (90 the– Sonogashira100%) in the Sonogashira coupling of couplingaryl iodides of aryl and bromidesiodides and with bromides arylacetylenes with arylacetylenes using water as using solvent water at 60 as ◦ solventC[52]. at Although 60 °C [52]. the Althoughcatalytic system the catalytic has shown system good has recyclabilityshown good with recyclability aryl iodides with (up aryl to iodides ﬁve runs), (up noto five reactivity runs), hasno reactivity has been detected with aryl chlorides. In addition, the reaction conditions involve the use of copper as cocatalysts and triphenylphosphine as ligand, which reduce the interest of this catalytic system. Moreover, PdNPs supported on other carbon-derived materials, such as partially reduced graphene oxide (PdNPs@PRGO, 23) [53], reduced graphene oxide (PdNPs@RGO, 24) [54], graphene oxide (PdNPs@GO, 25) [54,55], and nanoporous carbon hollow tubes (PdNPs@CHT, 26) [56] have generally shown good activity in the Sonogashira reaction of aryl halides (Figure 9).

Catalysts 2018, 8, 202 10 of 39 been detected with aryl chlorides. In addition, the reaction conditions involve the use of copper as cocatalysts and triphenylphosphine as ligand, which reduce the interest of this catalytic system. Moreover, PdNPs supported on other carbon-derived materials, such as partially reduced graphene oxideCatalysts (PdNPs@PRGO, 2018, 8, x FOR PEER 23REVIEW)[53], reduced graphene oxide (PdNPs@RGO, 24)[54], graphene10 oxide of 38 (PdNPs@GO, 25)[54,55], and nanoporous carbon hollow tubes (PdNPs@CHT, 26)[56] have generally shown goodCatalysts activity 2018, 8, x FOR in thePEER Sonogashira REVIEW reaction of aryl halides (Figure9). 10 of 38

Figure 9.FigurePdNPs 9. PdNPs supported supported on on carbonaceous carbonaceous catalyzing catalyzing the the Sonogashira Sonogashira coup coupling.ling. Conditions, Conditions, Figure substrate 9. PdNPs scope supported and yield range on carbonaceous (Scheme 2). catalyzing the Sonogashira coupling. Conditions, substrate scope and yield range (Scheme2 2).). Usually, these supported catalyst are easily deactivated after several reaction cycles [54]. Usually,Regardless these of the supported carbon-derived catalyst material are employed easily deactivated as support, the after afterstability several several and catalytic reaction reaction activity cycles cycles of [54]. [54]. Regardlesssupported of the PdNPs carbon-derivedcarbon in- derivedthe Sonogashira material coupling employed can be as improved support, following the stability different and strategies. catalytic One activity o off of them consists in the formation of an alloy with another metal, such as Au [57], Ni [58], Co [59–61], supported PdNPs in the Sonogashira coupling can be improved following different strategies. One supportedand PdNPsCu [62–64 in]. theThus, Sonogashira palladium-based coupling alloys candisplay be improvedpromising catalytic following activity different in the Sonogashira strategies. One of themof them consistscross consists-coupling in in the the reaction, formation formation as this of of approach an an alloy alloy usually with with anotherslows another down metal, metal, the undesired suchsuch asas nanoparticle AuAu [[57],57], Ni aggregation [[58],58], Co [59 [59––6161],], and Cu without[62 [62–64]. altering Thus, Thus, palladium palladium-basedthe initial shape-based of alloys the PdNPs. display In thisp promisingromising way, it hascatalytic been demonstrated activity in the a higherSonogashira cross-couplingcross-couplingcatalytic reaction,activity of asPdAuNPs this approach compared usually to PdNPs, slows both down supported the undesired undesired on carbon, nanoparticle in the Sonogashira aggregation withoutcoupling altering altering between the the initial initial phenyl shape shape iodide of the ofand the PdNPs. phenylacetylene PdNPs. In this In way,after this recycling itway, has beenit (Scheme has demonstrated been 4) [57]. demonstrated In this a highercase, the a catalytic higher gold acts as stabilizing agent for the Pd(0) species, allowing the conservation of the PdNP activitycatalytic ofact PdAuNPsivity of PdAuNPs compared compared to PdNPs, to both PdNPs, supported both supported on carbon, on in carbon, the Sonogashira in the Sonogashira coupling morphology [bimodal distribution containing small NPs (10–15 nm) along with aggregated particles betweencoupling(100 phenylbetween nm)] and iodide phenyl thus and the iodide catalytic phenylacetylene and activity phenylacetylene of the after system, recycling whichafter recycling(Schemeshows good4 )[(Scheme functional57]. In 4) this group [57]. case, Intolerance this the goldcase, actsthe asgold stabilizing actsand asexcellent agent stabilizing forreactivity the agentPd(0) for aliphatic species, for the acetylenes. allowing Pd(0) species, the conservation allowing of the the conserPdNP morphologyvation of the [bimodal PdNP distributionmorphology containing[bimodal distribution small NPs (10–15 containing nm) alongsmall withNPs (10 aggregated–15 nm) along particles with (100 aggregated nm)] and particles thus the catalytic(100 nm)] activity and thus of the system,catalytic which activity shows of the good system, functional which groupshows tolerancegood functional and excellent group reactivitytolerance forand aliphatic excellent acetylenes. reactivity for aliphatic acetylenes.

Scheme 4. Sonogashira coupling of phenylacetylene with phenyl iodide catalyzed by PdAuNPs@C compared to PdNPs@C.

A new and efficient catalyst based on PdCo alloy nanoparticles (2–3 nm) supported on polypropylenimine dendrimers grown on graphene nanosheets (PdCoNPs@PPIG, 27) has shown to

be very effective in the room-temperature Sonogashira coupling of aryl iodides, bromides, and Schemechlorides 4. Sonogashira with aromatic coupling and aliphatic of phenylacetylene terminal alkynes with under phenyl ultrasonic iodide Cu catalyzedcatalyzed-free and neat byby PdAuNPs@C PdAuNPs@Cconditions [59] (Scheme 5). Regarding recyclability, only a minor decrease of the reaction yield was observed compared to PdNPs@C. after six reaction cycles for the coupling between phenyl iodide and phenylacetylene (99% to 93%). A new and efficient catalyst based on PdCo alloy nanoparticles (2–3 nm) supported on polypropylenimine dendrimers grown on graphene nanosheets (PdCoNPs@PPIG, 27) has shown to be very effective in the room-temperature Sonogashira coupling of aryl iodides, bromides, and chlorides with aromatic and aliphatic terminal alkynes under ultrasonic Cu-free and neat conditions [59] (Scheme 5). Regarding recyclability, only a minor decrease of the reaction yield was observed after six reaction cycles for the coupling between phenyl iodide and phenylacetylene (99% to 93%).

Catalysts 2018, 8, 202 11 of 39

A new and efﬁcient catalyst based on PdCo alloy nanoparticles (2–3 nm) supported on polypropylenimine dendrimers grown on graphene nanosheets (PdCoNPs@PPIG, 27) has shown to be very effective in the room-temperature Sonogashira coupling of aryl iodides, bromides, and chlorides with aromatic and aliphatic terminal alkynes under ultrasonic Cu-free and neat conditions [59] (SchemeCatalysts 20185)., Regarding8, x FOR PEER recyclability, REVIEW only a minor decrease of the reaction yield was observed after11 of six 38 reaction cycles for the coupling between phenyl iodide and phenylacetylene (99% to 93%). Interestingly, Interestingly,even deactivated even aryl deactivated chlorides, aryl such chlor as 4-chlorotolueneides, such as 4 showed-chlorotoluene good reactivity showed withgood phenylacetylene reactivity with phenylacetyleneunder the optimized under reaction the optimized conditions. reaction conditions.

Scheme 5. Sonogashira coupling catalyzed by PdCoNPs@PPIG ( 27).

PdCu alloy nanoparticles supported on graphene-derived materials have been efficiently used PdCu alloy nanoparticles supported on graphene-derived materials have been efficiently used in the Sonogashira coupling of aryl halides with aliphatic and aromatic terminal alkynes [62–64]. in the Sonogashira coupling of aryl halides with aliphatic and aromatic terminal alkynes [62–64]. Particularly interesting has resulted the use of PdCuFeNPs supported on reduced graphene oxide Particularly interesting has resulted the use of PdCuFeNPs supported on reduced graphene oxide (PdCuFeNPs@RGO), which has shown higher efficiency than the corresponding PdCuNPs@RGO (PdCuFeNPs@RGO), which has shown higher efficiency than the corresponding PdCuNPs@RGO analogue in the Sonogashira coupling of a wide range of aryl halides with phenylacetylene, using analogue in the Sonogashira coupling of a wide range of aryl halides with phenylacetylene, using potassium hydroxide as base and cetyltrimethylammonium bromide as additive in water as solvent potassium hydroxide as base and cetyltrimethylammonium bromide as additive in water as solvent [63]. [63]. Both catalytic systems presented good recyclability (up to five cycles) in the coupling between Both catalytic systems presented good recyclability (up to five cycles) in the coupling between bromobenzene and phenylacetylene. The addition of non-precious metals such as Cu and Fe to the bromobenzene and phenylacetylene. The addition of non-precious metals such as Cu and Fe to Pd reduces the amount of the expensive metal of the alloy and improves the catalytic activity due to the Pd reduces the amount of the expensive metal of the alloy and improves the catalytic activity due a synergistic effect of Cu and Fe, accelerating the reductive elimination step of the catalytic cycle. to a synergistic effect of Cu and Fe, accelerating the reductive elimination step of the catalytic cycle. Multi-walled carbon nanotubes (MWCNTs) have been covalently functionalized with adequate Multi-walled carbon nanotubes (MWCNTs) have been covalently functionalized with adequate ligands to prepare the corresponding palladium species, which have been employed to catalyze the ligands to prepare the corresponding palladium species, which have been employed to catalyze Sonogashira reaction (Figure 10). Thus, the imine-derived catalysts Pd(II)Schiff base@MWCNTs (28) the Sonogashira reaction (Figure 10). Thus, the imine-derived catalysts Pd(II)Schiff base@MWCNTs [65] and Pd(0)IminoPy@MWCNTs (29) [66] can catalyze the coupling of aryl iodides and aryl iodides (28)[65] and Pd(0)IminoPy@MWCNTs (29)[66] can catalyze the coupling of aryl iodides and aryl and bromides, respectively. Pd(II)Schiff base@MWCNTs (28) is active using water as solvent or even iodides and bromides, respectively. Pd(II)Schiff base@MWCNTs (28) is active using water as solvent under neat conditions, affording the corresponding cross-coupling products with good to excellent or even under neat conditions, affording the corresponding cross-coupling products with good to yields, especially under aqueous conditions. Moreover, MWCNTs has been functionalized with the excellent yields, especially under aqueous conditions. Moreover, MWCNTs has been functionalized drug pramipexole and used for the supporting of PdNPs [67]. The resulting material with the drug pramipexole and used for the supporting of PdNPs [67]. The resulting material Pd(0)Pramipexole@MWCNTs (30) has been employed to catalyze the coupling of aryl iodides, Pd(0)Pramipexole@MWCNTs (30) has been employed to catalyze the coupling of aryl iodides, bromides bromides and chlorides with phenylacetylene, the catalyst being recovered after centrifugation and and chlorides with phenylacetylene, the catalyst being recovered after centrifugation and reused five reused five times keeping its activity. times keeping its activity. Graphene oxide (GO) has also been functionalized to support palladium species destined to catalyze the Sonogashira reaction (Figure 11). Thus, a NHC palladium(II) complex has been anchored to silica-bounded GO to give material 31 employed to catalyze the coupling of aryl iodides with phenylacetylene [68], showing recyclability during four reaction cycles (first cycle: 70; fourth cycle: 64%) in the cross-coupling between 2-iodothiophene and phenyl acetylene. In addition, a palladium(II) tetrasulfophthalocyanine immobilized on keratin protein grafted GO nanosheets 32, catalyzed the coupling of aryl iodides, bromides and chlorides with phenylacetylene, aryl chlorides affording rather low yields [69]. The recyclability of the system was not demonstrated in a Sonogashira process. These two catalysts required the use of copper(I)-cocatalysis using water as solvent.

Catalysts 2018, 8, x FOR PEER REVIEW 11 of 38

Interestingly, even deactivated aryl chlorides, such as 4-chlorotoluene showed good reactivity with phenylacetylene under the optimized reaction conditions.

Scheme 5. Sonogashira coupling catalyzed by PdCoNPs@PPIG (27).

PdCu alloy nanoparticles supported on graphene-derived materials have been efficiently used in the Sonogashira coupling of aryl halides with aliphatic and aromatic terminal alkynes [62–64]. Particularly interesting has resulted the use of PdCuFeNPs supported on reduced graphene oxide (PdCuFeNPs@RGO), which has shown higher efficiency than the corresponding PdCuNPs@RGO analogue in the Sonogashira coupling of a wide range of aryl halides with phenylacetylene, using potassium hydroxide as base and cetyltrimethylammonium bromide as additive in water as solvent [63]. Both catalytic systems presented good recyclability (up to five cycles) in the coupling between bromobenzene and phenylacetylene. The addition of non-precious metals such as Cu and Fe to the Pd reduces the amount of the expensive metal of the alloy and improves the catalytic activity due to a synergistic effect of Cu and Fe, accelerating the reductive elimination step of the catalytic cycle. Multi-walled carbon nanotubes (MWCNTs) have been covalently functionalized with adequate ligands to prepare the corresponding palladium species, which have been employed to catalyze the Sonogashira reaction (Figure 10). Thus, the imine-derived catalysts Pd(II)Schiff base@MWCNTs (28) [65] and Pd(0)IminoPy@MWCNTs (29) [66] can catalyze the coupling of aryl iodides and aryl iodides and bromides, respectively. Pd(II)Schiff base@MWCNTs (28) is active using water as solvent or even under neat conditions, affording the corresponding cross-coupling products with good to excellent yields, especially under aqueous conditions. Moreover, MWCNTs has been functionalized with the drug pramipexole and used for the supporting of PdNPs [67]. The resulting material Pd(0)Pramipexole@MWCNTs (30) has been employed to catalyze the coupling of aryl iodides, bromidesCatalysts 2018 and, 8, 202chlorides with phenylacetylene, the catalyst being recovered after centrifugation12 and of 39 reused five times keeping its activity.

Catalysts 2018, 8, x FOR PEER REVIEW 12 of 38

Figure 10. Palladium species on functionalized multi-walled carbon nanotubes as catalysts for the Sonogashira reaction. Conditions, substrate scope and yield range (Scheme 2).

Graphene oxide (GO) has also been functionalized to support palladium species destined to catalyze the Sonogashira reaction (Figure 11). Thus, a NHC palladium(II) complex has been anchored to silica-bounded GO to give material 31 employed to catalyze the coupling of aryl iodides with phenylacetylene [68], showing recyclability during four reaction cycles (first cycle: 70; fourth cycle: 64%) in the cross-coupling between 2-iodothiophene and phenyl acetylene. In addition, a palladium(II) tetrasulfophthalocyanine immobilized on keratin protein grafted GO nanosheets 32, catalyzed the coupling of aryl iodides, bromides and chlorides with phenylacetylene, aryl chlorides affordingFigure rather 10. Palladium low yields species [69]. on functionalized The recyclability multi multi-walled -walled of the carbon system nanotubes was not as demonstratedcatalysts for the in a SonogashiraSonogashirSonogashira process.a reaction.reaction These. Conditions, two catalysts substrate required scope and the yield use range of copper(I) (Scheme2 2).-).cocatalysis using water as solvent. Graphene oxide (GO) has also been functionalized to support palladium species destined to catalyze the Sonogashira reaction (Figure 11). Thus, a NHC palladium(II) complex has been anchored to silica-bounded GO to give material 31 employed to catalyze the coupling of aryl iodides with phenylacetylene [68], showing recyclability during four reaction cycles (first cycle: 70; fourth cycle: 64%) in the cross-coupling between 2-iodothiophene and phenyl acetylene. In addition, a palladium(II) tetrasulfophthalocyanine immobilized on keratin protein grafted GO nanosheets 32, catalyzed the coupling of aryl iodides, bromides and chlorides with phenylacetylene, aryl chlorides affording rather low yields [69]. The recyclability of the system was not demonstrated in a Sonogashira process. These two catalysts required the use of copper(I)-cocatalysis using water as solvent.

Figure 11. PalladiumPalladium species species immobilized on on functifunctionalizedonalized graphene oxide as catalysts for the Sonogashira reaction.reaction. Conditions, substrate scope and yield range (Scheme2 2).).

Figure 11. Palladium species immobilized on functionalized graphene oxide as catalysts for the Sonogashira reaction. Conditions, substrate scope and yield range (Scheme 2).

Catalysts 2018, 8, 202 13 of 39

4. Functionalized Silica-Supported Palladium Catalysts The use of silica as a support for PdNPs has several advantages compared to other type of inorganics, since silica materials of several types, i.e., amorphous or mesoporous, are cheap and readily accessible, have good porosity, large surface area and chemical and mechanical stability. In addition, differentCatalysts 2018 functional, 8, x FOR PEER groups REVIEW can be anchored to the silica surface to effectively immobilize and stabilize13 of 38 PdNPs. This can minimize possible metal leaching and allows the easy recovery and reuse of the catalyst,reuse of therefore the catalyst, playing therefore a central playing role in a centralC–C coupling role in reactions, C–C coupling generally reactions, under generally phosphine under and copper-freephosphine and heterogeneous copper-free conditions heterogeneous [70,71 conditions]. [70,71]. Conveniently functionalized silica silica particles particles have have been been prepared prepared by by grafting grafting methods, methods, serving serving as assupport support to immobilized to immobilized palladium palladium catalysts. catalysts. Thus, Thus,amine amine-silica-silica NPs (NH NPs2-SiO (NH2) 2have-SiO 2been) have used been to usedimmobili to immobilizedzed highly branchedhighly branched polyethylenimine polyethylenimine capped capped and stabilized and stabilized PdNPs PdNPs (PEI-PdNPs). (PEI-PdNPs). This ThisPd/NH Pd/NH2-SiO2 -SiO(33) 2 (Figure(33) (Figure 12) was 12) wasused used as an as anefficient efficient catalyst catalyst in in the the phosphine phosphine and and copper-freecopper-free Sonogashira coupling coupling reaction, reaction, among among other other C-C C coupling-C coupling processes, processes, using usingethylene ethy glycollene as glycol solvent. as Goodsolvent. yields Good were yields obtained were in obtained the reaction in the between reaction phenylacetylene between phenylacetylene and aryl iodides and or aryl bromobenzene. iodides or Thebromobenzene. catalyst was recoveredThe catalyst by was centrifugation recovered andby centrifugation reused for three and times reused with somefor three decrease times in with the yieldssome beingdecrease observed in the (fromyields 98% being in theobserved first to (from 80% in 98% the thirdin the run) first [ 72to]. 80% In addition, in the third the run) use of [72]. acetylacetonate In addition, (acac)the use silica of acetylacetonate supported particles (acac) (SiOsilica2-acacPdNPs) supported particles34 (Figure (SiO 122-acacPdNPs)) allowed to 34 perform (Figure the 12) coupling allowed reactionsto perform between the coupling aryl iodides, reactions bromides between and even aryl chlorides iodides, with bromides phenylacetylene and even in refluxing chlorides water with as solvent,phenylacety underlene copper-free in refluxing conditions water [ as73 ]. solvent, Aryl halides under containing copper-free electron-withdrawing conditions [73]. Aryl substituents halides gavecontaining better results electron than-withdrawing those bearing substituents electron-donating gave better groups, results ortho than substitution those bearing in the aromatic electron- ringdonating leading groups, to lower ortho yields substitution with longer in the reaction aromatic times. ring The leading immobilized to lower catalyst yields waswith easily longer recovered reaction bytimes. filtration The immobilized and used in catalyst five consecutive was easily runs recovered without by loss filtration of activity. and Moreover, used in five nanosilica consecutive particles runs withwithout a 3,5-bis-(2-benzothiazolyl)pyridine loss of activity. Moreover, nanosilica linker coordinating particles with the a metal 3,5-bis35-(2(Figure-benzothiazolyl)pyridine 12), catalyzed the copper-freelinker coordinating Sonogashira the metal reaction 35 (Figure between 12), aromaticcatalyzed halidesthe copper and-free phenylacetylene Sonogashira reaction under aqueousbetween conditions,aromatic halides affording and phenylacetylene good yields. As under expected, aqueous less reactiveconditions, aryl affording chlorides good gave yields. lower As yields expected, than iodidesless reactive or bromides aryl chlorides [74]. These gave results lower were yields compared than iodides with the or non-supported bromides [74]. homogeneous These resul catalyst,ts were andcompared although with the the last non was-supported more active, homogeneous it could not catalyst, be recovered, and although catalyst the35 beinglast was reused more five active, times it withcould only not abe slight recovered, decrease catalyst on the 35 activity. being reused five times with only a slight decrease on the activity.

Figure 12.12. Silica-supportedSilica-supported palladiumpalladium catalystscatalysts forfor thethe SonogashiraSonogashira reaction.reaction. Conditions,Conditions, substratesubstrate scopescope andand yieldyield rangerange (Scheme(Scheme2 2).).

Catalysts 2018, 8, 202 14 of 39

PdNPs were immobilized on silica containing a propylamine-cyanuric linker (SiO2-pA-Cyan) that serve to anchor different metal species. Hence, cysteine reacted with this type of functionalized silica providing catalyst 36 (Figure 13). Using this catalyst, the reaction between several aromatic halides, including chlorides, was performed under copper-free aqueous conditions, leading to good yields. The catalyst was recovered by filtration and reused at least five times achieving similar yields and evidencing the linkage between the thiol groups with the palladium atom [75]. N-Heterocyclic carbene palladium complexes can be also supported on SiO2-pA-Cyan. The achieved catalyst 37 showed its Catalystefficiencys 2018 in, 8 Suzuki, x FOR PEER and REVIEW Sonogashira coupling reactions (Figure 13). In this case, aryl chlorides14 were of 38 not suitable, but good yields were obtained in the reaction between aromatic iodide and bromide andderivatives bromide and derivati phenylacetylene.ves and phenylacetylene. The recovery and The reusability recovery ofand the reusability catalyst was of demonstrated the catalyst was by demonstratedusing it in five by runs using without it in five detrimental runs without in the detrimental obtained results in the [ 76obtained]. results [76].

Figure 13. SilicaSilica bonded bonded propylamine propylamine cyanuric cyanuric palladium palladium cata catalystslysts for for the the Sonogashira Sonogashira reaction reaction.. Conditions, substrate scope and yield range (Scheme2 2).).

The silica surface can be modified by grafting polymeric chains, combining the compatibility of The silica surface can be modified by grafting polymeric chains, combining the compatibility of the the interfacial polymer with the organic solvents and the high mechanical stability of the silica (Figure interfacial polymer with the organic solvents and the high mechanical stability of the silica (Figure 14). 14). Thus, poly(vinylpyridine)-grafted silica containing PdNPs (38) was prepared, showing its Thus, poly(vinylpyridine)-grafted silica containing PdNPs (38) was prepared, showing its catalytic catalytic activity in the copper-free Sonogashira cross coupling reaction between electron-rich, activity in the copper-free Sonogashira cross coupling reaction between electron-rich, electron-neutral electron-neutral and electro-poor aryl iodides and bromides with phenylacetylene, providing the and electro-poor aryl iodides and bromides with phenylacetylene, providing the expected products in expected products in moderate to good yields [77]. When aryl chlorides were used as substrates, the moderate to good yields [77]. When aryl chlorides were used as substrates, the addition of a catalytic addition of a catalytic amount of TBAB (0.01 mol%) was required. This catalyst was recovered by amount of TBAB (0.01 mol%) was required. This catalyst was recovered by filtration and reused in six filtration and reused in six consecutive runs with only a slight decrease on the activity, ICP-AES consecutive runs with only a slight decrease on the activity, ICP-AES analysis of the recovered catalyst analysis of the recovered catalyst showing a negligible leaching of the metal. In addition, the use of showing a negligible leaching of the metal. In addition, the use of polyvinylpyrrolidine-silica hybrid polyvinylpyrrolidine-silica hybrid as support for PdNPs 39 were used as catalyst in the reaction as support for PdNPs 39 were used as catalyst in the reaction between aromatic iodides and bromides, between aromatic iodides and bromides, leading to the corresponding products in good yields leading to the corresponding products in good yields (Figure 14)[78]. The use of aryl chlorides (Figure 14) [78]. The use of aryl chlorides containing electron-donor groups as substituents needed containing electron-donor groups as substituents needed the presence of TBAB (5 mol%) affording the the presence of TBAB (5 mol%) affording the expected products in low yields. Better results were expected products in low yields. Better results were achieved when electron-poor aryl chlorides were achieved when electron-poor aryl chlorides were used as substrate under similar reaction conditions. used as substrate under similar reaction conditions. After the reaction, the supported catalyst was After the reaction, the supported catalyst was recovered by filtration and reused up to six times recovered by filtration and reused up to six times without changes in the obtained results. Moreover, without changes in the obtained results. Moreover, PdNPs immobilized in polymeric N-heterocyclic PdNPs immobilized in polymeric N-heterocyclic carbene grafted-silica 40 exhibited an excellent activity carbene grafted-silica 40 exhibited an excellent activity in Sonogashira coupling processes [79]. Aryl in Sonogashira coupling processes [79]. Aryl iodides, bromides and chlorides, as well as heterocyclic iodides, bromides and chlorides, as well as heterocyclic halides coupled with phenylacetylene halides coupled with phenylacetylene afforded the corresponding products, the presence of TBAB afforded the corresponding products, the presence of TBAB (0.01 mol%) being required when using (0.01 mol%) being required when using aromatic chlorides. Although the recyclability of the catalyst aromatic chlorides. Although the recyclability of the catalyst was not checked in the Sonogashira was not checked in the Sonogashira reaction, it was investigated in a Heck reaction, being possible reaction, it was investigated in a Heck reaction, being possible its reuse at least 12 times. The true its reuse at least 12 times. The true heterogeneity of the catalyst was demonstrated by inductively heterogeneity of the catalyst was demonstrated by inductively coupled plasma (ICP) analysis and coupled plasma (ICP) analysis and hot filtration test. hot filtration test. Dendrimeric chains have been used to host metal NPs, driving to high stability by encapsulation, thus avoiding their agglomeration. The dendrimer periphery structure can be tailored to affect the solubility of the hybrid system. Thus, silica NPs from rice husks ashes have been employed as solid support to anchor poly(amidoamine) dendrimeric branches, leading to a material that was employed to encapsulate PdNPs. The obtained catalyst 41 was tested in the coupling reaction between aromatic halides, including chlorides and heterocyclic bromides, and several acetylenic substrates, using water as solvent [80] (Figure 14). The reaction yield and time resulted affected by electronic and steric effects on the aromatic rings and by the presence of chlorides as substrates. The recovery of the catalyst was performed by centrifugation and was reused in six consecutive runs without deterioration of the catalytic activity. Hot filtration test and ICP of the recovered catalyst showed only a slight leaching of palladium, confirming the heterogeneity of the catalyst.

Catalysts 2018, 8, 202 15 of 39 Catalysts 2018, 8, x FOR PEER REVIEW 15 of 38

Figure 14. 14.Immobilized Immobilized PdNPs PdNPs on on polymer-grafted polymer-grafted silica silica as catalysts as catalysts in the Sonogashira in the Sonogashira cross-coupling cross- reaction.coupling Conditions,reaction. Conditions, substrate substrate scope and scope yield and range yield (Scheme range2 ).(Scheme 2).

Several types of mesoporous silica NPs have been studied as support for PdNPs. These materials Dendrimeric chains have been used to host metal NPs, driving to high stability by encapsulation, have large surface areas and void volume and differ on their symmetry (for instance, MCM-41 and thus avoiding their agglomeration. The dendrimer periphery structure can be tailored to affect the SBA-15 are hexagonal while MCM-48 or SBA-16 are cubic), and porosity, all having high stability, solubility of the hybrid system. Thus, silica NPs from rice husks ashes have been employed as solid chemical inertness and accessibility for further functionalization. These features make them good support to anchor poly(amidoamine) dendrimeric branches, leading to a material that was employed candidates to serve as support for metal species (Figure 15). Thus, the incorporation of a carbene to encapsulate PdNPs. The obtained catalyst 41 was tested in the coupling reaction between aromatic ligand to mesoporous silica MCM-41 led to catalyst 42 suitable to catalyze the coupling of aryl iodides halides, including chlorides and heterocyclic bromides, and several acetylenic substrates, using water and bromides with phenylacetylene in piperidine as solvent [81]. Addition of ethyl acetate to the as solvent [80] (Figure 14). The reaction yield and time resulted affected by electronic and steric effects reaction mixture and filtration of the catalyst allowed its recovery and reuse for five runs with only on the aromatic rings and by the presence of chlorides as substrates. The recovery of the catalyst a slight decrease on the achieved yields, the heterogeneity of the catalyst being demonstrated by ICP was performed by centrifugation and was reused in six consecutive runs without deterioration of the analysis of the reused catalysts and by a hot filtration test. Similar results were obtained using catalytic activity. Hot filtration test and ICP of the recovered catalyst showed only a slight leaching of mesoporous pyridyl functionalized MCM-48 43 under almost identical reaction conditions [82]. In palladium, confirming the heterogeneity of the catalyst. this case, the recovery of the catalyst by filtration and reusing (up to five times), evidenced a lost in Several types of mesoporous silica NPs have been studied as support for PdNPs. These materials the catalyst activity in the last run due to leaching of the palladium. The hot filtration test indicates have large surface areas and void volume and differ on their symmetry (for instance, MCM-41 and that the reaction follows a heterogeneous pathway. Moreover, SBA-15 with pendent 3- SBA-15 are hexagonal while MCM-48 or SBA-16 are cubic), and porosity, all having high stability, mercaptopropyl groups 44 was prepared and used as catalyst under similar reaction conditions, chemical inertness and accessibility for further functionalization. These features make them good giving the expected products in excellent yields (Figure 15) [83]. A slight decrease of the activity of candidates to serve as support for metal species (Figure 15). Thus, the incorporation of a carbene the catalysts was observed after its recovery and reuse in six consecutive runs. Finally, when 1,2- ligand to mesoporous silica MCM-41 led to catalyst 42 suitable to catalyze the coupling of aryl iodides diaminocyclohexane silica mesoporous SBA-16 45 was used as support, the reaction also admitted and bromides with phenylacetylene in piperidine as solvent [81]. Addition of ethyl acetate to the the use of aryl chlorides as substrates, although yields ranged from 68% to 72% in this case (Figure reaction mixture and filtration of the catalyst allowed its recovery and reuse for five runs with only 15) [84]. The catalyst was reused up to five times with only a slight decrease in the achieved yields a slight decrease on the achieved yields, the heterogeneity of the catalyst being demonstrated by being observed and attributed to some palladium leaching. ICP analysis of the reused catalysts and by a hot filtration test. Similar results were obtained using

Catalysts 2018, 8, 202 16 of 39 mesoporous pyridyl functionalized MCM-48 43 under almost identical reaction conditions [82]. In this case, the recovery of the catalyst by filtration and reusing (up to five times), evidenced a lost in the catalyst activity in the last run due to leaching of the palladium. The hot filtration test indicates that the reaction follows a heterogeneous pathway. Moreover, SBA-15 with pendent 3-mercaptopropyl groups 44 was prepared and used as catalyst under similar reaction conditions, giving the expected products in excellent yields (Figure 15)[83]. A slight decrease of the activity of the catalysts was observed after its recovery and reuse in six consecutive runs. Finally, when 1,2-diaminocyclohexane silica mesoporous SBA-16 45 was used as support, the reaction also admitted the use of aryl chlorides as substrates, although yields ranged from 68% to 72% in this case (Figure 15)[84]. The catalyst was reused up to five times with only a slight decrease in the achieved yields being observed and attributed toCatalyst somes 2018 palladium, 8, x FOR leaching.PEER REVIEW 16 of 38

Figure 15.15. Mesoporous silica-supportedsilica-supported palladium catalyst used in thethe SonogashiraSonogashira cross-couplingcross-coupling reaction.reaction. Conditions, substrate scope and yield rangerange (Scheme(Scheme2 2).).

Other palladium ligands have been supported on mesoporous silica, as shown in Figure 16. Other palladium ligands have been supported on mesoporous silica, as shown in Figure 16. Thus, ethylendiaminetetraacetic acid (EDTA) has been anchored to SBA-15 and complexed with Thus, ethylendiaminetetraacetic acid (EDTA) has been anchored to SBA-15 and complexed with palladium to afford catalyst 46, which was used in the coupling reaction of several aromatic halides, palladium to afford catalyst 46, which was used in the coupling reaction of several aromatic halides, including chlorides, under copper and phosphine-free conditions [85]. The obtained final yields were including chlorides, under copper and phosphine-free conditions [85]. The obtained ﬁnal yields excellent when electron-withdrawing substituents were bonded to the aryl moiety. The catalyst were excellent when electron-withdrawing substituents were bonded to the aryl moiety. The catalyst reusability was not shown for the Sonogashira coupling, although the recovered catalyst after reusability was not shown for the Sonogashira coupling, although the recovered catalyst after ﬁltration filtration was reused in a Suzuki coupling reaction. Only a slight decrease in the yields after the fourth was reused in a Suzuki coupling reaction. Only a slight decrease in the yields after the fourth cycle cycle was observed. In addition, 2,4,6,triallyloxy-1,3,5-triazine (TAT) was covalently attached to was observed. In addition, 2,4,6,triallyloxy-1,3,5-triazine (TAT) was covalently attached to mesoporous mesoporous silica SBA-15 leading to catalyst 47, which was used in the Sonogashira reaction [86]. silica SBA-15 leading to catalyst 47, which was used in the Sonogashira reaction [86]. The reaction The reaction between different aryl iodides with several substituted acetylene derivatives proceeded in high yields, evidencing the tolerance of the catalyst towards the presence of a wide range of functional groups. Although the reaction with aromatic acetylenes did not require the presence of copper salts, 5 mol% of CuI was necessary for the progress of the reaction with aliphatic alkynes. The reusability of the catalyst up to five times was studied in a Heck reaction. Moreover, the radical oligomerization of a bisvinylthiazolium salt in the presence of mercapto-functionalized mesoporous silica SBA15 gave a material that was able to immobilize palladium atoms. The generated supported catalyst 48 was used in the Sonogashira coupling of several phenylacetylene derivatives with different aromatic iodides in a reusable acetonitrile/water azeotrope as reaction medium [87]. The reaction was carried out using N-methylpiperazine as a base or PS-supported piperazine, affording the expected products in similar yields, although longer reaction times were required when the heterogeneous base was used. The use of the supported base allowed the recovery of the catalyst/base system by filtration, which was reused in up to five consecutive runs without detriment of the achieved results. However, when the soluble base was used, reusing was only possible for a second

Catalysts 2018, 8, 202 17 of 39 between different aryl iodides with several substituted acetylene derivatives proceeded in high yields, evidencing the tolerance of the catalyst towards the presence of a wide range of functional groups. Although the reaction with aromatic acetylenes did not require the presence of copper salts, 5 mol% of CuI was necessary for the progress of the reaction with aliphatic alkynes. The reusability of the catalyst up to five times was studied in a Heck reaction. Moreover, the radical oligomerization of a bisvinylthiazolium salt in the presence of mercapto-functionalized mesoporous silica SBA15 gave a material that was able to immobilize palladium atoms. The generated supported catalyst 48 was used in the Sonogashira coupling of several phenylacetylene derivatives with different aromatic iodides in a reusable acetonitrile/water azeotrope as reaction medium [87]. The reaction was carried out using N-methylpiperazine as a base or PS-supported piperazine, affording the expected products in similar yields, although longer reaction times were required when the heterogeneous base was used. The use of the supported base allowed the recovery of the catalyst/base system by filtration, which was reused in up to five consecutive runs without detriment of the achieved results. However, when the soluble base was used, reusing was only possible for a second run. A hot filtration test and a mercury test was performed showing that the process take place mainly through the formation of PdNPs. Furthermore, 2-D-hexagonal mesoporous silica (PMO) bearing a phloroglucinol-diimine moiety was used to immobilize palladium species, and the obtained catalyst 49 was used in the Sonogashira reaction (Figure 16)[88]. Thus, coupling of phenylacetylene with aromatic iodides were performed using water as reaction media, while the use of aromatic bromides needed the use of DMF as solvent. The catalyst was recovered and reused, observing a decrease in the yield from 90% to 75% after the fourth cycle. The use of sol-gel co-condensation protocols have shown as another way to immobilize palladium metal in a silica matrix. Thus, two different silylated Pd-NHC complexes, having either a bidentate acetylacetonate ligand or a monoligation through a 3-chloropyridyl moiety, were immobilized on hybrid silica by applying a sol-gel process affording catalysts 50 [89]. The reaction between phenylacetylene and 4-bromoacetophenone was carried out using a 0.2 mol% of each one of the catalysts in the presence of tetrabutylammonium acetate in DMF as solvent at 120 ◦C (Scheme6). The final alkyne coupling product was formed in ca. 90% yield in just 1 h, the reaction being faster when using the monoligated catalyst. The catalysts were recovered by centrifugation and reused after five reaction runs with a decrease of the achieved yields, no formation of NPs being observed. The hot filtration test suggested a homogeneous reaction pathway, in which the silica material acted as a reservoir of the palladium species that reacted in the solution. Sol-gel entrapped SiliaCat, an organoceramic matrix with high catalyst loading and surface area, containing PdNPs (0.1 mol%) has shown to promote the copper-free Sonogashira reaction between phenylacetylene and aryl iodides, using potassium carbonate as base in refluxing ethanol or methanol, achieving, after 0.5 h to 3 h, the corresponding products in quantitative yields [90]. When o-iodomethylbenzene was used as substrates under similar reaction conditions, only a 77% yield was obtained. In the reaction of 4-bromonitrobenzene with phenylacetylene, the catalyst amount was increased to 1 mol% to achieve the coupling product in quantitative yield in the presence of triethylamine under refluxing aqueous DMF. The reaction could be performed in water and using potassium carbonate as a base in the presence of tetrabutylammonium bromide as phase transfer agent. However, the obtained yields for the coupling of aryl bromides and phenylacetylene were quite disappointing under the last conditions. The use of microwave irradiation in methanol as solvent allowed obtaining the reaction products in higher yields with small catalyst loading (0.1 mol%). Under these conditions, the catalyst was recovered by filtration and reused for five times with retention of the catalyst activity. In addition, the SiliaCat bearing diphenylphosphine (DPP) moieties as ligands, was used to immobilize palladium and the material was assayed as catalyst in continuous-flow Sonogashira reaction process between 3-iodo-N-Boc(aza)indoles and tolylacetylene (Scheme7)[ 91]. Full conversion was reached in just 2 min at 60 ◦C in DMF as solvent. The reaction was also carried out under batch conditions required longer reaction times (h versus min). The reusability of the catalyst Catalysts 2018, 8, x FOR PEER REVIEW 17 of 38 run. A hot filtration test and a mercury test was performed showing that the process take place mainly through the formation of PdNPs. Furthermore, 2-D-hexagonal mesoporous silica (PMO) bearing a phloroglucinol-diimine moiety was used to immobilize palladium species, and the obtained catalyst 49 was used in the Sonogashira reaction (Figure 16) [88]. Thus, coupling of phenylacetylene with aromatic iodides were performed using water as reaction media, while the use of aromatic bromides needed the use of DMF as solvent. The catalyst was recovered and reused, observing a decrease in the yield from 90% to 75% after the fourth cycle. The use of sol-gel co-condensation protocols have shown as another way to immobilize palladium metal in a silica matrix. Thus, two different silylated Pd-NHC complexes, having either a bidentate acetylacetonate ligand or a monoligation through a 3-chloropyridyl moiety, were immobilized on hybrid silica by applying a sol-gel process affording catalysts 50 [89]. The reaction between phenylacetylene and 4-bromoacetophenone was carried out using a 0.2 mol% of each one of the catalysts in the presence of tetrabutylammonium acetate in DMF as solvent at 120 °C (Scheme 6). The final alkyne coupling product was formed in ca. 90% yield in just 1 h, the reaction being faster Catalysts 2018, 8, 202 18 of 39 when using the monoligated catalyst. The catalysts were recovered by centrifugation and reused after five reaction runs with a decrease of the achieved yields, no formation of NPs being observed. The washot filtration studied washing test suggested the sealed a homogeneous cartridge containing reaction the pathway, catalyst in with which DMF, the which silica gavematerial a clean acted reactor as a thatreservoir was reusedof the palladium up to eight species times, observingthat reacted only in the a small solution. decrease in the yields after the eighth run.

Figure 16. 16. Mesoporous silica-supportedsilica-supported catalysts used for for the the Sonogashira Sonogashira reaction. reaction. Conditions, substrate scopescope andand yieldyield rangerange (Scheme(Scheme2 2).).

Catalyst s 2018, 8, x FOR PEER REVIEW 18 of 38

SchemeScheme 6. SilicaSilica-supported-supported Pd Pd-NHC-NHC complexes used as catalysts used in a Sonoga Sonogashirashira reaction.

Sol-gel entrapped SiliaCat, an organoceramic matrix with high catalyst loading and surface area, containing PdNPs (0.1 mol%) has shown to promote the copper-free Sonogashira reaction between phenylacetylene and aryl iodides, using potassium carbonate as base in refluxing ethanol or methanol, achieving, after 0.5 h to 3 h, the corresponding products in quantitative yields [90]. When o-iodomethylbenzene was used as substrates under similar reaction conditions, only a 77% yield was obtained. In the reaction of 4-bromonitrobenzene with phenylacetylene, the catalyst amount was increased to 1 mol% to achieve the coupling product in quantitative yield in the presence of triethylamine under refluxing aqueous DMF. The reaction could be performed in water and using potassium carbonate as a base in the presence of tetrabutylammonium bromide as phase transfer agent. However, the obtained yields for the coupling of aryl bromides and phenylacetylene were quite disappointing under the last conditions. The use of microwave irradiation in methanol as solvent allowed obtaining the reaction products in higher yields with small catalyst loading (0.1 mol%). Under these conditions, the catalyst was recovered by filtration and reused for five times with retention of the catalyst activity. In addition, the SiliaCat bearing diphenylphosphine (DPP) moieties as ligands, was used to immobilize palladium and the material was assayed as catalyst in continuous- flow Sonogashira reaction process between 3-iodo-N-Boc(aza)indoles and tolylacetylene (Scheme 7) [91]. Full conversion was reached in just 2 min at 60 °C in DMF as solvent. The reaction was also carried out under batch conditions required longer reaction times (h versus min). The reusability of the catalyst was studied washing the sealed cartridge containing the catalyst with DMF, which gave a clean reactor that was reused up to eight times, observing only a small decrease in the yields after the eighth run.

Scheme 7. Sonogashira coupling of 3-iodo-N-Boc(aza)indoles and tolylacetylene under continuous- flow conditions.

5. Magnetic Material-Supported Palladium Catalysts Magnetic materials have an extra advantage to any other support when recovery is intended. Thus, they can be easily separated from the reaction medium just by using a magnet (the so-called magnetic purification or magnetic decantation), avoiding the tedious recovery of catalyst from colloidal mixtures by filtration and/or centrifugation strategies, typically used for other heterogeneous supports. In this field, magnetite, an iron(II) and (III) oxide in a cubic inverse spinel structure, is the most used support [9], although other related materials employed recently will also be presented. There are different methodologies to incorporate palladium species, to the support,

Catalysts 2018, 8, x FOR PEER REVIEW 18 of 38

Scheme 6. Silica-supported Pd-NHC complexes used as catalysts used in a Sonogashira reaction.

Catalystsa clean 2018reactor, 8, 202 that was reused up to eight times, observing only a small decrease in the yields19 after of 39 the eighth run.

Scheme 7. 7. SonogashiraSonogashira coupling coupling of 3-iodo of-N 3-iodo--Boc(aza)indolesN-Boc(aza)indoles and tolylacetylene and tolylacetylene under continuous under- flowcontinuous-ﬂow conditions. conditions.

5. Magnetic Material Material-Supported-Supported Palladium Catalysts Magnetic materials have an extra advantage to to any any other other support support when when recovery recovery is is intended. intended. Thus, they can be easily separatedseparated from the reaction medium just by using a magnet (the so-calledso-called magnetic purification purification or or magnetic magnetic decantation), decantation), avoiding avoiding the tedious the tedious recovery recovery of catalyst of catalystfrom colloidal from colloidalmixtures by mixtures filtration and/orby filtration centrifugation and/or strategies, centrifugation typically strategies, used for other typically heterogeneous used for supports. other CatalysthetIn thiserogeneouss 2018 field,, 8, magnetite,x FOR supports. PEER REVIEW an In iron(II) this field, and magnetite, (III) oxide inan airon(II) cubic inverse and (III) spinel oxide structure, in a cubic is inverse the most19 spinel usedof 38 structure,support [9 is], the although most used other support related [9], materials although employed other related recently materials will also employed be presented. recently There will also are suchbedifferent presented. as impregnation, methodologies There are coating, to different incorporate grafting, methodologies palladium and coating species, to– grafting.incorporate to the Each support, palladium preparation such asspecies, impregnation, methodologies to the support, coating, have advantagesgrafting, and and coating–grafting. disadvantages, Eachwhich preparation should be considered methodologies when have a catalyst advantages is prepared. and disadvantages, which The should impregnation be considered method when is athe catalyst most is straightforward, prepared. simple, and inexpensive protocol to incorporateThe impregnation the catalytic methodmetal species is the to most the support straightforward, and involves simple, the evaporation and inexpensive or precipitation protocol to ofincorporate the metal the precursor catalytic contained metal species in a solution,to the support followed and byinvolves an ulterior the evaporation drying step. or precipitationThe particle distributionof the metal and precursor morphology contained are governed in a solution, by different followed factors, by an ulterior including drying support step. porosity, The particle pH, viscositydistribution of solution, and morphology drying rates. are The governed impregnation by different of palladium factors, on including magnetite support was introduced porosity, for pH, theviscosity Sonogashira of solution, coupling drying reaction rates. The using impregnation 2-iodoaniline of palladium derivatives on magnetite and substituted was introduced aromatic for and the aliphaticSonogashira 1-alkynes coupling [92]. reaction Recently, using a similar 2-iodoaniline catalyst derivativeshas been used and in substituted a tandem aromaticSonogashira and reaction aliphatic cyclization1-alkynes[ 92 process]. Recently, of o a-iodoanilines similar catalyst and has terminal been used alkynes in a tandem to give Sonogashira the corresponding reaction cyclization indole derivativesprocess of o at-iodoanilines high temperatures, and terminal the presence alkynes to of give Cu(I) the cocatalyst corresponding being indole crucial derivatives [93] (Scheme at high 8). However,temperatures, the yieldthe presence was lower of Cu(I) when cocatalyst 2-bromoaniline being crucial was [ used.93] (Scheme The impregnated8). However, palladium the yield was on magnetitelower when was 2-bromoaniline recovered by wasmagnetic used. decantation The impregnated and reused palladium ten times on magnetite without wasany recovereddetrimental by effect.magnetic In fact, decantation the TEM and images reused of ten fresh times and without recycled any detrimentalcatalyst, as effect. well as In size fact, distribution the TEM images, were of practicallyfresh and recycled identical. catalyst, The applicability as well as size was distribution, highlighted were by performing practically an identical. example The of applicability gram-scale reaction.was highlighted by performing an example of gram-scale reaction.

SchemeScheme 8. TandemTandem Sonogashira-cyclization Sonogashira-cyclization process process catalyzed catalyzed by impregnated by impregnated palladium palladium on magnetite. on magnetite.

Instead of magnetite, a zinc ferrite ZnFe2O4, the place of Fe(II) atoms in the inverse spinel being occupiedInstead by of the magnetite, Zn(II) atoms] a zinc has ferrite been ZnFe recently2O4, the used place as support of Fe(II) for atoms the impregnationin the inverse ofspinel palladium being occupiedspecies. Thus,by the the Zn(II) Sonogashira atoms] has reaction been recently between used iodoarenes as support and for phenylacetylene the impregnation was of performed palladium in species.reﬂuxing Thus, ethanol the asSonogashira solvent, affording reaction the between corresponding iodoarenes products and phenylacetylene with good results was (eight performed examples, in refluxing82–90% yield) ethanol [94 as]. Thesolvent, catalyst affording was separated the corresponding of the reaction products medium with by good a magnet results and (eight reused examples, at least 82for–90% three yield) cycles. [94]. The The ICP catalyst analysis wa ofs reactionseparated medium of the showedreaction somemedium palladium by a magnet leaching. and reused at least for three cycles. The ICP analysis of reaction medium showed some palladium leaching. The magnetic supports have been coated by other materials to avoid the aggregation of magnetic nanoparticles to the cluster and to protect them from abrasion and degradation under harsh conditions. Thus, magnetite has been coated with the polysaccharide agarose, and PdNPs has been deposited on this surface. The Sonogashira reaction with phenylacetylene was performed in polyethylene glycol-200 at 130 °C, giving moderate to good results (13 examples, 53–95% yield) even in the case of using brominated or chlorinated arenes, the reaction with chloroarenes needing harsher reaction conditions and longer reaction times [95]. However, no data from the possibility of catalyst recycling was given. In addition, magnetite has also been coated with graphene oxide, the final treatment with N-hydroxysuccinimide and diethylenetriamine favoring the incorporation of the PdNPs. The Sonogashira coupling reaction with 0.5 mol% of the aforementioned catalyst in DMSO at 120 °C gave the expected product with excellent results for iodoarenes and moderated ones for bromoarenes (16 examples 32–100% yield) [96]. The catalyst could be re-used up to six cycles, but a slight decrease of activity after each cycle was observed. The grafting process of palladium species, using tailored ligands which can bind effectively to the magnetite surface, has been used in the context of the Sonogashira reaction. The presence of organic ligands prevents sinterization processes as well as the degradation of the PdNPs. Thus, different trioxysilane derivatives have been introduced recently as linkers (Figure 17). The catalyst 51 has been used in the Sonogashira process between haloarenes and phenylacetylene, giving the expected disubstituted alkynes with moderate to excellent results [97]. The reaction allowed using not only iodides and bromides but also chlorides, with only a small decrease in the yield and increase

Catalysts 2018, 8, 202 20 of 39

The magnetic supports have been coated by other materials to avoid the aggregation of magnetic nanoparticles to the cluster and to protect them from abrasion and degradation under harsh conditions. Thus, magnetite has been coated with the polysaccharide agarose, and PdNPs has been deposited on this surface. The Sonogashira reaction with phenylacetylene was performed in polyethylene glycol-200 at 130 ◦C, giving moderate to good results (13 examples, 53–95% yield) even in the case of using brominated or chlorinated arenes, the reaction with chloroarenes needing harsher reaction conditions and longer reaction times [95]. However, no data from the possibility of catalyst recycling was given. In addition, magnetite has also been coated with graphene oxide, the final treatment with N-hydroxysuccinimide and diethylenetriamine favoring the incorporation of the PdNPs. The Sonogashira coupling reaction with 0.5 mol% of the aforementioned catalyst in DMSO at 120 ◦C gave the expected product with excellent results for iodoarenes and moderated ones for bromoarenes (16 examples 32–100% yield) [96]. The catalyst could be re-used up to six cycles, but a slight decrease of activity after each cycle was observed. The grafting process of palladium species, using tailored ligands which can bind effectively to the magnetite surface, has been used in the context of the Sonogashira reaction. The presence of organic ligands prevents sinterization processes as well as the degradation of the PdNPs. Thus, different trioxysilane derivatives have been introduced recently as linkers (Figure 17). The catalyst 51 has been used in the Sonogashira process between haloarenes and phenylacetylene, giving the expected disubstituted alkynes with moderate to excellent results [97]. The reaction allowed using not only iodides and bromides but also chlorides, with only a small decrease in the yield and increase in the reaction time.Catalyst Thes 2018, catalyst8, x FOR PEER was REVIEW recycled up to seven times with only a marginal decrease20 of 38 in the final yield, showingin the reaction the high time. stability The catalyst of thewas recycled catalyst. upA to similarseven times catalyst with only preparation a marginal decrease was followed in the for the generationfinal of yield,52, and, showing although the high the stability results of the seemed catalyst. toA similar be similar catalyst to preparation those obtained was followed formerly, for the lack in the quantificationthe generation of of the52, and amount, although of palladium,the results seemed as well to be as similar the recyclability, to those obtained makes formerly, these the results not lack in the quantification of the amount of palladium, as well as the recyclability, makes these results comparablenot [comparable98]. [98].

Figure 17. Magnetite grafted palladium catalysts for the Sonogashira reaction. Conditions, substrate Figure 17.scopeMagnetite and yield grafted range (Scheme palladium 2). catalysts for the Sonogashira reaction. Conditions, substrate scope and yield range (Scheme2). A β-cyclodextrin-palladium catalyst 53 (Figure 17) has also been used in the Sonogashira reaction with arylacetylenes. The reaction was successfully performed for either iodoarenes or bromoarenes, obtaining similar results [99]. The recyclability of the catalyst was not assayed in a Sonogashira but in a Suzuki reaction. In addition, not only processes of silanization have been used to prepare grafted- palladium catalysts, but also phosphorylation processes, as shown in the case of catalyst 54 (Figure 17). This catalyst has been used with different iodo- and bromoarenes and aromatic and aliphatic acetylene derivatives to give the expected products in excellent yields and short reaction times. The catalyst could be recycled up to seven times with a slightly decrease in the final results [100]. The formation of coated-grafted palladium catalysts is the most difficult and expensive approach when immobilizing palladium catalysts over magnetite, but it is frequently the preferred method since it combines the advantage of previous ones, such is the stability of the material and the fine- tuning of the catalyst by the presence of the ligand. The standard protocol involves the sonication of NPs of Fe3O4 and coating with a thin layer of silica, using tetraalkoxysilanes via a sol-gel process. The ligand is anchored by refluxing the corresponding triethoxysilane derivative and the coated nanoparticle in toluene. The final treatment with a source of palladium, usually a salt of palladium (II), gave the pre-catalyst. This pre-catalyst is reduced either previously to reaction or in situ to

Catalysts 2018, 8, 202 21 of 39

A β-cyclodextrin-palladium catalyst 53 (Figure 17) has also been used in the Sonogashira reaction with arylacetylenes. The reaction was successfully performed for either iodoarenes or bromoarenes, obtaining similar results [99]. The recyclability of the catalyst was not assayed in a Sonogashira but in a Suzuki reaction. In addition, not only processes of silanization have been used to prepare grafted-palladium catalysts, but also phosphorylation processes, as shown in the case of catalyst 54 (Figure 17). This catalyst has been used with different iodo- and bromoarenes and aromatic and aliphatic acetylene derivatives to give the expected products in excellent yields and short reaction times. The catalyst could be recycled up to seven times with a slightly decrease in the final results [100]. The formation of coated-grafted palladium catalysts is the most difficult and expensive approach when immobilizing palladium catalysts over magnetite, but it is frequently the preferred method since it combines the advantage of previous ones, such is the stability of the material and the fine-tuning of the catalyst by the presence of the ligand. The standard protocol involves the sonication of NPs of Fe3O4 and coating with a thin layer of silica, using tetraalkoxysilanes via a sol-gel process. The ligand is anchored by refluxing the corresponding triethoxysilane derivative and the coated nanoparticle in toluene. The final treatment with a source of palladium, usually a salt of palladium (II), gave the pre-catalyst. This pre-catalyst is reduced either previously to reaction or in situ to generate the corresponding PdNPs surrounded by heteroatoms of the ligand (Figure 18). In this way, the phosphane-catalyst 55 was prepared, the presence of PdNPs being determined by X-ray photoelectron spectroscopy (XPS) at the end of the reaction. The Sonogashira coupling reaction of several iodo- or bromoarenes with terminal alkynes proceeded completely and generated the expected products in good to excellent yields, the results with hindered 2-substituted arenes being noticeably lower. The reaction failed when chloroarenes were used as starting reagents, recovering the starting materials unchanged. The ICP analysis of reaction media showed only a 0.2% of palladium leaching, which is in concordance with the reuse of catalyst up to eight-times without depletion [101]. Not only phosphines have been used as linker-ligands, but also nitrogen containing ligands, such as 2-tetrazole-aniline derivative in catalyst 56. The Sonogashira coupling reaction of several iodo-, bromo- and chloroarenes with terminal alkynes gave the expected products with the yield being directly related with the halogen in the initial arene, iodoarenes giving the best results and chloroarenes the worst. The catalytic system could be recycled by magnetic decantation and reused up to six-times without detrimental effect on the yield [102]. Moreover, the heterogeneous imine-palladium catalyst 57 has also been tested in the Sonogashira coupling reaction of halogenated arenes and phenylacetylene and, as in a previous case, the results depended on the halogen, the best results being obtained for the iodinated derivatives. The reaction was also performed with aliphatic alkynes, but the reaction time had to be increased, compared to when phenylacetylene was employed [103]. No recycling experiments were conducted with this catalyst. A bisindole-palladium catalyst 58 has been used as catalyst in the Sonogashira reaction, the reaction affording good results for structurally diverse haloarenes and terminal alkynes, including heteroaromatic systems. As in previous cases, the best results were obtained for iodinated derivatives while the worse was obtained for chlorinated ones. The heterogeneity of the process was proved by the Hg (0) test, as well as by the hot-filtration reaction. The catalyst was isolated by magnetic decantation and re-used up to seven folds with only a marginal decrease in the results. This fact is in concordance with the leaching of only 1% of palladium, according to ICP analyses of the crude solution [104]. Furthermore, aryl halides and phenylacetylene were submitted to the Sonogashira reaction catalyzed by the salen-material 59 (Figure 18). As expected, the reaction with haloarenes bearing electron donating groups went to completion in longer reaction times that those with electron-withdrawing ones. The catalyst was recycled and reused six times with a small decrease in the yield. In fact, the ICP analysis of crude solution showed only a 0.4% of palladium leaching, which increased up to 4.9% after sixth cycle [105]. Catalysts 2018, 8, x FOR PEER REVIEW 21 of 38 generate the corresponding PdNPs surrounded by heteroatoms of the ligand (Figure 18). In this way, the phosphane-catalyst 55 was prepared, the presence of PdNPs being determined by x-ray photoelectron spectroscopy (XPS) at the end of the reaction. The Sonogashira coupling reaction of several iodo- or bromoarenes with terminal alkynes proceeded completely and generated the expected products in good to excellent yields, the results with hindered 2-substituted arenes being noticeably lower. The reaction failed when chloroarenes were used as starting reagents, recovering the starting materials unchanged. The ICP analysis of reaction media showed only a 0.2% of palladiumCatalysts 2018 leaching,, 8, 202 which is in concordance with the reuse of catalyst up to eight-times without22 of 39 depletion [101].

FigureFigure 18. 18. MagnetiteMagnetite-Silica-Silica coa coated-graftedted-grafted palladium palladium catalysts catalysts for for the the Sonogashira Sonogashira reaction reaction.. Conditions, Conditions, substratesubstrate scope scope and and yield yield range range (Scheme (Scheme 2).2).

Not only phosphines have been used as linker-ligands, but also nitrogen containing ligands, There are other types of protecting shells different from silica (Figure 19). Thus, in the catalyst such as 2-tetrazole-aniline derivative in catalyst 56. The Sonogashira coupling reaction of several 60, over the typical magnetite-silica core–shell composite, another organic shell was obtained by polymerization of (3-methacryloxypropyl)trimethoxysilane. This organic surface was modiﬁed by a subsequent polymerization of glycidyl methacrylate. The reaction of the obtained epoxide-composite with polyethylenimime gave the composite, which after addition of palladium source and reduction permitted the preparation of catalyst 60 [106]. This supported palladium species was successfully used in the Sonogashira reaction, being recycled and reused up to eight times with only a marginal decrease in the yield. Catalysts 2018, 8, 202 23 of 39 Catalysts 2018, 8, x FOR PEER REVIEW 23 of 38

Figure 19.Figure Magnetite 19. Magnetite coated coated-grafted-grafted palladium palladium catalysts catalysts for for the the Sonogashira Sonogashira reaction. reaction Conditions,. Conditions, substratesubstrate scope and scope yield and yieldrange range (Scheme (Scheme 2).2 ).

An alternativeInstead ofway silica, to titania build can up be a used magnetically as final shell. recoverable Thus, the preparation material of is catalyst to anchor,61 (Figure not 19 only) the was similar to the above presented but changing tetraalkoxysilanes by titanium tetraalkoxydes. catalytic The metallic efficiency species, of this composite-catalystbut also NPs, to was any examined support in the (Figure Sonogashira 21). This reaction, strategy and the has process been used starting fromworked potato efficiently starch, for iodoarenes, its reaction even with for the a related core–shell bromo- composite and chloroarenes, of magnetite although-silica in these modified surface silanolcases longer groups reactions as chloride times were giving needed the to magnetic reach similar recoverable yields. The material. composite 61Thecould final be adsorptio reused n of palladiumfive salt times and with in asitu marginal reduction decrease by in the the yield.support The hotlead filtration the catalyst test showed 65, which the heterogeneity was used of to the catalyze the Sonogashiraprocess [107 coupling.]. The reaction worked well for both electron-rich and electron-poor Not only magnetite could be the core of the composite material, but also maghemite (γ-Fe2O3) haloareneswith and a similar phenylacetylene, spinel structure obtaining (Figure 20 ). the Thus, expected the pyridine 1,2-diarylethyne maghemite coated-grafted products incatalyst high yields [111]. As 62inhas previous been successfully cases, the used best in results the classical in terms Sonogashira of reaction reaction time with and phenylacetylene, yields were the obtained use of when iodoareneschloroarenes were used, needing and longerthe worst reaction when times the and relate reaching chloroarenes lower yields were that the employed. related iodoarenes The catalyst [108]. could be recycledIn addition,and reused another up possibilityto five folds, is the but stabilization an increase of the of palladiumthe reaction by carbine-phospanetime was needed, ligands, to maintain the initialas yields. in thecase However, of supported different catalyst techniques,63, which allowed including to perform TEM theimage cross-coupling and FT-IR reaction, did not using show any water as solvent and very low catalyst loading [109]. The Sonogashira reaction was carried out with change ofdifferent the reused haloarenes, catalyst. including iodo, bromo and chloro derivatives. However, as in previous cases, the use of chloro derivatives implied longer reactions times and lower yields. The catalyst could be isolated by magnetic decantation and reused up to ten times with a minimum decrease in the yield. Furthermore, the maghemite composite supported catalyst 64 has only been used for the Sonogashira reaction between iodobenzene and phenylacetylene (Figure 20), although its preparation represents a new variant since the linkage between the palladium-containing organic tail and the solid surface was due to the formation of multiple hydrogen bonding in the dendritic unit [110]. This new system opens the door for the design of other type of catalysts. An alternative way to build up a magnetically recoverable material is to anchor, not only the catalytic metallic species, but also NPs, to any support (Figure 21). This strategy has been used

Catalysts 2018, 8, x FOR PEER REVIEW 23 of 38

Figure 19. Magnetite coated-grafted palladium catalysts for the Sonogashira reaction. Conditions, substrate scope and yield range (Scheme 2). Catalysts 2018, 8, 202 24 of 39 An alternative way to build up a magnetically recoverable material is to anchor, not only the catalytic metallic species, but also NPs, to any support (Figure 21). This strategy has been used starting from potato starch, its reaction with a core–shellcore–shell composite of magnetite-silicamagnetite-silica modifiedmodified surface silanol groups as chloride giving the magnetic recoverable material. The The final final adsorptio adsorptionn of palladium salt andand inin situsitu reductionreduction by by the the support support lead lead the the catalyst catalyst65 ,65 which, which was was used used to catalyzeto catalyze the theSonogashira Sonogashira coupling. coupling. The reaction The reaction worked worked well for well both for electron-rich both electron and electron-poor-rich and electron haloarenes-poor haloarenesand phenylacetylene, and phenylacetylene, obtaining the obtaining expected the 1,2-diarylethyne expected 1,2-diarylethyne products in products high yields in [ high111]. yields As in [111].previous As in cases, previous the best cases, results the best in terms results of reactionin terms timeof reaction and yields time wereand yields obtained were when obtained iodoarenes when iodoareneswere used, andwere the used, worst and when the worst the relate when chloroarenes the relate chloroarenes were employed. were Theemployed. catalyst The could catalyst be recycled could beand recycled reused and up toreused five folds, up to butfive an folds, increase but an of increase the reaction of the time reaction was needed, time was to needed, maintain to themaintain initial theyields. initial However, yields. However, differenttechniques, different techniques, including including TEM image TEM and image FT-IR, and did FT not-IR show, did anynot show change any of changethe reused of the catalyst. reused catalyst.

Catalysts 2018, 8, x FOR PEER REVIEW 24 of 38

FigureFigure 20. 20.Maghemite Maghemite coated-grafted coated-grafted palladium palladium catalysts catalysts for for the the Sonogashira Sonogashira reaction. reaction. Conditions, Conditions, substratesubstrate scope scope and and yield yield range range (Scheme (Scheme2). 2).

Figure 21. Magnetic decorated palladium catalysts for the Sonogashira reaction. Conditions, substrate scope and yield range (Scheme 2).

The last recent example of this section used a copper ferrite spinel as magnetic part. This spinel was linked to a silica surface through an aminopropylsilaneoxy linker, and over this material PdNPs were deposited to obtain material 66. The catalyzed Sonogashira reaction was carried out using different functionalized iodo- and bromoarenes [112], the presence of electron-withdrawing groups at the p-position of the haloarene enhancing the chemical yield. It should be pointed out that the magnetic decantation of the catalyst and its reuse had a negative impact on the final yield, as it was explained by the high palladium leaching (6%), according to AAS analysis of the crude solution.

6. Hybrid Material-Supported Palladium Catalysts The typical reduction of palladium salts in the presence of different hybrid materials has been employed for the preparation of heterogeneous catalysts. The generated PdNPs immobilized in these

Catalysts 2018, 8, x FOR PEER REVIEW 24 of 38

CatalystsFigure2018 ,20.8, 202Maghemite coated-grafted palladium catalysts for the Sonogashira reaction. Conditions,25 of 39 substrate scope and yield range (Scheme 2).

FigureFigure 21. 21. MagneticMagnetic decorated decorated palladium palladium catalysts catalysts for for the the Sonogashira Sonogashira reaction reaction.. Condi Conditions,tions, substrate substrate scopescope and and yield yield range range (Scheme (Scheme 2).2).

The last recent example of this section used a copper ferrite spinel as magnetic part. This spinel The last recent example of this section used a copper ferrite spinel as magnetic part. This spinel was linked to a silica surface through an aminopropylsilaneoxy linker, and over this material PdNPs was linked to a silica surface through an aminopropylsilaneoxy linker, and over this material PdNPs were deposited to obtain material 66. The catalyzed Sonogashira reaction was carried out using were deposited to obtain material 66. The catalyzed Sonogashira reaction was carried out using different functionalized iodo- and bromoarenes [112], the presence of electron-withdrawing groups different functionalized iodo- and bromoarenes [112], the presence of electron-withdrawing groups at the p-position of the haloarene enhancing the chemical yield. It should be pointed out that the at the p-position of the haloarene enhancing the chemical yield. It should be pointed out that the magnetic decantation of the catalyst and its reuse had a negative impact on the final yield, as it was magnetic decantation of the catalyst and its reuse had a negative impact on the ﬁnal yield, as it was explained by the high palladium leaching (6%), according to AAS analysis of the crude solution. explained by the high palladium leaching (6%), according to AAS analysis of the crude solution.

6.6. Hybrid Hybrid Material Material-Supported-Supported Palladium Palladium Catalysts Catalysts TheThe typical typical reduction reduction of of palladium palladium salts salts in in the the presence presence of of different different hybrid hybrid materials materials has has been been employedemployed for for the the preparation preparation of of heterogeneous heterogeneous catalysts. catalysts. The The generated generated PdNPs PdNPs immobilized immobilized in in these these materials catalyzed the copper-free Sonogashira reaction (Scheme9), allowing to increase the catalytic activity of the palladium and to reduce the amount of metal required for the process. In this context, PdNPs were prepared in a calcium-cholate hydrogel (PdNPs@Ca-Ch, 67), the growth and stabilization of the PdNPs being assisted by the hydrogel matrix. This PdNPs/Ca-Ch hybrid xerogel catalyzed the copper-free Sonogashira reaction between iodoarenes and phenylacetylene, using pyrrolidine as base in water as solvent [113]. Unfortunately, this hybrid xerogel resulted degraded under the reaction conditions, making it impossible to recycle. In addition, PdNPs have been supported on a TiO2-cellulose composite (PdNPs@TiO2-Cell, 68), proving to be an effective catalyst to perform the coupling of aryl bromides with terminal alkynes (Scheme9)[ 114], although its recyclability was not demonstrated in a Sonogashira coupling. Moreover, PdCu bimetallic NPs have been supported on a polymeric vinylimidazole ligand modiﬁed magnesium oxide, and this material (PdCu@MgO) exhibits high catalytic activity in the Sonogashira coupling reaction of aryl iodides, bromides and chlorides with low Pd loading (0.05–0.2 mol%). This catalyst is recovered and recycled for eleven consecutive runs preserving its catalytic activity in the model reaction of iodobenzene with phenylacetylene for at least eight cycles [115]. Catalysts 2018, 8, x FOR PEER REVIEW 25 of 38 materials catalyzed the copper-free Sonogashira reaction (Scheme 9), allowing to increase the catalytic activity of the palladium and to reduce the amount of metal required for the process. In this context, PdNPs were prepared in a calcium-cholate hydrogel (PdNPs@Ca-Ch, 67), the growth and stabilization of the PdNPs being assisted by the hydrogel matrix. This PdNPs/Ca-Ch hybrid xerogel catalyzed the copper-free Sonogashira reaction between iodoarenes and phenylacetylene, using pyrrolidine as base in water as solvent [113]. Unfortunately, this hybrid xerogel resulted degraded under the reaction conditions, making it impossible to recycle. In addition, PdNPs have been supported on a TiO2-cellulose composite (PdNPs@TiO2-Cell, 68), proving to be an effective catalyst to perform the coupling of aryl bromides with terminal alkynes (Scheme 9) [114], although its recyclability was not demonstrated in a Sonogashira coupling. Moreover, PdCu bimetallic NPs have been supported on a polymeric vinylimidazole ligand modified magnesium oxide, and this material (PdCu@MgO) exhibits high catalytic activity in the Sonogashira coupling reaction of aryl iodides, bromides and chlorides with low Pd loading (0.05–0.2 mol%). This catalyst is recovered and recycled for eleven consecutive runs preserving its catalytic activity in the model reaction of iodobenzene with Catalysts 2018, 8, 202 26 of 39 phenylacetylene for at least eight cycles [115].

SchemeScheme 9. 9. PdNPsPdNPs supported supported on on hybrid hybrid materials materials employed employed in in the the copper copper-free-free Sonogashira Sonogashira reaction. reaction. Conditions,Conditions, substrate substrate scope scope and and yield yield range. range.

Cyclodextrins (CDs) can act as transfer shuttles to promote biphasic processes due to their Cyclodextrins (CDs) can act as transfer shuttles to promote biphasic processes due to their hydrophilic hydrophilic exterior and hydrophobic interior cavities, being suitable to immobilize PdNPs. Thus, a exterior and hydrophobic interior cavities, being suitable to immobilize PdNPs. Thus, a hybrid system

based on covalent conjugation of tosylated cyclodextrin to thiosemicarbazide-functionalized halloysite nanotubes (PdNPs@CD-T-HNTs, 69) demonstrated to be effective in the coupling of several terminal acetylenes and halobenzenes (Scheme9). The study confirmed a synergistic effect between HNTs and CD, being recycled up to 13 cycles with just a slight loss of activity [116]. A hybrid material has also been prepared using cyclodextrins and carbon nanotubes (CNTs) (PdNPs@CD-CNT), and has been used in the coupling of phenylacetylene and iodobenzene with high activity (93% yield of diphenylacetylene), the catalyst being recycled six times with only a slight loss of activity [117]. The use of covalent organic frameworks (COFs) [118] and metal–organic frameworks (MOFs) [119,120] as supports of NPs has also been considered due to their good properties in terms of stability, recyclability, high surface area and high pore volume. Thus, highly dispersed PdNPs have been immobilized into the covalent organic framework TpPa-1 by a simple solution infiltration method followed by NaBH4 reduction, providing the heterogeneous catalyst PdNPs@TpPa-1 (70). This hybrid material resulted active as catalyst in the Sonogashira coupling between aryl halides and alkynes Catalysts 2018, 8, x FOR PEER REVIEW 26 of 38 hybrid system based on covalent conjugation of tosylated cyclodextrin to thiosemicarbazide- functionalized halloysite nanotubes (PdNPs@CD-T-HNTs, 69) demonstrated to be effective in the coupling of several terminal acetylenes and halobenzenes (Scheme 9). The study confirmed a synergistic effect between HNTs and CD, being recycled up to 13 cycles with just a slight loss of activity [116]. A hybrid material has also been prepared using cyclodextrins and carbon nanotubes (CNTs) (PdNPs@CD-CNT), and has been used in the coupling of phenylacetylene and iodobenzene with high activity (93% yield of diphenylacetylene), the catalyst being recycled six times with only a slight loss of activity [117]. The use of covalent organic frameworks (COFs) [118] and metal–organic frameworks (MOFs) [119,120] as supports of NPs has also been considered due to their good properties in terms of stability, recyclability, high surface area and high pore volume. Thus, highly dispersed PdNPs have been immobilized into the covalent organic framework TpPa-1 by a simple solution infiltration method followed by NaBH4 reduction, providing the heterogeneous catalyst PdNPs@TpPa-1 (70). Catalysts 2018, 8, 202 27 of 39 This hybrid material resulted active as catalyst in the Sonogashira coupling between aryl halides and alkynes (Scheme 9), recycling of the catalyst showing a loss of a 25% of yield after the fourth cycle [121].(Scheme In the9), recyclingcase of MOFs, of the MIL catalyst-101 showing and MCoS a loss-1 have of a 25%been of em yieldployed after to the stabilize fourth PdNPs. cycle [ 121 Thus,]. In the the hybridcase of MOFs,materials MIL-101 PdNPs@MIL and MCoS-1-101 have(71) and been PdNPs@MCoS employed to stabilize-1 (72) PdNPs. have been Thus, easily thehybrid obtained materials by a simplePdNPs@MIL-101 impregnation (71) and method, PdNPs@MCoS-1 being active (72 ) catalyzing have been easily the copper obtained-free by Sonogashira a simple impregnation reaction. Heterogeneousmethod, being activecatalyst catalyzing 71 was effective the copper-free in the coupling Sonogashira of terminal reaction. alkynes Heterogeneous with bromoarenes catalyst 71 andwas bromoheteroareneseffective in the coupling [122], of whereasterminal alkynes catalyst with72 was bromoarenes assayed and in iodo bromoheteroarenes-, bromo-, and [ chloroarenes122], whereas (Schemecatalyst 729) was[123]. assayed Both MOF in iodo-,-based bromo-, catalysts and were chloroarenes reused in (Scheme up to five9)[ cycles123]. Both(ca. 6% MOF-based yield drop catalysts for 71 andwere ca. reused 4% yield in up drop to fivefor 72 cycles). (ca. 6% yield drop for 71 and ca. 4% yield drop for 72). 1,31,3-Bis(4-carboxyphenyl)imidazolium-Bis(4-carboxyphenyl)imidazolium chloride chloride has has been been e employedmployed as as a a linker linker in in the the preparation preparation ofof a a MOF MOF in in combination combination with with zinc zinc nitrate, nitrate, being being subsequently subsequently altered altered to to create create NHC NHC-palladium(II)-palladium(II) complexes.complexes. This This modified modified MOFMOF showedshowed a a high high density density and and uniform uniform distribution distribution of theof the active active sites sites and andcatalyzed catalyzed the Sonogashira the Sonog reactionashira reaction between between aryl iodides, aryl bromides iodides, or bromides chlorides andor chlorides arylacetylenes, and arylacetylenes,using potassium using carbonate potassium as base carbonate and DMF as base as solvent and DMF at 100 as solvent◦C, retaining at 100 its°C, catalytic retaining activity its catalytic for at activityleast four for cyclesat least without four cycles losing without its structural losing its integrity structural [124 integrity]. Similarly, [124]. dicarboxylic Similarly, dicarboxylic acid palladium acid palladiumcomplex 73 complex(Figure 7322 )(Figure has been 22) assembled has been with assembled zinc nitrate with forming zinc nitrate a mesoporous forming a palladium(II) mesoporous palladium(II)coordination polymer coordination Pd(II)-CP. polymer This protocol Pd(II)- allowedCP. This the protocol immobilization allowed of palladium the immobilization bis(phosphane) of palladiumcomplexes, bis(phosphane) being a structural complexes, part of a MOF. being This a structura preparedl Pd(II)-CPpart of a proved MOF. This to be prepared active as catalyst, Pd(II)-CP in provedcombination to be active with CuI,as catalyst, for the in Sonogashira combination coupling with CuI, of for iodobenzene the Sonogashira and phenylacetylenecoupling of iodobenzene in a 55% andyield phenylacetylene after 24 h [125]. Thisin a heterogeneous55% yield after catalyst 24 h [125]. resulted This stable heterogeneous enough to be catalyst reused resulted more than stable four enoughtimes with to be neither reused palladium more than nor four zinc times leaching. with neither palladium nor zinc leaching.

FigureFigure 22. 22. Palladium(II)Palladium(II) complex complex 7373 employedemployed as as linker linker in in the the preparation preparation of of a a MOF. MOF.

7.7. Inorganic Inorganic Material Material-Supported-Supported Palladium Palladium Catalysts Catalysts NonNon-functionalized-functionalized purely purely inorganic inorganic materials materials have have been been used used for for the the immobilization immobilization of of palladiumpalladium species, species, and and some some of of the the most most studied studied are are zeolites. zeolites. These These materials materials have have been been disclosed disclosed as as excellentexcellent supports supports for for palladium palladium catalysts, catalysts, mainly mainly PdNPs, PdNPs, able to able perform to perform different different coupling cou reactions,pling reactions,the Sonogashira the Sonogashira coupling coupling being among being them.among Therefore,them. Therefore, examples examples dealing dealing with thewith use the of use such of suchsupports supports for the for immobilization the immobilization of PdNPs of PdNPs and their and use their in Sonogashirause in Sonogashira couplings couplings have been have reported been reportedin the last in years.the last Thus, years. the Thus, use the of the use natural-occurring, of the natural-occurring, inexpensive inexpensive and readily and readily available available zeolite clinoptiolite as support of PdNPs has been described. The catalyst [Pd(0)@AT-Nano CP, 74] was prepared in a straightforward manner from the so-called nanozeolite clinoptiolite (Nano CP) after activation and dealumination with H2SO4 (AT-Nano CP), and subsequent treatment with K2PdCl4 and reduction with hydrazine [126]. After characterization of the heterogeneous catalyst, conﬁrming the presence of PdNPs (<10 nm) in the mesoporous inorganic structure, the copper-free Sonogashira coupling was tested in water as solvent at 60 ◦C. The reaction of aryl iodides, bromides and chlorides with terminal alkynes afforded the corresponding coupling products with good to excellent yields using 0.06 mol% of Pd(0), regardless the nature of the aryl halide and the terminal alkyne employed. It is worth mentioning that the heterogeneity was demonstrated since no leaching of PdNPs was observed. Additionally, the Pd(0)@AT-Nano CP catalyst could be reused up to eight times without detriment in yields and with only a slight increase in reaction time when the model reaction between iodobenzene and phenylacetylene was carried out. Catalysts 2018, 8, x FOR PEER REVIEW 27 of 38 zeolite clinoptiolite as support of PdNPs has been described. The catalyst [Pd(0)@AT-Nano CP, 74] was prepared in a straightforward manner from the so-called nanozeolite clinoptiolite (Nano CP) after activation and dealumination with H2SO4 (AT-Nano CP), and subsequent treatment with K2PdCl4 and reduction with hydrazine [126]. After characterization of the heterogeneous catalyst, confirming the presence of PdNPs (<10 nm) in the mesoporous inorganic structure, the copper-free Sonogashira coupling was tested in water as solvent at 60 °C. The reaction of aryl iodides, bromides and chlorides with terminal alkynes afforded the corresponding coupling products with good to excellent yields using 0.06 mol% of Pd(0), regardless the nature of the aryl halide and the terminal alkyne employed. It is worth mentioning that the heterogeneity was demonstrated since no leaching of PdNPs was observed. Additionally, the Pd(0)@AT-Nano CP catalyst could be reused up to eight Catalysts 2018, 8, 202 28 of 39 times without detriment in yields and with only a slight increase in reaction time when the model reaction between iodobenzene and phenylacetylene was carried out. Another recent example of a zeolite as inorganic palladium support is the use of the commercially availableavailable ion exchange NaY zeolite,zeolite, whichwhich waswas treatedtreated withwith [Pd(NH[Pd(NH33))44]Cl2 and, after several thermal treatments under under oxidative oxidative (O (O2) and2) and reductive reductive (H2) (H atmospheres,2) atmospheres, afforded afforded the Pd(0) the-loaded Pd(0)-loaded NaY zeolite NaY zeolite(Pd-NaY, (Pd-NaY, 75) [127].75 )[ Under127]. optimized Under optimized conditions, conditions, azaindoles azaindoles and pyrrolo and-quinolines pyrrolo-quinolines were obtained were obtainedthrough a through tandema Sonogashira tandem Sonogashira couplingcoupling-cyclizationcyclization reaction (Scheme reaction (Scheme10). For such10). Forpurpose, such purpose,iodo-N- iodo-substitutedN-substituted aminopyridines aminopyridines and aminoquinolines and aminoquinolines were employed were as employed starting materials, as starting obtaining materials, the obtainingcorresponding the corresponding products in yields products ranging in yields from moderate ranging from to high. moderate When tothe high. recyclability When the of recyclability the catalyst ofwas the essayed, catalyst a wassignificant essayed, drop a signiﬁcant in the yield drop (from in the71% yield to 62%) (from along 71% with to 62%) an important along with increase an important of the increasereaction time of the (from reaction 6 to time16 h) (fromwas observed 6 to 16 h) after was the observed third cycle. after the third cycle.

Scheme 10. 10. Pd(0)-Pd(0)-NaYNaY (75)-catalyzed (75)-catalyzed synthesis synthesis of heterocycles of heterocycles through tandem through a Sonogashira tandem a- Sonogashira-cyclizationcyclization reaction. reaction.

Another family of silicates extensively used for the immobilization of metal catalysts are the Another family of silicates extensively used for the immobilization of metal catalysts are the readily available montmorillonites (MMT), and recently Na+-Montmorillonite (Na-MMT) has been readily available montmorillonites (MMT), and recently Na+-Montmorillonite (Na-MMT) has been the the starting point for supporting PdNPs and Pd/Cu nanoalloys. Thus, after the activation of Na-MMT starting point for supporting PdNPs and Pd/Cu nanoalloys. Thus, after the activation of Na-MMT with H2SO4 generating nanopores in the structure, PdNPs were located after treatment of the MMT with H2SO4 generating nanopores in the structure, PdNPs were located after treatment of the MMT with a palladium(II) source and further reduction. Once the PdNPs@MMT catalyst (76) was fully with a palladium(II) source and further reduction. Once the PdNPs@MMT catalyst (76) was fully characterized, the copper-free Sonogashira reaction between different aryl iodides and alkyl and characterized, the copper-free Sonogashira reaction between different aryl iodides and alkyl and arylacetylenes was assayed, obtaining excellent yields in all cases (Figure 23) [128]. These good results arylacetylenes was assayed, obtaining excellent yields in all cases (Figure 23)[128]. These good results were maintained for three cycles after the recovery of the catalyst. In another example, palladium(II) were maintained for three cycles after the recovery of the catalyst. In another example, palladium(II) and different metal salts [Cu(II), Fe(II), and Ni(II)] were co-precipitated on the MMT surface, giving and different metal salts [Cu(II), Fe(II), and Ni(II)] were co-precipitated on the MMT surface, giving rise to the corresponding PdNPs/MetalNPs@MMT catalysts after sonication and reduction. Under rise to the corresponding PdNPs/MetalNPs@MMT catalysts after sonication and reduction. Under optimized reaction conditions, these catalysts were employed in the Sonogashira reaction, the best optimized reaction conditions, these catalysts were employed in the Sonogashira reaction, the best results being achieved when PdNPs/CuNPs@MMT (77) was the catalyst employed (Figure 23) [129]. results being achieved when PdNPs/CuNPs@MMT (77) was the catalyst employed (Figure 23)[129]. Thus, the reaction with unactivated and activated aryl iodides with alkyl and arylacetylenes Thus, the reaction with unactivated and activated aryl iodides with alkyl and arylacetylenes produced the corresponding products with yields ranging from moderate to high, respectively. It is remarkable that the reaction using PdNPs@MMT or CuNPs@MMT independently barely worked, suggesting a synergistic effect of both metals. Unfunctionalized inorganic silicon-based materials can also act as support for PdNPs, which has been shown recently by the use of a pH-responsive mesoporous silica nanocomposite [130]. This kind of silica can be highly dispersed in an organic phase by adjusting pH (9–10) hence preserving the beneﬁts of homogeneous catalysts. Thus, this support was embedded with PdNPs and tested in the Sonogashira reaction (catalyst 78) using triethylamine as base in a Et2O/H2O (1/1, v/v) solvent mixture, with a 1 mol% Pd loading at room temperature. Under these conditions, aryl iodides gave rise to the coupling products in high yields, the corresponding aryl bromides producing moderate yields Catalysts 2018, 8, 202 29 of 39

Catalysts 2018, 8, x FOR PEER REVIEW 28 of 38 at best. Interestingly, the catalyst was easily recovered just adjusting pH to 3–4, the heterogeneous producedspecies remaining the corresponding in the aqueous products phase with under yields these ranging acidic from conditions moderate and to the high, products respectively. being easily It is remarkableextracted from that the the ethereal reaction layer. using Once PdNPs@MMT the pH was readjustedor CuNPs@MMT to basic independently conditions (9–10), barely the catalystsworked, suggestingreverted to a the synergistic organic phase effect keeping of both themetals. catalytic efﬁciency almost unaltered for ﬁve cycles.

Figure 23. MontmorilloniteMontmorillonite-immobilized-immobilized PdNPs PdNPs as as catalysts catalysts for for the the Sonogashira reaction reaction.. Conditions, Conditions, substrate scope and yield range (Scheme 22).).

Unfunctionalized inorganic silicon-based materials can also act as support for PdNPs, which has More recently, silicon carbide has been described in the literature for immobilizing PdNPs [131]. been shown recently by the use of a pH-responsive mesoporous silica nanocomposite [130]. This kind The application of such heterogeneous catalyst 79 in the Sonogashira coupling with phenylacetylene of silica can be highly dispersed in an organic phase by adjusting pH (9–10) hence preserving the was tested using both, activated and unactivated aryl iodides and bromides, obtaining excellent benefits of homogeneous catalysts. Thus, this support was embedded with PdNPs and tested in the and moderate conversions, respectively, when the reaction was performed under UV-irradiation Sonogashira reaction (catalyst 78) using triethylamine as base in a Et2O/H2O (1/1, v/v) solvent mixture, (400–800 nm). The reaction seemingly follows a photocatalytic pathway, since the reaction conversion with a 1 mol% Pd loading at room temperature. Under these conditions, aryl iodides gave rise to the drops dramatically in the dark. A possible electron-transfer from the semiconductor support to PdNPs coupling products in high yields, the corresponding aryl bromides producing moderate yields at best. has been suggested, hence increasing their activity when irradiated with the appropriate wavelength. Interestingly, the catalyst was easily recovered just adjusting pH to 3–4, the heterogeneous species This catalyst proven to be recyclable up to ﬁve cycles with slight decrease in activity (99% to 89%), remaining in the aqueous phase under these acidic conditions and the products being easily extracted probably due to some Pd leaching observed analyzing the metal content after the last run. from the ethereal layer. Once the pH was readjusted to basic conditions (9–10), the catalysts reverted Another kind of inorganic supports frequently found in heterogenous catalysis for the to the organic phase keeping the catalytic efficiency almost unaltered for five cycles. immobilization of metal NPs are metal oxides. Thus, readily available titania (TiO ), which is very More recently, silicon carbide has been described in the literature for immobilizing2 PdNPs [131]. stable and active as photocatalyst, was used as support for PdNPs creating material 80 and enhancing The application of such heterogeneous catalyst 79 in the Sonogashira coupling with phenylacetylene their performance as catalysts in the Sonogashira coupling when irradiated with 465 nm LED [132] was tested using both, activated and unactivated aryl iodides and bromides, obtaining excellent and (Figure 24). High yields were obtained using aryl iodides and terminal alkynes, although the catalyst moderate conversions, respectively, when the reaction was performed under UV-irradiation (400– reusability test revealed a slight drop in the yield in the second cycle and no conversion in the third cycle. 800 nm). The reaction seemingly follows a photocatalytic pathway, since the reaction conversion Possible catalyst poisoning by accumulation of stilbene sub-product formation has been suggested as drops dramatically in the dark. A possible electron-transfer from the semiconductor support to the main reason for such behavior. However, the PdNPs@TiO (80) catalyst was regenerated with a PdNPs has been suggested, hence increasing their activity when2 irradiated with the appropriate photo-treatment using the radical photo-initiator Irgacure® 2959 and UV light, restoring most of the wavelength. This catalyst proven to be recyclable up to five cycles with slight decrease in activity catalyst performance. In addition, zinc oxide (ZnO), also readily available and with similar properties (99% to 89%), probably due to some Pd leaching observed analyzing the metal content after the last than TiO , was used as support for PdNPs. The formed Pd(0)@ZnO (81) catalyzed the Sonogashira run. 2 coupling in the presence of catalytic amounts of CuI under aqueous conditions (Figure 24)[133]. Another kind of inorganic supports frequently found in heterogenous catalysis for the Activated and unactivated aryl iodides and activated aryl bromides and chlorides were coupled with immobilization of metal NPs are metal oxides. Thus, readily available titania (TiO2), which is very phenylacetylene, obtaining high to excellent yields. The catalyst was recycled up to ﬁve runs without stable and active as photocatalyst, was used as support for PdNPs creating material 80 and enhancing Catalystany decreases 2018, 8, inx FOR yields. PEER REVIEW 29 of 38 their performance as catalysts in the Sonogashira coupling when irradiated with 465 nm LED [132] (Figure 24). High yields were obtained using aryl iodides and terminal alkynes, although the catalyst reusability test revealed a slight drop in the yield in the second cycle and no conversion in the third cycle. Possible catalyst poisoning by accumulation of stilbene sub-product formation has been suggested as the main reason for such behavior. However, the PdNPs@TiO2 (80) catalyst was regenerated with a photo-treatment using the radical photo-initiator Irgacure® 2959 and UV light, restoring most of the catalyst performance. In addition, zinc oxide (ZnO), also readily available and with similar properties than TiO2, was used as support for PdNPs. The formed Pd(0)@ZnO (81) catalyzedFigure the 24. SonogashiraTitaniaTitania and and zinc zinc coupling oxide oxide-immobilizedimmobilized in the presence PdNPs PdNPs of as as catalytic catalysts catalysts amounts for for the the SonogashiraSonogashira of CuI under reaction reaction. aqueous. conditionsConditions, (Figure substrate 24) [133]. scope Activated and yield andrange unactivated (Scheme 22).). aryl iodides and activated aryl bromides and chlorides were coupled with phenylacetylene, obtaining high to excellent yields. The catalyst was recycledMetal up hydroxides to five runs canwithout be also any employeddecrease in for yields. supporting metal catalysts. Thus, PdNPs were immobilized on Al(OH)3 by mixing the Pd(II) precursor with Al(OiPr)3, obtaining the corresponding PdNPs@Al(OH)3 (82) after the corresponding treatment [134]. This catalyst resulted very active in the copper-free Sonogashira reaction of aryl and heteroaryl bromides and chlorides with aryl and heteroarylacetylenes, obtaining higher yields when the aryl bromides were employed (Figure 25). Surprisingly, a better catalytic performance was observed when the in situ catalyst preparation method was employed than when PdNPs were supported on preformed Al(OH)3. The catalyst was recycled up to six times without any loss in activity, being the leached palladium negligible after the last cycle. Another natural occurring hydroxide, the hydroxyapatite [Ca5(PO4)3(OH); HAP] was prepared by a precipitation and calcination procedure. Different HAPs were prepared under various pH conditions and the PdNPs were supported on them, catalyst PdNPs@HAP-12 (83) (pH maintained to 12 in the HAP preparation) proving to perform the best for the Sonogashira coupling between activated and unactivated aryl and heteroaryl iodides and bromides and terminal acetylenes (Figure 25) [135]. Recyclability experiments demonstrated that the catalytic activity was maintained for four cycles, observing almost no leaching of Pd (0).

Figure 25. PdNPs supported on metal hydroxides as catalysts for Sonogashira couplings. Conditions, substrate scope and yield range (Scheme 2).

Although uncommon, PdNPs can also be supported on other native metals. This is the case of a nano-Pd/Cu catalytic system, which was evaluated in Sonogashira couplings of aryl iodides and bromides with terminal alkynes, obtaining moderate to high yields using triethylamine as base and solvent [136]. It was also observed the presence of certain amounts of PdO, which apparently favors the catalyst activity. The catalyst was recycled up to two runs adding triphenylphosphine in each cycle to enhance the stability of palladium species and prevent deactivation. However, almost no conversion was observed after the third cycle due to a significant palladium leaching and changes in catalyst morphology.

8. Selection of The Most Synthetically Useful Catalysts From a critical point of view, among all the array of presented catalysts, only some of them can really be considered as promising for general synthetic purposes. Thus, catalysts that have only been assayed in the cross-coupling of the “easy” aryl iodides and terminal acetylenes results nowadays of limited general synthetic usefulness, although conceptually interesting in some cases. However, those being able to catalyze the reaction using aryl bromides and chlorides result more active and, in principle, with a more general applicability, particularly if this is demonstrated carrying out a good amount of reactions with these substrates. Moreover, as the recyclability of the catalyst is a crucial

Catalysts 2018, 8, x FOR PEER REVIEW 29 of 38

Figure 24. Titania and zinc oxide-immobilized PdNPs as catalysts for the Sonogashira reaction. Catalysts 2018, 8, 202 30 of 39 Conditions, substrate scope and yield range (Scheme 2).

Metal hydroxides can be also employed for supporting supporting metal metal catalysts. catalysts. Thus, Thus, PdNPs PdNPs were immobilizedimmobilized on Al(OH) 3 byby mixing mixing the the Pd(II) Pd(II) precursor precursor with with Al(OiPr) Al(OiPr)3,, obtaining obtaining the the corresponding corresponding PdNPs@Al(OH)33 (82(82) )after after the the corresponding corresponding treatment treatment [134] [134. This]. This catalyst catalyst resulted resulted very very active active in the in copperthe copper-free-free Sonogashira Sonogashira reaction reaction of arylof aryl and and heteroaryl heteroaryl bromides bromides and and chlorides chlorides with with aryl aryl and and heteroarylacetylenes, obtaining obtaining higher higher yields yields when when the the aryl aryl bromides bromides were were employed employed (Figure (Figure 25).25). Surprisingly, a a better better catalytic catalytic performance performance was was observed observed when when the in the situ in catalyst situ catalyst preparation preparation method methodwas employed was employed than when than PdNPs when were PdNPs supported were supported on preformed on preformed Al(OH)3 .Al(OH) The catalyst3. The wascatalyst recycled was recycledup to six up times to six without times anywithout loss inany activity, loss in beingactivity, the being leached the palladium leached palladium negligible negligible after the lastafter cycle. the lastAnother cycle. natural Another occurring natural hydroxide, occurring the hydroxide, hydroxyapatite the hydroxyapatite [Ca5(PO4)3(OH); [Ca HAP]5(PO4)3 was(OH); prepared HAP] bywas a preparedprecipitation by a and precipitation calcination and procedure. calcination Different procedure. HAPs Different were prepared HAPs were under prepared various under pH conditions various pHand conditions the PdNPs and were the supported PdNPs on were them, supported catalyst PdNPs@HAP-12on them, catalyst (83 PdNPs@HAP) (pH maintained-12 (83 to) 12 (pH in maintainedthe HAP preparation) to 12 in the provingHAP preparation) to perform proving the best to for perform the Sonogashira the best for coupling the Sonogashira between activatedcoupling betweenand unactivated activated aryl and and unactivated heteroaryl aryl iodides and heteroaryl and bromides iodides and and terminal bromides acetylenes and terminal (Figure acetylenes 25)[135]. (FigureRecyclability 25) [135]. experiments Recyclabili demonstratedty experiments that demonstrated the catalytic that activity the catalytic was maintained activity was for maintained four cycles, forobserving four cycles, almost observing no leaching almost of Pdno (0).leaching of Pd (0).

Figure 25. PdNPsPdNPs supported supported on on metal metal hydroxides hydroxides as as catalysts catalysts for for Sonogashira Sonogashira couplings couplings.. Conditi Conditions,ons, substratesubstrate scope scope and and yield range (Scheme 22).).

Although uncommon, PdNPs can also be supported on other native metals. This is the case of a Although uncommon, PdNPs can also be supported on other native metals. This is the case of nano-Pd/Cu catalytic system, which was evaluated in Sonogashira couplings of aryl iodides and a nano-Pd/Cu catalytic system, which was evaluated in Sonogashira couplings of aryl iodides and bromides with terminal alkynes, obtaining moderate to high yields using triethylamine as base and bromides with terminal alkynes, obtaining moderate to high yields using triethylamine as base and solvent [136]. It was also observed the presence of certain amounts of PdO, which apparently favors solvent [136]. It was also observed the presence of certain amounts of PdO, which apparently favors the catalyst activity. The catalyst was recycled up to two runs adding triphenylphosphine in each the catalyst activity. The catalyst was recycled up to two runs adding triphenylphosphine in each cycle to enhance the stability of palladium species and prevent deactivation. However, almost no cycle to enhance the stability of palladium species and prevent deactivation. However, almost no conversion was observed after the third cycle due to a significant palladium leaching and changes in conversion was observed after the third cycle due to a signiﬁcant palladium leaching and changes in catalyst morphology. catalyst morphology.

8. Selection Selection of of T Thehe Most Most Synthetically Synthetically Useful Catalysts From a critical point of of view, view, among all the array of presented catalysts catalysts,, only some of them can reallyreally be considered considered as promising for general synthetic purposes. Thus, Thus, catalysts catalysts that that have have only only been been assayed in in the the cro cross-couplingss-coupling of of the the “easy “easy”” aryl aryl iodides iodides and and terminal terminal acetylenes acetylenes results results nowadays nowadays of limitedof limited general general synthetic synthetic usefulness, usefulness, although although conceptually conceptually interesting interesting in in some some cases. cases. However, However, thosethose being being able able to to catalyze catalyze the the reaction reaction using using aryl aryl bromides bromides and and chlorides chlorides result result more more active active and, and, in principle,in principle, with with a more a more general general applicability, applicability, particularly particularly if ifthis this is is demonstrated demonstrated carrying carrying out out a a good good amount of of reactions with these substrates. Moreover, Moreover, as as the the recyclability recyclability of of the the catalyst catalyst is is a a crucial subject when dealing with solid-supported catalytic systems, a significative number of reaction cycles using the recovered catalyst should be presented when considering its potential usefulness. With all these strict considerations in mind, Table1 compiles a selection of the catalysts which can be considered synthetically most relevant, ordered by the material used as support. Only catalysts fulfilling all the following requirements are included: (a) can catalyze the coupling of aryl bromides and/or chlorides and terminal acetylenes; (b) have been employed in, at least, 10 reactions involving these halides; and (c) have been reused in, at least, five reaction cycles. Catalysts 2018, 8, 202 31 of 39

Table 1. Selected supported catalysts working with aryl bromides and/or chlorides in the Sonogashira reaction. Only catalysts used in 10 or more reactions involving aryl bromides and chlorides and employed in ﬁve or more reaction cycles are included.

Supporting Material Catalyst Loading (mol%) ArBr ArCl Additive No. Examples a No. Cycles Ref. 1 0.5 + + TBAB (ArCl) 13 5 [14] 2 1.0 + - - 12 5 [15] 3 0.1 + + - 15 5 [16] Organic polymer 6 1.0 + + - 20 5 [19] 8 1.0 + + - 12 5 [24] 16 1.0 + + - 15 5 [32] 17 1.0 + + - 14 5 [33] Carbon-based 30 0.1 + + - 10 6 [67] 34 0.04 + + - 13 5 [73] Functionalized silica 38 0.5 + + TBAB (ArCl) 12 6 [77] 41 0.085 + + - 27 6 [80] 51 0.1 + + - 10 7 [97] 58 0.18 + + - 18 7 [104] Magnetic 59 1.0 + + - 12 6 [105] 60 0.1 + + - 15 8 [106] 63 0.04 + + 14 10 [109] Hybrid 69 6.0 + + - 12 13 [116] 74 0.06 + + - 10 8 [126] Inorganic 82 0.2 + + TBAB 44 6 [134] a Total number of reactions carried out using aryl bromides and chlorides.

In Table1, it can be observed that very active catalysts can be obtained with palladium species anchored to all kind of supports. The higher number of catalysts fulﬁlling the above-mentioned requirements is situated in the organic–polymer supported section. The use of these supports has a longer history within the study of immobilized catalytic species, therefore the appearance of many developments is logical. However, it is interesting to note that the recyclability of those systems, even the bests, still results not particularly remarkable. A good number of interesting catalysts have been found when using magnetic materials as support, particularly when recyclability of the system is considered. In addition, some particularly active supported catalysts can also be found when using functionalized silica as supporting material, but still very few catalysts overcome the selection when carbon-based, hybrid or purely inorganic materials are used as supports, something which can be attributed to the novelty of their use as immobilization materials.

9. Conclusions This review presents how palladium species supported on many different materials have been successfully described as catalysts for the Sonogashira reaction in the last years. Two types of palladium catalysts have been reported independently of the support, palladium nanoparticles immobilized on the support and palladium complexes linked to the support, although, in this last case, the complex is usually just a precursor of the palladium nanoparticles. It is interesting to note that the Sonogashira cross-coupling reaction with these supported catalysts is frequently performed under convenient copper-free conditions. In addition, the development of procedures based on the use of aqueous or neat water as solvent has also been carried out. However, many of these catalytic systems still lack a broad applicability and are effective only for the coupling of the “easy” aryl iodides, being employed only in a model reaction. The general use of aryl chlorides as coupling partners remains an insufﬁciently solved matter. No doubt that the search of more effective supported catalytic systems, suitable to perform the coupling on a broad array of substrates, under mild and environmentally friendly reaction conditions and allowing its reuse in many cycles without deterioration will continue in the next years. Catalysts 2018, 8, 202 32 of 39

Author Contributions: R.C. and I.M.P. conceived, searched the reported papers and wrote the paper; D.A.A., A.B., C.G., G.G. and D.J.R. searched the reported papers and wrote the paper. Acknowledgments: We thank the financial support from the Spanish Ministerio de Economía, Industria y Competitividad (CTQ2015-66624-P) and the University of Alicante (UAUSTI16-03, AUSTI16-10, VIGROB-173, and VIGROB-285). Conflicts of Interest: The authors declare no conflicts of interest.

References

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