The Current Status of Heterogeneous Palladium Catalysed Heck and Suzuki Cross-Coupling Reactions

molecules

Review The Current Status of Heterogeneous Palladium Catalysed Heck and Suzuki Cross-Coupling Reactions

Philani P. Mpungose 1 ID , Zanele P. Vundla 1, Glenn E. M. Maguire 2 and Holger B. Friedrich 1,*

1 Catalysis Research Group, School of Chemistry and Physics, University of KwaZulu-Natal, Westville Campus, Durban 4000, South Africa; [email protected] (P.P.M.); [email protected] (Z.P.V.) 2 School of Chemistry and Physics, University of KwaZulu-Natal, Varsity Drive, Durban 4001, South Africa; [email protected] * Correspondence: [email protected]; Tel.: +27-31-2603107; Fax: +27-31-2603091

Received: 31 May 2018; Accepted: 23 June 2018; Published: 10 July 2018

Abstract: In the last 30 years, C–C cross coupling reactions have become a reliable technique in organic synthesis due their versatility and efﬁciency. While drawbacks have been experienced on an industrial scale with the use of homogenous systems, many attempts have been made to facilitate a heterogeneous renaissance. Thus, this review gives an overview of the current status of the use of heterogeneous catalysts particularly in Suzuki and Heck reactions. Most recent developments focus on palladium immobilised or supported on various classes of supports, thus this review highlights and discuss contributions of the last decade.

Keywords: C–C cross coupling; Heck cross-coupling; Suzuki cross-coupling; heterogeneous palladium catalysis

1. Introduction The importance of carbon–carbon bond forming reactions is well documented in literature [1–3]. The industrial importance of Suzuki and Heck cross-coupling reactions along with numerous others in this general field has sparked great interest in C–C bond formation reactions. In addition, the lack of a universal set of reaction conditions for every catalyst system and the drawbacks of industrially employed catalyst systems continue to fuel this interest. Heck and Suzuki reactions are typically catalysed by palladium based homogenous systems that have illustrated high turnover frequency (TOFs). These homogeneous catalysts require the use of ligands (phosphine or N-heterocyclic) to form active catalysts. As a result, separation of these catalysts (the ligand, the Pd metal or the complex) from the reaction media has presented the greatest challenge in this field. Consequently, the catalyst gets incorporated into the final product, resulting in loss of catalyst and a devalued product especially since these reactions are at the forefront of the production in the pharmaceutical industry. Successful separation of these homogeneous catalysts from the product solution requires the use of expensive nanofiltration membranes or an extensive (and usually destructive) column chromatography separation. Table1 summarises the maximum limits of residual metal catalysts acceptable in the pharmaceutical industry. These low allowed concentrations have prompted the development of recoverable and reuseable catalyst systems to decrease product contamination and alleviate the loss of catalyst. Many attempts have been made over the years to heterogenise homogeneous systems and to develop heterogeneous systems to displace homogenous systems and this review aims at highlighting recent contributions of the last decade at achieving this.

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Table 1. Maximum acceptable concentration limits for the residues of metal catalysts that can be present in pharmaceutical products [4].

Concentration (ppm) Metal Oral Parenteral Pd, Pt, Ir, Rh, Ru, Os 5 0.5 Mo, V, Ni, Cr 10 1.0 Cu, Mn 15 1.5 Zn, Fe 20 2.0

The main challenge in the development of heterogeneous catalytic systems for C–C cross-coupling reactions has been in establishing the nature of the active catalyst species. While literature on homogeneous systems is well developed with the mechanism well understood, the contrary is observed for heterogeneous catalysts. The true nature of the active catalyst when a palladium containing solid material is employed as a catalyst is still a highly debated issue in the field of cross-coupling reactions [5]. In most research papers, the “true nature” of the active form of palladium is ambiguous; claims exist in the literature supporting both soluble molecular and nanoparticle catalysts, as well as truly heterogeneous insoluble Pd catalysts [5–7]. More specifically, the question is whether the oxidative addition of the aryl halide (Ar–X) occurs on the surface of the solid catalyst (heterogeneous catalysis) or on leached metal atoms (homogeneous catalysis). The literature is currently divided on this matter; some researchers recognise the solid pre-catalyst as a “reservoir” of soluble catalytically active palladium species [4,8–10]. Others claim to have developed truly heterogeneous systems, with catalysis taking place on the surface of the solid palladium based heterogeneous catalyst [11,12]. Common heterogeneous cross-coupling catalysts mainly differ in: (i) chemical nature (organic, inorganic, or hybrid organic-inorganic) of the solid matrix entrapping the Pd catalyst and (ii) the nature of the catalyst attachment (chemical or physical entrapment) [13]. There are also examples of efficient catalysts for cross-coupling reactions based on colloidal palladium particles. The usefulness of the developed catalytic system is usually determined by its activity, selectivity and the life-time of the catalyst [14]. The catalytic activity is essentially a measure of percentage of reactants that are converted to product(s); while the catalytic selectivity is a measure of the percentage of the reactants that are converted to useful or desired product(s). The life-time of a catalyst is the time that the catalyst will maintain the required level of activity and selectivity [14]. The life-time of the catalyst can also be estimated by the number of times it can be recovered and reused. Lastly, the efficiency of a catalytic process is measured in turnover number (TON) and turnover frequency (TOF). In the following discussion, the catalytic properties discussed above will be used to determine the efficiency of the selected examples of most common palladium catalyzed heterogeneous catalytic systems for Heck and Suzuki cross-coupling reactions. The aim of the discussion is not to be exhaustive but rather to report on recent and noteworthy research progress aimed at developing heterogeneous palladium based catalytic systems.

2. “Naked” Palladium Nanoparticles as Pre-Catalysts Palladium nanoparticles have become one of the most interesting forms of heterogeneous catalysts because of their size- and shape-dependence, as well as their efficient catalytic activities in cross-coupling reactions [13,15]. The “naked” palladium nanoparticles are the simplest form of heterogeneous catalyst for C–C cross-coupling reactions. However, their use has been limited by the lack of efficient separation procedures; available separation techniques such as filtration and centrifugation are not very effective in achieving complete recovery of the nanoparticles. Additionally, nanoparticles are susceptible to oxidation, resulting in complicated work up procedures in the attempt to avoid deactivation. Furthermore, nanoparticles are also prone to agglomeration or sintering upon heating, leading to formation of insoluble non-catalytic palladium black [13]. Scheme1 shows that a palladium metal aggregate can serve as catalytically active palladium reservoir. In situ, the palladium Molecules 2018, 23, 1676 3 of 24 metalMolecules aggregates 2018, 23 produce, x FOR PEER kinetically REVIEW stable palladium nanoparticles that facilitate the heterogeneous3 of 23 catalytic cycle. However, single palladium atoms usually leach out from the surface of the palladium catalytic cycle. However, single palladium atoms usually leach out from the surface of the palladium nanoparticle and participate in the homogeneous catalytic cycle. nanoparticle and participate in the homogeneous catalytic cycle.

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catalytic cycle. However, single palladium atoms usually leach out from the surface of the palladium nanoparticle and participate in the homogeneous catalytic cycle.

Scheme 1. Possible reaction pathways operating in Pd nanoparticle catalysed Suzuki and Heck cross‐ Scheme 1. Possible reaction pathways operating in Pd nanoparticle catalysed Suzuki and Heck couplings [12] (Adapted with permission from American Chemical Society). cross-couplings [12] (Adapted with permission from American Chemical Society). Alternatively, supported palladium nanoparticles as catalyst for C–C cross‐coupling reactions Alternatively,are being developed. supported Most palladium often, palladium nanoparticles nanoparticle as catalyst become for less C–C catalytically cross-coupling active upon reactions are beingimmobilisation developed. on a solid Most support. often, palladiumTherefore, an nanoparticle improved catalytic become system less with catalytically desirable aspects active of upon immobilisationboth systemsScheme on (high a 1. solid Possible activity support. reaction and easy pathways Therefore, recovery) operating an is in improvedneeded. Pd nanoparticle It is catalytic envisaged catalysed system Suzuki that better and with Heck understanding desirable cross‐ aspects of of both systemsthe reactivity (highcouplings of activity palladium[12] (Adapted and nanoparticle easywith permission recovery) can from is leadAmerican needed. to the Chemical It design is envisaged Society). of more that efficient better heterogeneous understanding of the reactivitycatalyst for ofAlternatively, C–C palladium cross‐ couplingsupported nanoparticle reactions. palladium can nanoparticles lead to the designas catalyst of for more C–C efﬁcient cross‐coupling heterogeneous reactions catalyst for C–C cross-couplingare being developed. reactions. Most often, palladium nanoparticle become less catalytically active upon 3. Palladiumimmobilisation Nanoparticles on a solid support.on Carbonaceous Therefore, an Supports improved catalytic system with desirable aspects of 3. PalladiumPalladiumboth Nanoparticles systems supported (high activity onon Carbonaceouscarbonaceousand easy recovery) supports Supports is needed. has It been is envisaged widely thatapplied better in understanding C–C cross‐coupling of the reactivity of palladium nanoparticle can lead to the design of more efficient heterogeneous reactions (Scheme 2) [16–18]. Amongst these, palladium on activated carbon (Pd/C) is by far the most Palladiumcatalyst supported for C–C cross on‐coupling carbonaceous reactions. supports has been widely applied in C–C cross-coupling frequently used catalyst in heterogeneous Pd‐catalyzed coupling reactions. This is because of its reactions (Scheme2)[ 16–18]. Amongst these, palladium on activated carbon (Pd/C) is by far the efficiency3. Palladium and commercial Nanoparticles availability on Carbonaceous [16–18]. Supports It can be purchased in various quantities with a mostpalladium frequently content used catalystranging from in heterogeneous 1–20%. In addition, Pd-catalyzed charcoal couplingas a solid reactions.support ensures This isa higher because of its efﬁciency andPalladium commercial supported availability on carbonaceous [16 supports–18]. It has can been be widely purchased applied in in C–C various cross‐ quantitiescoupling with a surfacereactions area compared (Scheme 2) to[16–18]. the corresponding Amongst these, aluminapalladium and on activated silica supported carbon (Pd/C) catalysts is by far [18]. the Palladiummost palladiumon activatedfrequently content carbon used ranging catalystis reported from in heterogeneous 1–20%. to be stable In addition, Pdin ‐catalyzedair and charcoalwater, coupling acids asreactions. aand solid bases, This support isand because it ensuresoften of itsdoesn’t a higher surfacerequire areaefficiency reactions compared and to commercialbe to performed the corresponding availability under an [16–18]. inert alumina atmosphere It can andbe purchased silica [18,19]. supported Asin avarious result, catalystsquantities Pd/C catalyzed [with18]. a Palladium Heck on activatedand Suzukipalladium carbon cross content‐ iscoupling reported ranging reactions from to be 1–20%. stablehave Inbeen inaddition, air performed and charcoal water, under as acidsa solida variety and support bases, of reactionsensures and a ithigherconditions, often doesn’t requireincluding reactionssurface in areaorganic to be compared performed media to [20–23],the under corresponding aqueous an inert aluminamedia atmosphere [24–26], and silica [and18 supported,19 under]. As catalystsmicrowave a result, [18]. Pd/C conditionsPalladium catalyzed [27– Heck on activated carbon is reported to be stable in air and water, acids and bases, and it often doesn’t and Suzuki31]. Generally, cross-coupling the Pd/C catalyst reactions can convert have been a large performed variety of substrates under a variety with good of to reactions excellent conditions,yields, and itrequire is recoverable reactions toand be recyclableperformed underover manyan inert cycles atmosphere [16–18]. [18,19]. As a result, Pd/C catalyzed Heck includingand in organic Suzuki cross media‐coupling [20–23 reactions], aqueous have mediabeen performed [24–26 ],under and a under variety microwave of reactions conditions, conditions [27–31]. Generally,including the Pd/C in organic catalyst media can [20–23], convert aqueous a large media variety [24–26], of and substrates under microwave with good conditions to excellent [27– yields, and it is recoverable31]. Generally, and the Pd/C recyclable catalyst overcan convert many a large cycles variety [16– of18 substrates]. with good to excellent yields, and it is recoverable and recyclable over many cycles [16–18].

Scheme 2. Schematic illustration of palladium nanoparticles supported on carbonaceous material as efficient catalyst for C–C cross‐coupling reactions [32] (Adapted with permission from John Wiley Scheme 2. Schematic illustration of palladium nanoparticles supported on carbonaceous material as Schemeand 2.Sons).Schematic illustration of palladium nanoparticles supported on carbonaceous material as efficient catalyst for C–C cross‐coupling reactions [32] (Adapted with permission from John Wiley efficient catalystand Sons). for C–C cross-coupling reactions [32] (Adapted with permission from John Wiley and Sons).

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JadhavMolecules et 2018 al., 23 recently, x FOR PEER (2016) REVIEW developed a greener, cost effective and operationally convenient4 of 23 Pd/CMolecules based 2018 catalytic, 23, x FOR system PEER REVIEW for Suzuki and Heck cross-coupling reactions [33]. In their setup,4 of 23 the Jadhav et al. recently (2016) developed a greener, cost effective and operationally convenient Pd/C catalystPd/CJadhav based was et catalytic dispersedal. recently system in (2016) an for aqueous developedSuzuki and hydrotropic a Heck greener, cross mediumcost‐coupling effective (sodium reactions and operationally xylene [33]. In sulphonate their convenientsetup, solution)the that hadPd/CPd/C surfactant-like based catalyst catalytic was dispersed properties system for in an andSuzuki aqueous thus and stabilised hydrotropic Heck cross the medium‐coupling Pd/C (sodium catalyst reactions xylene (Figure [33]. sulphonate 1In). their The hydrotropismsetup, solution) the allowsPd/C forthat catalyst easyhad surfactant solubility was dispersed‐like of properties several in an aqueous types and thus ofhydrotropic stabilised organic functionalities themedium Pd/C catalyst(sodium in(Figure xylene water, 1). sulphonate The without hydrotropism solution) the need for toxicthat andallows had volatile surfactant for easy organic solubility‐like co-solvent. properties of several and In addition,types thus stabilisedof organic good the functionalities to Pd/C excellent catalyst yields in (Figure water, of the without1). The desired hydrotropism the productneed for were obtainedallowstoxic and forand the easy volatile catalytic solubility organic system of co several‐solvent. was types In recycled addition, of organic three good functionalities timesto excellent without yields in anywater, of the signiﬁcant desiredwithout product the loss need inwere activity.for Lastly,toxic theyobtained and reported volatile and the thatorganic catalytic the co palladium‐ solvent.system was In metal addition, recycled was goodthree “not totimes leached” excellent without out yields any into of significant the the productdesired loss product solution. in activity. were Hence, Lastly, they reported that the palladium metal was “not leached” out into the product solution. this systemobtained is and highly the desirablecatalytic system from economicalwas recycled as three well times as environmental without any significant points of loss view. in activity. Lastly,Hence, they this reported system is that highly the desirable palladium from metal economical was “not as wellleached” as environmental out into the points product of view. solution. Hence, this system is highly desirable from economical as well as environmental points of view.

Figure 1. Plausible mechanism of the C–C bond forming reactions in the presence of a hydrotrope Figure 1. Plausible mechanism of the C–C bond forming reactions in the presence of a hydrotrope (sodium (sodium xylene sulphonate solution) [33] (Adapted with permission from The Royal Society of Chemistry). xylene sulphonate solution) [33] (Adapted with permission from The Royal Society of Chemistry). Figure 1. Plausible mechanism of the C–C bond forming reactions in the presence of a hydrotrope (sodiumCarbon xylene nanotubes sulphonate (CNTs) solution) have [33] emerged (Adapted aswith highly permission efficient from supports The Royal forSociety palladium of Chemistry). and they Carbonhave been nanotubes extensively (CNTs) used have as alternatives emerged to as activated highly efﬁcient carbon supports supports [12,32,34,35]. for palladium The CNTs and they can have been extensivelybe Carbonevenly distributednanotubes used as alternatives (CNTs)in solution have due to emerged activatedto their as small highly carbon size, efficient supportsthus increasing supports [12,32 interactionfor,34 palladium,35]. The between CNTsand theythe can be evenlyhave distributedreactants been extensively and in the solution catalyst. used due as In alternatives to most their cases, small to theactivated size, activity thus carbon of increasing CNTs supports in interactionC–C [12,32,34,35]. cross‐coupling between The CNTsreactions the reactants can and thebe depends catalyst.evenly distributed on In their most preparation cases, in solution the method activity due [35].to oftheir In CNTs a recentsmall in review, C–Csize, thus cross-coupling by Labuloincreasing et al., interaction reactions a wide range dependsbetween of surface onthe their functionalization techniques for carbon nanotubes that improve their properties as catalyst supports preparationreactants method and the [35 catalyst.]. In a recent In most review, cases, by the Labulo activity et al.,of CNTs a wide in range C–C cross of surface‐coupling functionalization reactions was reported [34]. The resulting CNTs catalysts displayed superior catalytic performance and better techniquesdepends for on carbon their preparation nanotubes method that improve [35]. In a their recent properties review, by as Labulo catalyst et al., supports a wide range was of reported surface [34]. functionalizationrecyclability in C–Ctechniques cross‐coupling for carbon reactions. nanotubes Scheme that 3 improve shows the their graphical properties representation as catalyst of supports surface The resulting CNTs catalysts displayed superior catalytic performance and better recyclability in C–C wasfunctionalization reported [34]. The and resulting palladium CNTs nanoparticle catalysts loading displayed onto superior carbon nanotubes. catalytic performance and better cross-couplingrecyclability reactions. in C–C cross Scheme‐coupling3 shows reactions. the Scheme graphical 3 shows representation the graphical of representation surface functionalization of surface and palladiumfunctionalization nanoparticle and palladium loading nanoparticle onto carbon loading nanotubes. onto carbon nanotubes.

Scheme 3. Graphical representation of Pd nanoparticles supported on carbon nanotubes [34] (Adapted with permission from Springer Nature).

Scheme 3. Graphical representation of Pd nanoparticles supported on carbon nanotubes [34] Scheme(Adapted 3. Graphical with permission representation from Springer of Pd nanoparticles Nature). supported on carbon nanotubes [34] (Adapted with permission from Springer Nature).

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Molecules 2018, 23, x FOR PEER REVIEW 5 of 23 Lakshminarayana et al. [32] extended the study by investigating the inﬂuence of various Lakshminarayana et al. [32] extended the study by investigating the influence of various carbonaceous materials as supports in C–C cross-coupling reactions. They prepared and studied carbonaceous materials as supports in C–C cross‐coupling reactions. They prepared and studied palladium oxide (PdO) nanoparticles impregnated on nanocarbon supports, such as single walled palladium oxide (PdO) nanoparticles impregnated on nanocarbon supports, such as single walled carbon nanotubes (SWCNT), multiwalled carbon nanotubes (MWCNT), carbon nanoﬁber (CNF), carbon nanotubes (SWCNT), multiwalled carbon nanotubes (MWCNT), carbon nanofiber (CNF), graphene oxide (GO), and reduced graphene oxide (RGO) [32]. The prepared catalysts were graphene oxide (GO), and reduced graphene oxide (RGO) [32]. The prepared catalysts were characterized fully and then explored in Heck cross-coupling reactions to assess their catalytic characterized fully and then explored in Heck cross‐coupling reactions to assess their catalytic activity. Graphene oxide (GO) was found to be the best support for PdO (Table2). The enhanced activity. Graphene oxide (GO) was found to be the best support for PdO (Table 2). The enhanced catalytic activity of PdO/GO was believed to be due to the combined effect of a high degree of catalytic activity of PdO/GO was believed to be due to the combined effect of a high degree of surface‐ surface-bound oxygenated moieties, high surface area, electron conductivity and the mesoporous bound oxygenated moieties, high surface area, electron conductivity and the mesoporous nature of nature of graphene oxide. graphene oxide. Table 2. Performance of PdO supported carbon materials in the Heck coupling reaction [32] (Adapted Table 2. Performance of PdO supported carbon materials on Heck coupling reaction [32] (Adapted with permission from John Wiley and Sons). with permission from John Wiley and Sons).

a b −1 CatalystCatalysta Reaction TimeReaction (min) Time (min)Yield (%) b Yield (%) TOFTOF (h−1) (h ) PdO/SWCNT 20 72 939 PdO/SWCNT 20 72 939 PdO/MWCNTPdO/MWCNT 1515 6363 10801080 PdO/CNFPdO/CNF 4040 3838 274 274 PdO/GOPdO/GO 55 8080 41444144 PdO/RGOPdO/RGO 9090 6868 194 194 a a ReactionReaction Conditions: Conditions: Iodobenzene Iodobenzene (0.25 (0.25 mmol), mmol), ethyl ethyl acrylate acrylate (0.5 mmol), (0.5 mmol), PdO/support PdO/support (10 mol (10 %), mol K2CO %),3 (0.5 mmol), DMSO (dimethylsuloxide) (1 mL) at 150 ◦C. b GC yields. K2CO3 (0.5 mmol), DMSO (dimethylsuloxide) (1 mL) at 150 °C. b GC yields.

4. Palladium Nanoparticles on Metal Oxide Supports 4. Palladium Nanoparticles on Metal Oxide Supports AA significantsignificant numbernumber ofof researchersresearchers havehave devoteddevoted themselvesthemselves toto findingfinding aa newnew andand aa moremore efficient Pd/MxOy based heterogeneous catalyst for C–C cross-coupling reactions [36,37]. In this efficient Pd/MxOy based heterogeneous catalyst for C–C cross‐coupling reactions [36,37]. In this direction,direction, KöhlerKöhler andand co-workersco‐workers preparedprepared andand comparativelycomparatively studiedstudied thethe catalyticcatalytic activityactivity ofof Pd/Al2O3, Pd/TiO2, Pd/NaY, and Pd/CeO2 [38]. The catalysts were able to efficiently catalyse Pd/Al2O3, Pd/TiO2, Pd/NaY, and Pd/CeO2 [38]. The catalysts were able to efficiently catalyse Suzuki −1 Suzuki cross-coupling reactions and the obtained TOFs for each catalyst were: Pd/Al2O3 = 9600 h , cross‐coupling reactions and the obtained TOFs for each catalyst were: Pd/Al2O3 = 9600 h−1, Pd/TiO2 −1 −1 Pd/TiO2 = 9700 h , Pd/NaY = 4100, and Pd/CeO2 = 4100 h . The Pd/Al2O3 and Pd/TiO2 catalysts = 9700 h−1, Pd/NaY = 4100, and Pd/CeO2 = 4100 h−1. The Pd/Al2O3 and Pd/TiO2 catalysts showed very showed very similar and high catalytic activities, while the activities of Pd/NaY and Pd/CeO2 were similar and high catalytic activities, while the activities of Pd/NaY and Pd/CeO2 were much lower. much lower. The TOF values of Pd/NaY and Pd/CeO2 catalysts are almost half of those obtained The TOF values of Pd/NaY and Pd/CeO2 catalysts are almost half of those obtained with Pd/Al2O3 with Pd/Al2O3 and Pd/TiO2. These results clearly suggest that the nature of the support has a great and Pd/TiO2. These results clearly suggest that the nature of the support has a great influence on the influenceactivity of on the the catalyst. activity of the catalyst. InIn addition, addition, Köhler Köhler et al.et statedal. stated that thethat Pd the concentration Pd concentration in solution in solution during the during reaction the correlated reaction clearlycorrelated with clearly the progress with the of progress the reaction of the (Figure reaction2). Thus,(Figure this 2). clearly Thus, this suggests clearly that suggests the dissolved that the moleculardissolved palladiummolecular palladium represents represents the “true” catalyticallythe “true” catalytically active species, active and species, the prepared and the Pd/M preparedxOy solids are simply precursors to the “true catalyst”. Furthermore, they found that the dissolved “Pd is Pd/MxOy solids are simply precursors to the “true catalyst”. Furthermore, they found that the depositeddissolved back”“Pd is onto deposited the support back” at onto the endthe support of the reaction. at the end This of phenomenon the reaction. is This commonly phenomenon referred is tocommonly as the palladium referred “release-captureto as the palladium or dissolution-redeposition”“release‐capture or dissolution mechanism‐redeposition” [39]. mechanism [39].

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% Leaching % Conversion Temperature 90 120 80 100 70 C 

60 80 /

% 60 40 30 40 Tem p eratu re 20 20 10 0 0 Molecules 2018, 23, x FOR PEER REVIEW 6 of 23 0 1020354050608090100120140200 Reaction Time (min) % Leaching % Conversion Temperature Figure90 2. Time‐dependent correlation of palladium leaching with the progress of the reaction 120[38] Figure 2. Time-dependent correlation of palladium leaching with the progress of the reaction [38] (Adapted with permission from John Wiley and Sons). (Adapted80 with permission from John Wiley and Sons). 100 70

In 2013, Amoroso et al. [10] extended the study of Köhler and co-workers [38] to examineC the 

60 80 / catalytic activity of Pd/MxOy type catalysts in more detail. More speciﬁcally, they wanted to investigate the inﬂuence50 of the “point of zero charge” on the catalytic activity of the Pd/MxOy type catalysts. The point% of zero charge (PZC) is commonly used in surface science to determine the ability60 of a given 40 solid material to adsorb ions. This concept describes the condition when the electrical charge density 30 40

on a surface of a solid is zero [40]. Generally, the PZC is represented as the pH value at which a solidTem p eratu re submerged20 in an electrolyte exhibits zero net electrical charge on the surface [40,41]. A given metal oxide (MxOy) surface will have a “positive charge” at solution pH values less than the PZC20 value and thus be a10 surface on which anions may adsorb. On the other hand, the metal oxide surface will have 2+ a negativeFigure0 charge 3. Representation at solution of pH adhesion values and greater release thanof Pd the from PZC CeO value2 and La and2O3 surfaces thus be under a surface catalytic0 on which cationsconditions may adsorb0 (pH [ 1020354050608090100120140200~40 10.5),41]. [40] The (Adapted later statement with permission is more from relevant The Royal to the Society current of Chemistry). discussion since the pH of the reaction mixture in most cross-coupling reactions is around 10, thus it is above the PZC values of In 2013, Amoroso et al. [10] extendedReaction the studyTime of(min) Köhler and co‐workers [38] to examine the the investigated metal oxide supports (Figure3). This allows one to investigate the degree of adhesion catalytic activity of Pd/MxOy type catalysts in more detail. More specifically, they wanted to of palladiumFigure onto2. Time the‐dependent support, correlation which in turnof palladium speaks toleaching the observed with the catalyticprogress of activity the reaction and the [38] degree investigate the influence of the “point of zero charge” on the catalytic activity of the Pd/MxOy type ofcatalysts. palladium(Adapted The leaching. point with permissionof zero charge from (PZC) John Wiley is commonly and Sons). used in surface science to determine the ability of a given solid material to adsorb ions. This concept describes the condition when the electrical charge density on a surface of a solid is zero [41]. Generally, the PZC is represented as the pH value at which a solid submerged in an electrolyte exhibits zero net electrical charge on the surface [41,42]. A given metal oxide (MxOy) surface will have a “positive charge” at solution pH values less than the PZC value and thus be a surface on which anions may adsorb. On the other hand, the metal oxide surface will have a negative charge at solution pH values greater than the PZC value and thus be a surface on which cations may adsorb [41,42]. The later statement is more relevant to the current discussion since the pH of the reaction mixture in most cross‐coupling reactions is around 10, thus it is above the PZC values of the investigated metal oxide supports (Figure 3). This allows one to investigate the degree of adhesion of palladium onto the support, which in turn speaks to the

observed catalytic activity and the degree of palladium leaching. Figure 3. Representation of adhesion and release of Pd2+ from CeO2 and La2O3 surfaces under catalytic Hence, Amoroso et al. [10] used the PZC values2+ of each support to investigate the role it plays Figure 3. Representation of adhesion and release of Pd from CeO2 and La2O3 surfaces under catalytic in theconditions adhesion (pHof the ~ 10.5) palladium [40] (Adapted nanoparticle with permission onto the from surface The Royalof the Society support of Chemistry).(Figure 3). Thus, they conditions (pH ~10.5) [42] (Adapted with permission from The Royal Society of Chemistry). In 2013, Amoroso et al. [10] extended the study of Köhler and co‐workers [38] to examine the catalytic activity of Pd/MxOy type catalysts in more detail. More specifically, they wanted to investigate the influence of the “point of zero charge” on the catalytic activity of the Pd/MxOy type catalysts. The point of zero charge (PZC) is commonly used in surface science to determine the ability of a given solid material to adsorb ions. This concept describes the condition when the electrical charge density on a surface of a solid is zero [41]. Generally, the PZC is represented as the pH value at which a solid submerged in an electrolyte exhibits zero net electrical charge on the surface [41,42]. A given metal oxide (MxOy) surface will have a “positive charge” at solution pH values less than the PZC value and thus be a surface on which anions may adsorb. On the other hand, the metal oxide surface will have a negative charge at solution pH values greater than the PZC value and thus be a surface on which cations may adsorb [41,42]. The later statement is more relevant to the current discussion since the pH of the reaction mixture in most cross‐coupling reactions is around 10, thus it is above the PZC values of the investigated metal oxide supports (Figure 3). This allows one to investigate the degree of adhesion of palladium onto the support, which in turn speaks to the observed catalytic activity and the degree of palladium leaching. Hence, Amoroso et al. [10] used the PZC values of each support to investigate the role it plays in the adhesion of the palladium nanoparticle onto the surface of the support (Figure 3). Thus, they

Molecules 2018, 23, 1676 7 of 24

Hence, Amoroso et al. [10] used the PZC values of each support to investigate the role it plays inMolecules the adhesion 2018, 23, x ofFOR the PEER palladium REVIEW nanoparticle onto the surface of the support (Figure3). Thus,7 they of 23 prepared and investigated the catalytic activity of Pd/La2O3, Pd/Pr6O11, Pd/Gd2O3, Pd/Sm2O3, prepared and investigated the catalytic activity of Pd/La2O3, Pd/Pr6O11, Pd/Gd2O3, Pd/Sm2O3, and and Pd/CeO2 catalysts. The physicochemical properties of these materials are tabulated in Table3. ThePd/CeO study2 catalysts. revealed The that physicochemical under basic reaction properties conditions of these (pH ~10.5),materials the are surfaces tabulated of metal in Table oxides 3. with The highstudy PZC revealed values that are under less negatively basic reaction charged conditions than the (pH surfaces ~ 10.5), ofthe metal surfaces oxides of metal with oxides low PZC with values. high PZC values are less negatively charged than the surfaces of metal oxides with low PZC values. Thus, Thus, the La2O3 support has the lowest density of negatively charged sites on the surface since it has the La2O3 support has the lowest density of negatively charged sites on the surface since it has the the highest PZC value. Hence, the higher reactivity of Pd/La2O3 is correlated to a marked degree highest2+ PZC value. Hence, the higher reactivity of Pd/La2O3 is correlated to a marked degree of Pd2+ of Pd leaching from the surface of La2O3, favoured by its less negatively charged surface. On the leaching from the surface of La2O3, favoured by its less negatively charged surface. On the contrary, contrary, the lowest activity observed with Pd/CeO2 is correlated to the higher degree of negatively chargedthe lowest surface activity that observed helps in with keeping Pd/CeO Pd2+2ions is correlated anchored to onto the the higher support degree (Figure of negatively3). charged surface that helps in keeping Pd2+ ions anchored onto the support (Figure 3).

Table 3. The physicochemical properties of the synthesised Pd/MxOy based catalysts and their catalytic activityTable 3. results The physicochemical [10] (Adapted with properties permission of fromthe synthesised Springer Nature). Pd/MxOy based catalysts and their catalytic activity results [10] (Adapted with permission from Springer Nature).

Compound Pd Loading Surface Area Pore Volume PZC Time TOF Compound Pd Loading Surface Pore Volume PZC −1 xa y a 2 2 3 3 Time (min) TOF (h −1 ) (Pd/M(Pd/MxOy) O ) (wt %) (wt %)Area (m /g) (m /g) (cm /g) (cm /g)(pH) (pH) (min) (h ) Pd/La2O3 1.76 16.6 0.24 8.8 13 9130 Pd/La2O3 1.76 16.6 0.24 8.8 13 9130 Pd/CeOPd/CeO2 2 1.931.93 31.531.5 0.180.18 6.76.7 260 260 450450 Pd/PrPd/Pr6O116O11 1.931.93 22.422.4 0.360.36 7.87.8 1717 69806980 Pd/Sm O 1.84 11.9 0.21 7.4 21 5650 Pd/Sm2 3 2O3 1.84 11.9 0.21 7.4 21 5650 Pd/Gd2O3 1.99 10.2 0.09 7.5 20 5940 Pd/Gd2O3 1.99 10.2 0.09 7.5 20 5940 a Reaction conditions: 1-bromo-4-nitrobenzene (0.5 mmol), 4-methylphenylboronic acid (0.6 mmol), K CO a 2 3 (0.6 Reaction mmol), catalyst,conditions: 1.5 mL 1‐bromo ethanol,‐4 0.5‐nitrobenzene mL water, temperature (0.5 mmol), = 25 4◦‐C.methylphenylboronic acid (0.6 mmol), K2CO3 (0.6 mmol), catalyst, 1.5 mL ethanol, 0.5 mL water, temperature = 25 °C. Figure4 further shows that there is a linear correlation between the yield of the coupling product Figure 4 further+ shows−PZC that there is a linear correlation between the yield of the coupling product and the PZC ([H3O ] = 10 ) value of the metal oxide support. Thus, the observed reactivity trend and the PZC ([H3O+] = 10−PZC) value of the metal oxide support. Thus, the observed reactivity trend over the MxOy support is related to the tendency of each Pd/MxOy system to deliver different amounts over the MxOy support is related to the tendency of each Pd/MxOy system to deliver different amounts of palladium into the solution. In summary, the above discussion shows that there is a close relation of palladium into the solution. In summary, the above discussion shows that there is a close relation between the “surface charge” (correlated to the PZC value) and the extent of palladium leaching at the between the “surface charge” (correlated to the PZC value) and the extent of palladium leaching at pH of catalysis (determined by reaction conditions). Thus, the more positively charged is the surface the pH of catalysis (determined by reaction conditions). Thus, the more positively charged is the (this is the case of Pd/La2O3), the more consistently Pd leaches, and therefore, a higher reaction rate surface (this is the case of Pd/La2O3), the more consistently Pd leaches, and therefore, a higher reaction is observed. In addition, a much slower reaction is observed when Pd/CeO2 is used as the catalyst, rate is observed. In addition, a much slower reaction is observed when Pd/CeO2 is used as the catalyst, which shows the lowest PZC value within the series of Pd/MxOy. Consequently, prolonged recycling which shows the lowest PZC value within the series of Pd/MxOy. Consequently, prolonged recycling is possible in the case of Pd/CeO2 due to minimal palladium leaching. Thus, from the studied series is possible in the case of Pd/CeO2 due to minimal palladium leaching. Thus, from the studied series of Pd/MxOy type catalysts, Pd/CeO2 was chosen as superior precatalyst based on the following of Pd/MxOy type catalysts, Pd/CeO2 was chosen as superior precatalyst based on the following considerations: (i) it can be recycled several times without a signiﬁcant decrease of activity (prolonged considerations: (i) it can be recycled several times without a significant decrease of activity recyclability) and (ii) the organic product is sparsely contaminated since there is minimal leaching of (prolonged recyclability) and (ii) the organic product is sparsely contaminated since there is minimal palladium into the solution. leaching of palladium into the solution. Molecules 2018, 23, 1676 8 of 24 Molecules 2018, 23, x FOR PEER REVIEW 8 of 23

80 Pd/La O 70 2 3

Pd/Pr6O11 60 Pd/Sm2O3 % Pd/Gd2O3

50 Yield 40

30 Product 20

10 Pd/CeO2 0 0 50 100 150 200 250 + H3O (nM)

Figure 4. Cross‐coupling reaction yield (after 2 min of reaction) vs. proton molar concentration (10−PZC) Figure 4. Cross-coupling reaction yield (after 2 min of reaction) vs. proton molar concentration (10−PZC) for Pd/MxOy [10] (Adapted with permission from Springer Nature). for Pd/MxOy [10] (Adapted with permission from Springer Nature).

Alternatively, the physicochemical properties of the support can be enhanced through substitution of a foreign metal ion in its lattice structure [43]. The substitution of foreign metal ions into the lattice of reducible oxides such as CeO2 and TiO2 to form ionic solid-solution oxides (Ce1-xMxO2-δ or Ti1-xMxO2-δ) has given materials which show high activity for a variety of catalytic reactions, especially in gas-phase oxidation reactions [11,43–48]. However, such catalysts have rarely been applied to C–C cross-coupling reactions [49–51]. Recently, Burange and co-workers [44] reported that the ionic ceria-zirconia (CeZrO4-δ) solid-solution oxides exhibit high redox properties and thermal stability that make them better catalyst supports than the pure metal oxide counterparts [52]. Hence, CeZrO4-δ solid-solution oxide was used to immobilise palladium nanoparticles and the resultant catalyst (Pd/CeZrO4-δ) was explored in Suzuki cross-coupling reactions (Figure5). The mechanistic 4+ 3+ investigation proved that the redox couple (Ce /Ce ) in the CeZrO4-δ support enhances the catalytic activity through creation of oxygen vacancies. Furthermore, the support displayed strong metal-support (Pd-CeZrO4-δ) interactions and hence, “no leaching” was observed. Thus, it was concluded that the reactions were “truly” heterogeneous [52]. Lichtenegger and co-workers [53] extended the Burange et al. [52] study by directly incorporating palladium ions into the lattice of the support (ceria), instead of modifying the properties of the support with a foreign metal. In their study, they used CeO2 and SnO2 as supports and prepared a series of corresponding ionic solid-solution oxides: Ce Pd O , Ce Sn Pd O , 0.99 0.01 2-δ 0.79 0.2 0.01 2- δ Ce0.495Sn0.495Pd0.01O2-δ, Ce0.20Sn0.79Pd0.01O2-δ, and Sn0.99Pd0.01O2-δ. These catalysts were thoroughly Figure 5. Plausible heterogeneous catalytic reaction mechanism suggested for Suzuki cross‐coupling explored in Suzuki coupling reactions of phenylboric acid with various bromoarenes (Figure6). over the Pd/CeZrO4‐δ redox catalyst [43] (Adapted with permission from John Wiley and Sons). The Ce0.79Sn0.2Pd0.01O2-δ, Ce0.20Sn0.79Pd0.01O2-δ, and Sn0.99Pd0.01O2-δ catalysts showed extraordinarily high activitiesAlternatively, in Suzuki the cross-coupling physicochemical reactions, properties while theof binarythe support solid-solution can be oxideenhanced Ce0.99 throughPd0.01O2- δ provedsubstitution to be the of leasta foreign active metal catalyst. ion in Thus, its lattice the Sn structure containing [44]. catalystsThe substitution were shown of foreign to be metal more ions active; however,into the the lattice results of reducible do not show oxides a clear such correlation as CeO2 and between TiO2 Snto loadingsform ionic and solid the‐solution catalytic oxides activity. Furthermore,(Ce1‐xMxO2‐δ completeor Ti1‐xMx conversionO2‐δ) has given was materials achieved which in ﬁve show subsequent high activity reactions for fora variety all catalysts, of catalytic except whenreactions, Ce0.99 Pdespecially0.01O2-δ inand gas Ce‐phase0.495Sn oxidation0.495Pd0.01 reactionsO2-δ were [11,44–49]. used. However, such catalysts have rarely been applied to C–C cross‐coupling reactions [50–52]. Recently, Burange and co‐workers [45] reported that the ionic ceria‐zirconia (CeZrO4‐δ) solid‐solution oxides exhibit high redox properties

Molecules 2018, 23, x FOR PEER REVIEW 8 of 23

80 Pd/La O 70 2 3

Pd/Pr6O11 60 Pd/Sm2O3 % Pd/Gd2O3

50 Yield 40

30 Product 20

10 Pd/CeO2 0 0 50 100 150 200 250 + H3O (nM)

Molecules 2018, 23, 1676 9 of 24 Figure 4. Cross‐coupling reaction yield (after 2 min of reaction) vs. proton molar concentration (10−PZC)

for Pd/MxOy [10] (Adapted with permission from Springer Nature).

Molecules 2018, 23, x FOR PEER REVIEW 9 of 23

and thermal stability that make them better catalyst supports than the pure metal oxide counterparts [43]. Hence, CeZrO4‐δ solid‐solution oxide was used to immobilise palladium nanoparticles and the resultant catalyst (Pd/CeZrO4‐δ) was explored in Suzuki cross‐coupling reactions (Figure 5). The mechanistic investigation proved that the redox couple (Ce4+/Ce3+) in the CeZrO4‐δ support enhances the catalytic activity through creation of oxygen vacancies. Furthermore, the support displayed strong metal‐support (Pd‐CeZrO4‐δ) interactions and hence, “no leaching” was observed. Thus, it was concluded that the reactions were “truly” heterogeneous [43]. Lichtenegger and co‐workers [53] extended the Burange et al. [43] study by directly incorporating palladium ions into the lattice of the support (ceria), instead of modifying the properties of the support with a foreign metal. In their study, they used CeO2 and SnO2 as supports and prepared a series of corresponding ionic solid‐solution oxides: Ce0.99Pd0.01O2‐δ, Ce0.79Sn0.2Pd0.01O2‐δ, Ce0.495Sn0.495Pd0.01O2‐δ, Ce0.20Sn0.79Pd0.01O2‐δ, and Sn0.99Pd0.01O2‐δ. These catalysts were thoroughly explored in Suzuki coupling reactions of phenylboric acid with various bromoarenes (Figure 6). The Ce0.79Sn0.2Pd0.01O2‐δ, Ce0.20Sn0.79Pd0.01O2‐δ, and Sn0.99Pd0.01O2‐δ catalysts showed extraordinarily high activities in Suzuki cross‐coupling reactions, while the binary solid‐solution oxide Ce0.99Pd0.01O2‐δ proved to be the least active catalyst. Thus, the Sn containing catalysts were shown to be more active; however, the results do not show a clear correlation between Sn loadings and the catalytic activity. FigureFigure 5. Plausible 5. Plausible heterogeneous heterogeneous catalytic catalytic reaction mechanism mechanism suggested suggested for forSuzuki Suzuki cross cross-coupling‐coupling Furthermore,over the completePd/CeZrO4 ‐δconversion redox catalyst was [43] achieved (Adapted in with five permission subsequent from reactions John Wiley for and all Sons). catalysts, except over the Pd/CeZrO4-δ redox catalyst [52] (Adapted with permission from John Wiley and Sons). when Ce0.99Pd0.01O2‐δ and Ce0.495Sn0.495Pd0.01O2‐δ were used. Alternatively, the physicochemical properties of the support can be enhanced through substitution of a foreign metal ion in its lattice structure [44]. The substitution of foreign metal ions 1st Run 2nd Run 3rd Run 4th Run 5th Run into the lattice of reducible oxides such as CeO2 and TiO2 to form ionic solid‐solution oxides (Ce1100‐xMxO2‐δ or Ti1‐xMxO2‐δ) has given materials which show high activity for a variety of catalytic reactions, especially in gas‐phase oxidation reactions [11,44–49]. However, such catalysts have rarely 90 been applied to C–C cross‐coupling reactions [50–52]. Recently, Burange and co‐workers [45] reported80 that the ionic ceria‐zirconia (CeZrO4‐δ) solid‐solution oxides exhibit high redox properties 70 %

/ 60 50 40 Conversion 30 20 10 0 Catalyst 1Catalyst 2 Catalyst 3Catalyst 4 Catalyst 5

Figure 6. The Suzuki coupling of 4‐bromotoluene with phenylboronic acid (after 30 min) using 0.5 Figure 6. The Suzuki coupling of 4-bromotoluene with phenylboronic acid (after 30 min) mol % Pd. Catalyst 1: Ce0.99Pd0.01O2‐δ, Catalyst 2: Ce0.79Sn0.2Pd0.01O2‐δ, Catalyst 3: Ce0.495Sn0.495Pd0.01O2‐δ, using 0.5 mol % Pd. Catalyst 1: Ce0.99Pd0.01O2-δ, Catalyst 2: Ce0.79Sn0.2Pd0.01O2-δ, Catalyst 3: Catalyst 4: Ce0.20Sn0.79Pd0.01O2‐δ, and Catalyst 5: Sn0.99Pd0.01O2‐δ [53] (Adapted with permission from CeElsevier).0.495Sn0.495 Pd0.01O2-δ, Catalyst 4: Ce0.20Sn0.79Pd0.01O2-δ, and Catalyst 5: Sn0.99Pd0.01O2-δ [53] (Adapted with permission from Elsevier). Thorough catalyst leaching, recovery and recyclability studies were conducted and the results demonstrateThorough a catalyst clear correlation leaching, recoverybetween andreactivity recyclability and amount studies of wereleached conducted palladium and (Figure the results 7). demonstrateHence, these a clear findings correlation also support between the reactivity hypothesis and that amount the coupling of leached reaction palladium is catalyzed (Figure by7). small Hence, theseamounts ﬁndings of leached also support palladium the hypothesis via a homogeneous that the coupling reaction mechanism. reaction is catalyzed by small amounts of leached palladium via a homogeneous reaction mechanism.

Molecules 2018, 23, 1676 10 of 24 Molecules 2018, 23, x FOR PEER REVIEW 10 of 23 Molecules 2018, 23, x FOR PEER REVIEW 10 of 23

Figure 7. Turnover frequency (TOF) vs. Pd‐concentration in the solution (Pd leached). Catalyst 1: Figure 7. Turnover frequency (TOF) vs. Pd-concentration in the solution (Pd leached). Catalyst 1: FigureCe 7.0.99 PdTurnover0.01O2‐δ, Catalystfrequency 2: (TOF)Ce0.79 Snvs.0.2 PdPd0.01‐concentrationO2‐δ, Catalyst in3: theCe solution0.495Sn0.495Pd (Pd0.01 Oleached).2‐δ, Catalyst Catalyst 4: 1: Ce0.99CePd0.200.01Sn0.79O2-Pdδ,0.01CatalystO2‐δ, and Catalyst 2: Ce0.79 5:Sn Sn0.20.99PdPd0.010.01OO2‐δ2- δ[53], Catalyst (Adapted 3: withCe 0.495permissionSn0.495 Pdfrom0.01 Elsevier).O2-δ, Catalyst 4: Ce0.99Pd0.01O2‐δ, Catalyst 2: Ce0.79Sn0.2Pd0.01O2‐δ, Catalyst 3: Ce0.495Sn0.495Pd0.01O2‐δ, Catalyst 4: Ce0.20Sn0.79Pd0.01O2-δ, and Catalyst 5: Sn0.99Pd0.01O2-δ [53] (Adapted with permission from Elsevier). Ce0.20Sn0.79Pd0.01O2‐δ, and Catalyst 5: Sn0.99Pd0.01O2‐δ [53] (Adapted with permission from Elsevier). To further explore this concept of “release‐capture mechanism” by ionic solid‐solution oxides Tocatalysts, further we explore have reported this concept on the application of “release-capture of a highly Pd mechanism” substituted ceria by ionic catalyst solid-solution (Pd0.09Ce0.91O2‐δ oxides) Toin the further Heck crossexplore‐coupling this concept reaction of[50]. “release Good to‐capture excellent mechanism” yields of substituted by ionic olefins solid were‐solution obtained oxides catalysts, we have reported on the application of a highly Pd substituted ceria catalyst (Pd0.090.09Ce0.910.91O2-2‐δδ) catalysts,with wethis have Pd0.09 Cereported0.91O2‐δ solid on the‐solution application catalyst. of However, a highly ourPd findingssubstituted also ceriarevealed catalyst that the (Pd catalysisCe O ) in the Heck cross-coupling reaction [49]. Good to excellent yields of substituted olefins were obtained in theoccurs Heck overcross the‐coupling reduced reactiontwo phase [50]. Pd0 Good/CeO2 andto excellent not on the yields as prepared of substituted monophasic olefins Pd0.09 wereCe0.91 obtainedO2‐δ with this(Scheme Pd0.090.09 4).CeCe In0.910.91 addition,OO2‐δ2- solidδ solid-solution it ‐wassolution observed catalyst. catalyst. that the However, However,Pd0/CeO2 ourformed our findings findings in situ also can also berevealed revealed easily recovered that that the the catalysisand catalysis 0 occursreused over theforthe several reducedreduced times two two without phase phase Pd anyPd/CeO0 /CeOsignificant22 andand notlossnot on inon efficiency the the as as prepared prepared and only monophasic monophasic a negligible Pd amountPd0.090.09CeCe 0.91of0.91 OO2-2‐δδ 0 (Schemepalladium 44).). In addition, addition,was detected it it was wasin the observed observed product solutionthat that the the (0.35Pd Pd0/CeO ppm)./CeO2 formedThe2 formed low inlevel situ in of situcan palladium canbe easily be concentration easily recovered recovered and reusedand reusedin thefor productseveral for several solutiontimes times without further without highlights any any significant significant the excellent loss loss abilityin inefficiency efficiency of ceria andto and re ‐onlyadsorb only a a leachednegligible negligible palladium amount amount of species, as discussed earlier. palladium was detected in the product solution (0.35 ppm). The The low low level level of of palladium palladium concentration concentration inin the the product product solution solution further further highlights the the excellent ability of ceria ceria to to re re-adsorb‐adsorb leached leached palladium palladium species, as discussed earlier.

Scheme 4. Proposed Heck coupling reaction mechanism catalysed by the Pd0.09Ce0.91O2‐δ precatalyst [50] (Adapted with permission from Elsevier).

We were also able to show that the reaction conditions greatly affect the catalysis. In this regard, we investigated the application of a Pd0.04Cu0.04Ce0.92O2‐δ (PdCuCeO) solid‐solution oxide on Suzuki Scheme 4. 4. ProposedProposed Heck Heck coupling coupling reaction reaction mechanism mechanism catalysed catalysed by the Pd by0.09 theCe0.91 PdO20.09‐δ precatalystCe0.91O2-δ cross‐coupling reactions (Scheme 5) [51]. The reactions were carried‐out under milder and more [50]precatalyst (Adapted [49 with] (Adapted permission with permissionfrom Elsevier). from Elsevier). environmentally friendly reaction conditions, using water as sole solvent and tetrapropylammonium bromide (TPAB) as a phase transfer catalyst. The catalytic results displayed good functional group We were also able to show that the reaction reaction conditions conditions greatly greatly affect affect the the catalysis. catalysis. In In this this regard, regard, we investigated thethe applicationapplication of of a a Pd Pd0.040.04CuCu0.040.04Ce0.92OO2‐δ2- δ(PdCuCeO)(PdCuCeO) solid solid-solution‐solution oxide oxide on on Suzuki Suzuki crosscross-coupling‐coupling reactions reactions (Scheme 55))[ [51].50]. The The reactions reactions were were carried carried-out‐out under under milder milder and more environmentally friendly reaction conditions, using water as sole sole solvent solvent and and tetrapropylammonium tetrapropylammonium bromide (TPAB) as a phase transfer catalyst. The catalytic results displayed good functional group

Molecules 2018, 23, 1676 11 of 24

Molecules 2018, 23, x FOR PEER REVIEW 11 of 23 bromide (TPAB) as a phase transfer catalyst. The catalytic results displayed good functional group tolerancetolerance and good to excellent yields of substitutedsubstituted biphenyls were obtained.obtained. However, catalyst leachingleaching and recyclability recyclability studies revealed that PdCuCeO acts as a Pd Pd reservoir reservoir and and that that the the reactions reactions were essentially essentially quasi quasi-heterogeneous,‐heterogeneous, occurring occurring over over recoverable recoverable Pd/TPAB Pd/TPAB aggregates aggregates (generated (generated in situ).in situ). The The PdCuCeO PdCuCeO solid solid-solution‐solution catalyst catalyst was was recovered recovered and and recycled recycled three three times; times; however, however, its catalyticits catalytic activityMolecules activity 2018 declined, 23 declined, x FOR with PEER with REVIEWeach each subsequent subsequent recycle. recycle. 11 of 23

tolerance and good to excellent yields of substituted biphenyls were obtained. However,Ar1X catalyst leaching and recyclability studies revealed that PdCuCeO acts as a Pd reservoir and that the reactions were essentially quasi‐heterogeneous, occurring over recoverable Pd/TPAB aggregates (generated in Assitu). prepared The Pd PdCuCeO0.04Cu0.04Ce 0.92solidO2-‐δsolution pre-catalyst catalyst was recovered and recycled three times; however, its catalytic activity declined with each subsequent recycle.Reaction conditions X O O O O induced Pd/Cu dissolution 0 Pd /TPAB 2+ 1 Pd Ce3+ Pd2+ C e4+ C u2+ Ce4+ Ar X Ar1 Pd/Cu reservoir As prepared Pd0.04Cu0.04Ce0.92O2-δ pre-catalyst Reaction conditions O O O O X induced Pd/Cu dissolution Ar1Ar2 Ar2B(OH) Pd0/TPAB 2 Pd2+ Ce3+ Pd2+ C e4+ C u2+ Ce4+ Scheme 5. A proposed reaction mechanism for the Pd0.04Cu0.04Ce0.92O2‐δ (PdCuCeO)Ar1 ‐ Scheme 5. A proposedPd/Cu reservoir reaction mechanism for the Pd0.04Cu0.04Ce0.92O2-δ (PdCuCeO)- tetrapropylammonium bromide (TPAB) catalysed quasi‐heterogeneous SM (Suzuki‐Miyaura) cross‐ tetrapropylammonium bromide (TPAB) catalysed quasi-heterogeneous SM (Suzuki-Miyaura) coupling reactions [51]. 1 2 2 cross-coupling reactions [50]. Ar Ar Ar B(OH)2

Scheme 5. A proposed reaction mechanism for the Pd0.04Cu0.04Ce0.92O2‐δ (PdCuCeO)‐ Hence, it can be concluded that most of the reported ionic solid‐solution oxides catalysts are Hence, ittetrapropylammonium can be concluded bromide that most(TPAB) of catalysed the reported quasi‐heterogeneous ionic solid-solution SM (Suzuki‐Miyaura) oxides cross catalysts‐ are simply precatalysts that act as a palladium reservoir for the active palladium species. Therefore, the simply precatalystscoupling reactions that act [51]. as a palladium reservoir for the active palladium species. Therefore, observed high activity and recyclability of the catalysts could be attributed to a Pd release‐capture the observed high activity and recyclability of the catalysts could be attributed to a Pd release-capture mechanism, asHence, discussed it can beearlier. concluded that most of the reported ionic solid‐solution oxides catalysts are mechanism,simply as discussedprecatalysts earlier. that act as a palladium reservoir for the active palladium species. Therefore, the observed high activity and recyclability of the catalysts could be attributed to a Pd release‐capture 5. Palladium Nanoparticle Immobilised on Magnetic Supports 5. Palladiummechanism, Nanoparticle as discussed Immobilised earlier. on Magnetic Supports Recent studies show that magnetic nanoparticles are excellent supports for various catalysts [54– Recent5. Palladium studies Nanoparticle show that Immobilised magnetic on nanoparticles Magnetic Supports are excellent supports for various 61]. Additionally, the magnetic properties can be exploited to improve catalyst separation from catalysts [54–61]. Additionally, the magnetic properties can be exploited to improve catalyst separation previous filtrationRecent andstudies centrifugation show that magnetic methods. nanoparticles Supported are excellent palladium supports magnetic for various catalysts catalysts [54–have the from previous filtration and centrifugation methods. Supported palladium magnetic catalysts have benefits of61]. easy Additionally, recovery thefrom magnetic the reaction properties media can beby exploited the application to improve of catalystan external separation magnetic from field the benefitsprevious of easy filtration recovery and from centrifugation the reaction methods. media Supported by the application palladium magnetic of an external catalysts magnetic have the field (Figure 8) [57]. Magnetic nanoparticles can be categorized into four main groups, namely; metals (Fe, (Figure8)[benefits57]. Magneticof easy recovery nanoparticles from the reaction can be media categorized by the application into four of main an external groups, magnetic namely; field metals Co, Ni), alloys(Figure (FePt, 8) [57]. FePd), Magnetic ferrites nanoparticles (CoFe2 canO4, beCuFe categorized2O4), and into most four mainnotably groups, metal namely; oxides metals (FeO, (Fe, Fe 2O3, (Fe, Co, Ni), alloys (FePt, FePd), ferrites (CoFe2O4, CuFe2O4), and most notably metal oxides (FeO, Fe3O4). IronCo, oxides Ni), alloys are (FePt, the most FePd), widely ferrites employed(CoFe2O4, CuFe in literature2O4), and most because notably they metal have oxides stronger (FeO, Fe magnetic2O3, Fe2O3, Fe3O4). Iron oxides are the most widely employed in literature because they have stronger propertiesFe and3O4). canIron be oxides synthesized are the most easily widely by employed co‐precipitation in literature methods because [62].they have stronger magnetic magnetic properties and can be synthesized easily by co-precipitation methods [62]. properties and can be synthesized easily by co‐precipitation methods [62].

Figure 8. FigureExamples 8. Examples of the useof the of use magnetic of magnetic separation separation through through the application application of an of external an external magnetic magnetic

ﬁeld [63] (Adaptedfield [63] (Adapted with permission with permission from from The The Royal Royal Society Society of of Chemistry).Chemistry). Figure 8. Examples of the use of magnetic separation through the application of an external magnetic field [63] (Adapted with permission from The Royal Society of Chemistry).

Molecules 2018, 23, 1676 12 of 24

MoleculesA growing 2018, 23 number, x FOR PEER of REVIEW these magnetic supports have been applied in the development12 of 23 of magneticallyMolecules 2018 recoverable, 23, x FOR PEER palladium REVIEW based heterogeneous catalysts for C–C cross-coupling12 reactions. of 23 A growing number of these magnetic supports have been applied in the development of Nasrollahzadeh and co-workers have explored the application of Pd/Fe3O4 magnetic nanoparticles as magneticallyA growing recoverable number palladiumof these magnetic based heterogeneous supports have catalysts been applied for C–C in crossthe development‐coupling reactions. of an efficient catalyst for C–C cross-coupling reactions [64]. The Pd/Fe3O4 magnetic catalyst was found Nasrollahzadeh and co‐workers have explored the application of Pd/Fe3O4 magnetic nanoparticles as to bemagnetically stable during recoverable the Suzuki palladium coupling based reaction heterogeneous and good catalysts yields (83–95%) for C–C cross were‐coupling obtained reactions. over a wide anNasrollahzadeh efficient catalyst and for co ‐C–Cworkers cross have‐coupling explored reactions the application [64]. The of Pd/FePd/Fe3O4 magnetic nanoparticles catalyst was asfound range of substrates. At the end of the Suzuki reaction the catalyst was recovered by the application of toan be efficient stable duringcatalyst the for SuzukiC–C cross coupling‐coupling reaction reactions and [64]. good The yields Pd/Fe (83–95%)3O4 magnetic were catalyst obtained was over found a wide an external magnet, and successively reused five times without significant loss of activity. rangeto be stableof substrates. during the At Suzuki the end coupling of the Suzukireaction reaction and good the yields catalyst (83–95%) was wererecovered obtained by overthe application a wide Although bare or “naked” iron oxide nanoparticles have been shown to be efficient supports for ofrange an external of substrates. magnet, At andthe endsuccessively of the Suzuki reused reaction five times the catalyst without was significant recovered loss by theof activity. application cross-couplingof anAlthough external reactions, magnet, bare or the “naked”and immobilization successively iron oxide reused of nanoparticles palladium five times directly withouthave been onsignificant theshown iron toloss oxide be of efficient activity. occasionally supports suffers for fromcross aggregation‐Althoughcoupling orbarereactions, surface or “naked” oxidation.the immobilization iron oxide The nanoparticles oxidation of palladium and have agglomeration been directly shown on to the be of efficient magneticiron oxide supports nanoparticles occasionally for resultssufferscross in the‐coupling from loss ofaggregation reactions, their magnetism; the or immobilization surface thus, oxidation. it is crucialof palladium The to develop oxidation directly efficient onand the agglomeration strategies iron oxide to occasionally strengthen of magnetic their chemicalnanoparticlessuffers stability from results [aggregation60]. In in this the regard, orloss surface of atheir wide oxidation. magnetism; range of The stabilizing thus, oxidation it is crucial or and coating toagglomeration develop materials, efficient includingof magnetic strategies organic to nanoparticles results in the loss of their magnetism; thus, it is crucial to develop efficient strategies to stabilizersstrengthen (polymers their chemical and surfactants) stability [60]. and In inorganic this regard, stabilizers a wide range (silica of and stabilizing carbon materials), or coating materials, have been strengthen their chemical stability [60]. In this regard, a wide range of stabilizing or coating materials, usedincluding to protect organic magnetic stabilizers nanoparticles (polymers [60 and,65]. surfactants) In this direction, and inorganic Kumar etstabilizers al. [66] developed (silica and efficientcarbon including organic stabilizers (polymers and surfactants) and inorganic stabilizers (silica and carbon C@Fematerials),O magnetic have core-shellbeen used nano-spheresto protect magnetic by coating nanoparticles the Fe O [60,65].nanoparticle In this direction, with a carbon Kumar shell et al. to materials),3 4 have been used to protect magnetic nanoparticles [60,65].3 4 In this direction, Kumar et al. protect[66] them developed from beingefficient corrupted C@Fe3O4 ormagnetic oxidized core under‐shell cross-couplingnano‐spheres by reaction coating conditions.the Fe3O4 nanoparticle Palladium [66] developed efficient C@Fe3O4 magnetic core‐shell nano‐spheres by coating the Fe3O4 nanoparticle waswith thenwith a immobiliseda carbon carbon shellshell onto protect the synthesized themthem from from C@Febeing being corrupted3 Ocorrupted4 magnetic or oroxidized oxidized core-shell under under to cross form cross‐coupling a‐ structurallycoupling reaction reaction stable conditions. Palladium was then immobilised on the synthesized C@Fe3O4 magnetic core‐shell to form Pd/[email protected] catalyst Palladium (Figures was then9 and immobilised 10). This catalyst on the synthesized was efficiently C@Fe3 usedO4 magnetic as a heterogeneous core‐shell to form catalyst 3 4 for Heckaa structurally structurally cross-coupling stablestable Pd/C@Fe reactions3OO and4 catalyst catalyst good (Figures to(Figures excellent 9 9and and yields 10). 10). This wereThis catalyst obtained.catalyst was was efficiently The efficiently catalyst used wasused as a easily as a separatedheterogeneousheterogeneous from the catalyst reaction forfor mixture HeckHeck cross cross through‐coupling‐coupling application reactions reactions and of and angood good external to excellentto excellent magnet yields yields and were the were obtained. catalyst obtained. was reusedTheThe five catalystcatalyst times waswas without easily any separatedseparated significant fromfrom drop the the inreaction reaction activity. mixture mixture The authors through through claim application application that this of catalytic anof externalan external system is “trulymagnetmagnet heterogeneous” andand thethe catalyst even waswas though reusedreused some five five times leachingtimes without without was any observed. any significant significant They drop drop concluded in activity.in activity. that The their Theauthors authors catalytic claim that this catalytic system is “truly heterogeneous” even though some leaching was observed. systemclaim is advantageous that this catalytic because system of is its“truly heterogeneity, heterogeneous” high even stability, though gram some scale leaching applicability, was observed. magnetic TheyThey concludedconcluded that theirtheir catalyticcatalytic systemsystem is is advantageous advantageous because because of ofits itsheterogeneity, heterogeneity, high high separability, and consequent reusability [66]. stability,stability, gramgram scale applicability, magnetic magnetic separability, separability, and and consequent consequent reusability reusability [66]. [66].

FigureFigure 9. Schematic 9. Schematic illustration illustration of of synthesis synthesis steps steps forfor C@Fe 3O3O4 core4 core-shell‐shell nano nano-spheres‐spheres [66] [(Adapted66] (Adapted Figure 9. Schematic illustration of synthesis steps for C@Fe3O4 core‐shell nano‐spheres [66] (Adapted withwith permission permission from from Elsevier). Elsevier). with permission from Elsevier).

Figure 10. Graphical illustration of Pd/C@Fe3O4 catalysed cross‐coupling reactions [66] (Adapted with permission from Elsevier). Figure 10. Graphical illustration of Pd/C@Fe3O4 catalysed cross‐coupling reactions [66] (Adapted with Figure 10. Graphical illustration of Pd/C@Fe O catalysed cross-coupling reactions [66] (Adapted permission from Elsevier). 3 4 with permission from Elsevier).

Molecules 2018, 23, 1676 13 of 24

Molecules 2018, 23, x FOR PEER REVIEW 13 of 23 Molecules 2018, 23, x FOR PEER REVIEW 13 of 23 The coated magnetic nanoparticles can be further modiﬁed by functionalising their surface with The coated magnetic nanoparticles can be further modified by functionalising their surface with variousThe functional coated magnetic groups (Figure nanoparticles 11). The can functionalization be further modified of the by surfacefunctionalising of magnetic their nanomaterialssurface with various functional groups (Figure 11). The functionalization of the surface of magnetic nanomaterials is anvarious important functional step ingroups the design (Figure of 11). supported The functionalization catalysts, because of the it surface signiﬁcantly of magnetic improves nanomaterials the physical is an important step in the design of supported catalysts, because it significantly improves the is an important step in the design of supported catalysts, because it significantly improves the and chemicalphysical and properties chemical of properties the magnetic of the supports magnetic supports [63]. [63]. physical and chemical properties of the magnetic supports [63].

Figure 11. Different approaches to functionalize magnetic nanoparticles (MNPs): (A) iron oxide Figure 11. Different approaches to functionalize magnetic nanoparticles (MNPs): (A) iron oxide MNPs; MNPs; (B) silica‐coated MNPs; and (C) carbon‐coated MNPs [63] (Adapted with permission from The (B) silica-coated MNPs; and (C) carbon-coated MNPs [63] (Adapted with permission from The Royal FigureRoyal 11. Society Different of Chemistry). approaches to functionalize magnetic nanoparticles (MNPs): (A) iron oxide SocietyMNPs; of ( Chemistry).B) silica‐coated MNPs; and (C) carbon‐coated MNPs [63] (Adapted with permission from The

RoyalHeidari Society and of Chemistry).co‐worker [67] used isoniazide to functionalize the surface of the Fe3O4@SiO2

Heidarimagnetic and nano co-worker‐support (Figure [67] used 12). The isoniazide isoniazide to groups functionalize were used the as surface linkers of to the immobilize Fe3O4@SiO 2 magneticpalladiumHeidari nano-support nanoparticlesand co‐worker (Figure and [67] prevent 12 used). Theagglomeration isoniazide isoniazide to on functionalize groupsthe surface were of thethe used Fe surface3O as4@SiO linkers of2 magnetic the to Fe immobilize3 Onano4@SiO‐ 2 magneticsupport nano[67].‐ supportThe resulting (Figure material,12). The Feisoniazide3O4@SiO2/isoniazide/Pd groups were catalyst,used as waslinkers explored to immobilize as a palladium nanoparticles and prevent agglomeration on the surface of the Fe3O4@SiO2 magnetic palladiumheterogeneous nanoparticles catalyst andin Suzuki prevent coupling agglomeration reactions andon the good surface to excellent of the Feyields3O4@SiO were2 obtained.magnetic Thenano ‐ nano-support [67]. The resulting material, Fe3O4@SiO2/isoniazide/Pd catalyst, was explored as supportauthors [67]. reported The that resulting the benefits material, of their Feheterogeneous3O4@SiO2/isoniazide/Pd catalyst system catalyst, were its washigh efficiencyexplored andas a a heterogeneous catalyst in Suzuki coupling reactions and good to excellent yields were obtained. heterogeneousreuse was easily catalyst achieved in Suzuki through coupling the use reactions of a magnet. and They good were to excellent able to recoveryields were and recycle obtained. their The The authors reported that the beneﬁts of their heterogeneous catalyst system were its high efﬁciency authorscatalyst reported six times that without the benefits any noticeable of their lossheterogeneous in activity. catalyst system were its high efficiency and andreuse reuse was was easily easily achieved achieved through through the use the of use a magnet. of a magnet. They Theywere able were to able recover to recover and recycle and recycletheir theircatalyst catalyst six sixtimes times without without any anynoticeable noticeable loss in loss activity. in activity.

Figure 12. Fe3O4@SiO2/isoniazide/Pd mediated Suzuki cross‐coupling reaction [67] (Adapted with permission from Elsevier).

Figure 12. Fe3O4@SiO2/isoniazide/Pd mediated Suzuki cross‐coupling reaction [67] (Adapted with Figure 12. Fe3O4@SiO2/isoniazide/Pd mediated Suzuki cross-coupling reaction [67] (Adapted with permission from Elsevier). permission from Elsevier).

Molecules 2018, 23, 1676 14 of 24

Molecules 2018, 23, x FOR PEER REVIEW 14 of 23 An interesting but slightly different approach was reported by Khalili and co-workers [12], An interesting but slightly different approach was reported by Khalili and co‐workers [12], who whoMolecules supported 2018, 23 palladium, x FOR PEER nanoparticlesREVIEW on an amino-vinyl silica functionalized magnetic14 of carbon23 supported palladium nanoparticles on an amino‐vinyl silica functionalized magnetic carbon nanotube (CNT). Their core–shell contains CNT@Fe3O4@SiO2-Pd in which the functionalized SiO2 nanotube (CNT). Their core–shell contains CNT@Fe3O4@SiO2‐Pd in which the functionalized SiO2 helps withAn the interesting stability but of slightly the Pd different nanoparticles approach and was is alsoreported responsible by Khalili for and the co‐ reductionworkers [12], of who Pd(II) to helps with the stability of the Pd nanoparticles and is also responsible for the reduction of Pd(II) to Pd(0)supported without the palladium need for nanoparticles adding external on reducingan amino agents‐vinyl (Figuresilica functionalized 13). This catalyst magnetic was successfullycarbon Pd(0) without the need for adding external reducing agents (Figure 13). This catalyst was successfully appliednanotube to Heck (CNT). and Their Suzuki core–shell cross-coupling contains CNT@Fe reactions3O4 and@SiO high2‐Pd in yields which were the functionalized obtained. In addition,SiO2 helpsapplied with to Heckthe stability and Suzuki of the cross Pd ‐nanoparticlescoupling reactions and is and also high responsible yields were for obtained.the reduction In addition, of Pd(II) the to the catalyst exhibited good recyclability, and was used for six consecutive recycles without a signiﬁcant Pd(0)catalyst without exhibited the needgood for recyclability, adding external and was reducing used foragents six consecutive(Figure 13). Thisrecycles catalyst without was asuccessfully significant loss inappliedloss catalytic in catalytic to Heck activity. activity. and Suzuki cross‐coupling reactions and high yields were obtained. In addition, the catalyst exhibited good recyclability, and was used for six consecutive recycles without a significant loss in catalytic activity.

Figure 13. A graphical illustration of the CNT@Fe3O4@SiO2‐Pd catalyst [12] (Adapted with permission Figure 13. A graphical illustration of the CNT@Fe O @SiO -Pd catalyst [12] (Adapted with permission from Springer Nature). 3 4 2 from Springer Nature). Figure 13. A graphical illustration of the CNT@Fe3O4@SiO2‐Pd catalyst [12] (Adapted with permission There are also numerous examples where organopalladium complexes, instead of palladium from Springer Nature). Therenanoparticles, are also have numerous been immobilised examples on where magnetic organopalladium supports [68,69]. complexes, Recently, Collinson instead of and palladium co‐ nanoparticles,workersThere [68] are have prepared also been numerous a [(NHC)Pd(allyl)Cl] immobilised examples on where magneticcomplex, organopalladium bearing supports an N complexes, [‐heterocyclic68,69]. Recently, instead carbene of (NHC) Collinsonpalladium and and co-workersnanoparticles,immobilised [68] prepared it onhave silica been a‐coated [(NHC)Pd(allyl)Cl] immobilised magnetic on nanoparticles magnetic complex, supports (Scheme bearing [68,69].6). an TheirN-heterocyclic Recently, strategy tries Collinson carbene to combine and (NHC) theco‐ and high activity of palladium–NHC catalysts with the facile separation and recyclability of a immobilisedworkers [68] it on prepared silica-coated a [(NHC)Pd(allyl)Cl] magnetic nanoparticles complex, bearing (Scheme an6 ).N‐ Theirheterocyclic strategy carbene tries (NHC) to combine and the heterogeneous catalyst. The catalyst was then explored on Suzuki coupling reactions and good to high activityimmobilised of palladium–NHC it on silica‐coated catalysts magnetic with nanoparticles the facile (Scheme separation 6). Their and recyclabilitystrategy tries to of combine a heterogeneous the highexcellent activity yields of were palladium–NHC obtained with catalystsa variety withof substrates. the facile However, separation the andimmobilised recyclability palladium of a catalyst. The catalyst was then explored on Suzuki coupling reactions and good to excellent yields heterogeneouscomplex could catalyst.not be reusedThe catalyst because was the then catalyst explored disassembled on Suzuki couplingor decomposed reactions under and goodSuzuki to were obtained with a variety of substrates. However, the immobilised palladium complex could not be excellentcoupling yieldsreaction were conditions. obtained The with recycled a variety catalyst of substrates. only achieved However, 20% theyield immobilised compared topalladium the 90% reusedcomplexyield because that could was the obtained catalystnot be reusedin disassembled its first because use. The orthe decomposedauthors catalyst suspected disassembled under that Suzuki the or basedecomposed coupling was responsible reaction under Suzukifor conditions. the The recycledcouplingdetachment catalystreaction of the conditions.magnetic only achieved silica The linker. recycled 20% yield catalyst compared only achieved to the 90%20% yield compared that was to obtained the 90% in its ﬁrst use.yield Thethat authorswas obtained suspected in its first that use. the The base authors was responsiblesuspected that for the the base detachment was responsible of the for magnetic the silicadetachment linker. of the magnetic silica linker.

Scheme 6. Immobilisation of the [N‐heterocyclic carbene (NHC)Pd(allyl)Cl] complex on silica‐coated magnetic nanoparticles [68] (Adapted with permission from Elsevier). Scheme 6. Immobilisation of the [N‐heterocyclic carbene (NHC)Pd(allyl)Cl] complex on silica‐coated Scheme 6. Immobilisation of the [N-heterocyclic carbene (NHC)Pd(allyl)Cl] complex on silica-coated magnetic nanoparticles [68] (Adapted with permission from Elsevier). magnetic nanoparticles [68] (Adapted with permission from Elsevier).

Molecules 2018, 23, 1676 15 of 24 Molecules 2018, 23, x FOR PEER REVIEW 15 of 23

BetterBetter resultsresults werewere obtainedobtained byby Fareghi-AlamdariFareghi‐Alamdari etet al.al. [[69]69] whowho supportedsupported bis(bis(NN-heterocyclic‐heterocyclic carbene)carbene) palladiumpalladium complexcomplex onon silicasilica coatedcoated magneticmagnetic nanoparticlesnanoparticles (Figure(Figure 14 14).).

Figure 14. Bis(N‐heterocyclic carbene) palladium complex supported on silica coated magnetic Figure 14. Bis(N-heterocyclic carbene) palladium complex supported on silica coated magnetic nanoparticles [69] (Adapted with permission from John Wiley and Sons). nanoparticles [69] (Adapted with permission from John Wiley and Sons). Their catalyst was efficiently used for Suzuki coupling reactions and at the end of the reaction, it wasTheir separated catalyst though was efﬁciently application used of an for external Suzuki magnet coupling and reactions recycled and for at six the consecutive end of the reactions. reaction, itHence, was separated it not easy though to identify application the reaction of an externalparameters magnet that andcaused recycled the Collinson for six consecutive and co‐workers reactions. [68] Hence,catalytic it system not easy to to be identify unrecyclable the reaction because parameters the reaction that conditions caused the are Collinson different and(Table co-workers 4). However, [68] catalyticthe most systemobvious to difference be unrecyclable is the choice because of the the base; reaction Collinson conditions and co are‐workers different used (Table NaOH,4). However, which is the most obvious difference is the choice of the base; Collinson and co-workers used NaOH, which is very harsh, while Fareghi‐Alamdari et al. used K2CO3. Hence, optimisation of reaction conditions is verycrucial harsh, in developing while Fareghi-Alamdari efficient and more et al. robust used Kcatalytic2CO3. Hence, systems. optimisation of reaction conditions is crucialIn insummary, developing the efﬁcient literature and shows more robustthat magnetic catalytic nanoparticle systems. ‐based catalytic systems have a huge potential in solving the recoverability and recyclability challenges [57]. Table 4. The reaction conditions for Suzuki cross-coupling reactions catalysed by supported palladium complexes in references [68,69]. Table 4. The reaction conditions for Suzuki cross‐coupling reactions catalysed by supported palladium complexes in references [68,69]. Reaction Conditions SolventReaction Base Conditions Temperature (◦C)

Collinson et al. [68] a IsopropanolSolvent Base NaOH Temperature 60(°C) b a Fareghi-AlamdariCollinson et al. et [al.69] [68] DMF/HIsopropanol2OK NaOH2CO 3 60 80 a ReactionFareghi conditions:‐Alamdari Bromotoluene et al. [69] (1.0 b mmol), phenylboronicDMF/H2O acid (1.05K2CO mmol),3 NaOH (1.180 mmol), catalyst b (1a Reaction mol % Pd), conditions: isopropanol Bromotoluene (1 mL). Reaction (1.0 conditions: mmol), phenylboronic Bromotoluene (1.0 acid mmol), (1.05 phenylboronic mmol), NaOH acid (1.1 (1.2 mmol), mmol), K CO (1.5 mmol), catalyst (0.12 mol % Pd), DMF/H O (2:1, 3 mL). catalyst2 3 (1 mol % Pd), isopropanol (1 mL).2 b Reaction conditions: Bromotoluene (1.0 mmol),

phenylboronic acid (1.2 mmol), K2CO3 (1.5 mmol), catalyst (0.12 mol % Pd), DMF/H2O (2:1, 3 mL). In summary, the literature shows that magnetic nanoparticle-based catalytic systems have a huge potential6. Polymer in Supported solving the Palladium recoverability Nanoparticles and recyclability challenges [57].

6. PolymerLiterature Supported reports Palladium have repeatedly Nanoparticles shown that palladium nanoparticles can be efficiently supported on polymer frameworks [70–77]. Recently, Nemygina and co‐workers immobilised Literature reports have repeatedly shown that palladium nanoparticles can be efﬁciently various palladium precursors (PdCl2, PdCl2(CH3CN)2, and PdCl2(PhCN)2) on amino‐functionalized supported on polymer frameworks [70–77]. Recently, Nemygina and co-workers immobilised hyper‐crosslinked polystyrene [78]. They then evaluated the influence of palladium oxidation state various palladium precursors (PdCl , PdCl (CH CN) , and PdCl (PhCN) ) on amino-functionalized (Pd(II) or Pd(0)) on the rate of Suzuki2 cross‐2coupling3 of2 4‐bromoanisole2 and2 phenylboronic acid. Their hyper-crosslinked polystyrene [78]. They then evaluated the inﬂuence of palladium oxidation state results revealed that the catalyst impregnated with a PdCl2(CH3CN)2 precursor resulted in better (Pd(II) or Pd(0)) on the rate of Suzuki cross-coupling of 4-bromoanisole and phenylboronic acid. catalytic activity (Scheme 7). The PdCl2(CH3CN)2 precursor was believed to be more active because it Their results revealed that the catalyst impregnated with a PdCl2(CH3CN)2 precursor resulted in experienced less hydrolysis and precipitation in comparison with PdCl2 and PdCl2(PhCN)2 under better catalytic activity (Scheme7). The PdCl (CH CN) precursor was believed to be more active Suzuki coupling reaction conditions. Lastly, they2 observed3 2 that unreduced, Pd(II) containing pre‐ because it experienced less hydrolysis and precipitation in comparison with PdCl and PdCl (PhCN) catalyst were more active [78]. 2 2 2 under Suzuki coupling reaction conditions. Lastly, they observed that unreduced, Pd(II) containing pre-catalyst were more active [78].

Molecules 2018, 23, 1676 16 of 24 Molecules 2018, 23, x FOR PEER REVIEW 16 of 23

Molecules 2018, 23, x FOR PEER REVIEW 16 of 23

Scheme 7. Catalysts of Suzuki cross‐coupling based on functionalized hyper‐crosslinked polystyrene Scheme 7. Catalysts for Suzuki cross-coupling based on functionalized hyper-crosslinked [78] (Adapted with permission from American Chemical Society). polystyrene [78] (Adapted with permission from American Chemical Society). Scheme 7. Catalysts of Suzuki cross‐coupling based on functionalized hyper‐crosslinked polystyrene Another[78] (Adapted interesting with permission strategy forfrom immobilising American Chemical palladium Society). on a polymer was reported by Li and coAnother‐workers interesting[79], who synthesised strategy for a immobilisingrobust and flexible palladium cellulose on sponge a polymer using was a dual reported‐cross by‐linking Li and co-workerscelluloseAnother [nanofiber79], who interesting synthesised(CNF) strategywith γ‐ a for robustglycidoxypropyltrimethoxysilane immobilising and flexible palladium cellulose on a sponge polymer (GPTMS) using was reportedand a dual-cross-linking polydopamine by Li and cellulose(PDA)co‐workers nanofiber (Scheme [79], (CNF)8). who The withsynthesised characterisationγ-glycidoxypropyltrimethoxysilane a robust results and flexible revealed cellulose that thesponge (GPTMS) palladium using and a polydopaminenanoparticlesdual‐cross‐linking were (PDA) (Schemehomogeneouslycellulose8). The nanofiber characterisation dispersed (CNF) on with resultsthe γ‐surfaceglycidoxypropyltrimethoxysilane revealed of the that cellulose the palladium nanofiber nanoparticles with (GPTMS) a narrow and were sizepolydopamine homogeneously distribution. dispersedThe(PDA) catalyst on (Scheme the was surface successfully 8). The of characterisation the applied cellulose to heterogeneous nanofiber results revealed with Suzuki a that narrow theand palladiumHeck size distribution.cross nanoparticles‐coupling The reactions. were catalyst wasLeaching successfullyhomogeneously of palladium applied dispersed was to heterogeneous negligibleon the surface and of Suzuki the the catalysts cellulose and Heck couldnanofiber cross-coupling be convenientlywith a narrow reactions. separated size distribution. Leaching from the of The catalyst was successfully applied to heterogeneous Suzuki and Heck cross‐coupling reactions. palladiumproducts was and negligible reused for andsix times the catalysts without loss could of activity be conveniently [79]. separated from the products and Leaching of palladium was negligible and the catalysts could be conveniently separated from the reused for six times without loss of activity [79]. products and reused for six times without loss of activity [79].

Scheme 8. Schematic of the stepwise formation of cellulose sponge supported palladium nanoparticlesScheme 8. [79]Schematic (Adapted of withthe permissionstepwise formation from American of cellulose Chemical sponge Society). supported palladium Schemenanoparticles 8. Schematic [79] (Adapted of the with stepwise permission formation from American of cellulose Chemical sponge Society). supported palladium 7. nanoparticlesPalladium Nanoparticles [79] (Adapted Immobilized with permission on from Hybrid American Inorganic Chemical‐Organic Society). Material 7. Palladium Nanoparticles Immobilized on Hybrid Inorganic‐Organic Material The hybrid inorganic–organic materials are crystalline systems in which both inorganic and 7. Palladium Nanoparticles Immobilized on Hybrid Inorganic-Organic Material organic Thestructural hybrid inorganic–organicelements co‐exist materialswithin a aresingle crystalline phase systems[80]. These in which hybrid both inorganic–organic inorganic and materialsTheorganic hybrid arestructural gaining inorganic–organic elements popularity co‐ existin materials cross within‐coupling area single crystalline reactions phase [80]. systems due Theseto their in hybrid which tunable inorganic–organic both pore inorganic size, high and materials are gaining popularity in cross‐coupling reactions due to their tunable pore size, high organicsurface structural areas, high elements crystallinity, co-exist and within structural a single diversity phase [81–87]. [80]. TheseMost hybrid hybrid inorganic–organic inorganic–organic surface areas, high crystallinity, and structural diversity [81–87]. Most hybrid inorganic–organic materialsmaterials are gainingare synthesised popularity through in cross-coupling functionalization reactions of duethe tosupport their tunable surface pore with size, appropriate high surface materials are synthesised through functionalization of the support surface with appropriate functional groups. This allows for a better control of the dimensions, dispersion and stability of the areas,functional high crystallinity, groups. This and allows structural for a diversitybetter control [81– of87 the]. Most dimensions, hybrid dispersion inorganic–organic and stability materials of the are palladium nanoparticles. Metal‐organic frameworks (MOFs) are one of the most popular classes of synthesisedpalladium through nanoparticles. functionalization Metal‐organic of the frameworks support surface (MOFs) with are one appropriate of the most functional popular classes groups. of This allowshybridhybrid for inorganic–organic a betterinorganic–organic control of materials the materials dimensions, and and they they dispersion are are frequentlyfrequently and explored stability as as of suitable suitable the palladium palladium palladium nanoparticles. supports supports Metal-organicin heterogeneousin heterogeneous frameworks cross cross‐coupling‐coupling (MOFs) reactions. reactions. are one ofFor For the example,example, most popular Shaikh and classesand coco‐workers‐workers of hybrid [88] [88] inorganic–organic used used a zeolitica zeolitic

Molecules 2018, 23, 1676 17 of 24 materials and they are frequently explored as suitable palladium supports in heterogeneous cross-couplingMoleculesMolecules 2018 2018, 23, ,23 x reactions., FORx FOR PEER PEER REVIEW REVIEW For example, Shaikh and co-workers [88] used a zeolitic imidazolate17 of17 23 of 23 framework (ZIF) to develop robust ZIF-supported palladium nanoparticles as a heterogeneous catalyst imidazolateimidazolate framework framework (ZIF)(ZIF) toto developdevelop robust ZIF‐‐supportedsupported palladiumpalladium nanoparticles nanoparticles as asa a for Heck cross-coupling reactions (Figure 15). The Pd/ZIF catalyst was found to be highly efﬁcient heterogeneousheterogeneous catalyst catalyst for for Heck Heck cross cross‐‐couplingcoupling reactions (Figure(Figure 15). 15). The The Pd/ZIF Pd/ZIF catalyst catalyst was was found found to to and could be re-used up to four times without any loss in catalytic efﬁciency [88]. be behighly highly efficient efficient and and could could be be re re‐used‐used upup toto fourfour times withoutwithout any any loss loss in in catalytic catalytic efficiency efficiency [88]. [88].

FigureFigure 15. 15.A A graphical graphical illustration illustration of of the the Pd/zeolitic Pd/zeolitic imidazolate (ZIF (ZIF-8‐8 catalyst) catalyst) [88] [88 (Adapted] (Adapted with with permissionFigurepermission 15. A from graphicalfrom John John Wiley illustrationWiley and and Sons). Sons). of the Pd/zeolitic imidazolate (ZIF‐8 catalyst) [88] (Adapted with permission from John Wiley and Sons). Another interesting example was reported by Kozell et al. [89] who immobilised palladium Another interesting example was reported by Kozell et al. [89] who immobilised palladium nanoparticlesAnother interesting on zirconium example phosphate was reported glycine by Kozelldiphosphonate et al. [89] whonanosheets immobilised (ZPGly). palladium The nanoparticles on zirconium phosphate glycine diphosphonate nanosheets (ZPGly). The immobilization nanoparticlesimmobilization on of palladiumzirconium nanoparticles phosphate onglycine ZPGly nanosheetsdiphosphonate provided nanosheets a stable catalyst (ZPGly). with high The of palladium nanoparticles on ZPGly nanosheets provided a stable catalyst with high palladium immobilizationpalladium content of palladium (up to 22 nanoparticles wt. %). This on Pd@ZPGly ZPGly nanosheets‐15 catalyst provided proved toa stablebe highly catalyst efficient with highin content (up to 22 wt. %). This Pd@ZPGly-15 catalyst proved to be highly efﬁcient in catalysing Suzuki palladiumcatalysing content Suzuki (upand toHeck 22 crosswt. %).‐couplings This Pd@ZPGly reactions. ‐Surprisingly,15 catalyst proved the authors to be reported highly thatefficient their in and Heck cross-couplings reactions. Surprisingly, the authors reported that their catalytic system catalysingcatalytic Susystemzuki operatesand Heck as crossan efficient‐couplings “heterogeneous” reactions. Surprisingly, system, even thoughthe authors 3–5 ppm reported of palladium that their operates as an efﬁcient “heterogeneous” system, even though 3–5 ppm of palladium leached (Table5). catalyticleached system (Table operates5). In addition, as an aefficient “release “heterogeneous” and catch” mechanism system, was even proposed though in 3–5which ppm soluble of palladium active Inpalladium addition, a species “release are and released catch” from mechanism the solid was Pd@ZPGly proposed‐15 incatalyst which during soluble the active oxidative palladium addition species of leached (Table 5). In addition, a “release and catch” mechanism was proposed in which soluble active arethe released halide fromand then the solidre‐deposited Pd@ZPGly-15 on the ZPGly catalyst support during as the a consequence oxidative addition of the reductive of the halide elimination and then palladium species are released from the solid Pd@ZPGly‐15 catalyst during the oxidative addition of re-depositedstep at the onend the of the ZPGly reaction support [89]. as a consequence of the reductive elimination step at the end of the the halide and then re‐deposited on the ZPGly support as a consequence of the reductive elimination reaction [89]. step at Tablethe end 5. ofSuzuki the reaction cross‐coupling [89]. reaction between 4‐bromobenzaldehyde and phenylboric acid Tablecatalysed 5. Suzuki by Pd@ZPGly cross-coupling‐15 (palladium reaction between nanoparticles 4-bromobenzaldehyde on zirconium phosphate and phenylboric glycine diphosphonate acid catalysed byTablenanosheets) Pd@ZPGly-15 5. Suzuki catalyst (palladium cross [89].‐coupling nanoparticles reaction on between zirconium 4‐ phosphatebromobenzaldehyde glycine diphosphonate and phenylboric nanosheets) acid catalystcatalysed [89 by]. Pd@ZPGly‐15 (palladium nanoparticles on zirconium phosphate glycine diphosphonate nanosheets) catalyst [89].

Entry a Yield (%) b Pd Leaching (ppm) Run 1 98 5 EntryRun a 2 Yield98 (%) b 3 Entry a Yield (%) b Pd LeachingPd Leaching (ppm) (ppm) RunRun 1 3 9898 3 5 a ReactionRunRun 2 conditions: 1 4‐Bromobenzaldehyde98 (1.0 98 mmol), phenylboronic acid (1.23 mmol), 5 K2CO3 (1.1 Run 2 98b 3 mmol),Run catalyst 3 (0.1 mol % Pd), ethanol98 (2.4 mL). GC (gas chromatography) yields.3 Run 3 98 3 a a Reaction conditions: 4‐Bromobenzaldehyde (1.0 mmol), phenylboronic acid (1.2 mmol), K2CO3 (1.1 ReactionA magnetically conditions: 4-Bromobenzaldehydeseparable version of (1.0 a mmol),hybrid phenylboronic organic‐inorganic acid (1.2 mmol),support K2 COwas3 (1.1 recently mmol), catalystreported b by(0.1mmol), Omar mol %andcatalyst Pd), co ethanol‐ workers(0.1 mol (2.4 mL).%[90]. Pd),b TheyGC ethanol (gas supported chromatography) (2.4 mL). palladium GC yields.(gas chromatography) on magnetically yields. separable organic‐silica hybrid nanoparticles that were functionalized with ionic liquid groups (Figure 16). The presence of A magnetically separable version of a hybrid organic‐inorganic support was recently reported ionic liquid groups within the framework of the hybrid nanoparticles enhanced the stability of the by Omar and co‐workers [90]. They supported palladium on magnetically separable organic‐silica

hybrid nanoparticles that were functionalized with ionic liquid groups (Figure 16). The presence of ionic liquid groups within the framework of the hybrid nanoparticles enhanced the stability of the Molecules 2018, 23, 1676 18 of 24

A magnetically separable version of a hybrid organic-inorganic support was recently reported by Omar and co-workers [90]. They supported palladium on magnetically separable organic-silica hybrid nanoparticles that were functionalized with ionic liquid groups (Figure 16). The presence ofMolecules ionic liquid2018, 23, groupsx FOR PEER within REVIEW the framework of the hybrid nanoparticles enhanced the stability18 of 23 of the palladium nanoparticles on the organic-silica nanoparticles. The resultant Pd/MNP@IL-SiO2 palladium nanoparticles on the organic‐silica nanoparticles. The resultant Pd/MNP@IL‐SiO2 catalyst catalyst was efficiently applied in Heck and Suzuki cross-coupling reactions and it demonstrated was efficiently applied in Heck and Suzuki cross‐coupling reactions and it demonstrated high high catalytic activity (Figure 16). The Pd/MNP@IL-SiO2 catalyst was also easily separated from the catalytic activity (Figure 16). The Pd/MNP@IL‐SiO2 catalyst was also easily separated from the reaction mixture by application of an external magnetic field and the catalyst could be recycled over reaction mixture by application of an external magnetic field and the catalyst could be recycled over five times without a significant loss in its catalytic activity. In conclusion, the authors envisaged that five times without a significant loss in its catalytic activity. In conclusion, the authors envisaged that thisthis andand similarsimilar catalyticcatalytic systemssystems could pave a way for for the the desired desired bridging bridging of of homogeneous homogeneous and and heterogeneousheterogeneous catalysis.catalysis.

Figure 16. Suzuki cross‐coupling reactions catalysed by the Pd/MNP@IL‐SiO2 (palladium Figure 16. Suzuki cross-coupling reactions catalysed by the Pd/MNP@IL-SiO2 (palladium nanoparticles on the organic‐silica nanoparticles) catalyst [90] (Adapted with permission from nanoparticles on the organic-silica nanoparticles) catalyst [90] (Adapted with permission from American Chemical Society). American Chemical Society).

Another special type of hybrid organic‐inorganic support was reported by Lin et al. who preparedAnother a retrievable special type Pd/CMC@Ce(OH) of hybrid organic-inorganic4 catalyst for support Suzuki wascoupling reported‐reactions by Lin [91]. et al. In who this preparedsystem, aCe(OH) retrievable4 was Pd/CMC@Ce(OH) coated with carboxymethylcellulose4 catalyst for Suzuki coupling-reactions (CMC) to form a [91 hybrid]. In this organic system,‐inorganic Ce(OH) 4 wasCMC@Ce(OH) coated with4 carboxymethylcellulosesupport (Scheme 9). Carboxymethylcellulose (CMC) to form a hybrid has organic-inorganic a large number CMC@Ce(OH) of inherent 4 supportcarboxylate (Scheme (–COO9). Carboxymethylcellulose−) and hydroxyl (–OH) groups has a large on its number molecular of inherent chain. Thus, carboxylate CMC is (–COO an excellent−) and hydroxylcation exchange (–OH) groups agent, on which its molecular makes chain. it an Thus, excellent CMC issupport an excellent for cationstabilization exchange of agent,palladium which makesnanoparticles. it an excellent While ceria support has for a unique stabilization ability of palladiumforming oxygen nanoparticles. vacancies, While that reduce ceria has Ce4+ a to unique Ce3+ abilityand create of forming an excess oxygen of negative vacancies, charge that reduce on its Cesurface.4+ to Ce The3+ andexcess create negative an excess charge of negative facilitates charge the oncoordination its surface. of The palladium excess negative nanoparticles charge to facilitates the surface, the coordination as discussed of earlier. palladium These nanoparticles interactions have to the surface,been shown as discussed to be earlier.crucial Thesein preventing interactions leaching have been and shown agglomeration to be crucial of incatalytic preventing palladium leaching andnanoparticles. agglomeration Scheme of catalytic 9 shows palladium an illustrative nanoparticles. diagram of Scheme the conceptual9 shows mechanism an illustrative of the diagram Suzuki of 3+ thereaction conceptual catalyzed mechanism by Pd(0)–CMC@Ce(OH) of the Suzuki reaction4. The Ce catalyzed3+ on the by surface Pd(0)–CMC@Ce(OH) of Ce(OH)4 enables4. The the Ce electronicon the surfacecharge oftransfer Ce(OH) that4 enables produces the electronica highly chargenegatively transfer charged that producespalladium a highlycenter. negativelyThis then chargedmakes palladiumpalladium center. a more This electron then makesrich site palladium for facile a oxidative more electron addition rich siteof aryl for facilehalides, oxidative and thus addition allows of arylcatalysis halides, to commence. and thus allows catalysis to commence. The Pd/CMC@Ce(OH)4 catalyst was applied to the Suzuki cross‐coupling reaction and good to excellent yields were obtained. It is believed that the activity of the catalyst was enhanced synergistically by the unique redox properties of Ce(OH)4 (Ce3+/Ce4+) and the coordination with the functional (carboxyl and hydroxyl) groups of the hybrid CMC@Ce(OH)4 support. Moreover, the catalyst could be easily separated by simple filtration and reused at least for five times without losing its activity. However, it was observed that Pd(0) species leached from the hybrid support during the reaction and were re–deposited onto the support at the end of the reaction. Therefore, the reaction mechanism is homogeneous in nature and the leached palladium species are the “true active species”.

Molecules 2018, 23, 1676 19 of 24 Molecules 2018, 23, x FOR PEER REVIEW 19 of 23

Scheme 9. Illustrative diagram of the conceptual mechanism of the Suzuki reaction catalyzed by Scheme 9. Illustrative diagram of the conceptual mechanism of the Suzuki reaction catalyzed by Pd/CMC@Ce(OH)4 [91] (Adapted with permission from Elsevier). Pd/CMC@Ce(OH)4 [91] (Adapted with permission from Elsevier). 8. Conclusions The Pd/CMC@Ce(OH)4 catalyst was applied to the Suzuki cross-coupling reaction and good to excellentIn conclusion, yields werethe literature obtained. survey It is shows believed that that remarkable the activity progress of the has catalyst been made was enhancedregarding the activity and recyclability of heterogeneous palladium based3+ catalytic4+ systems for C–C cross synergistically by the unique redox properties of Ce(OH)4 (Ce /Ce ) and the coordination with coupling reactions. However, thorough leaching and recyclability tests are still needed for most the functional (carboxyl and hydroxyl) groups of the hybrid CMC@Ce(OH)4 support. Moreover, thereported catalyst heterogeneous could be easily catalytic separated systems by simple to unequivocally ﬁltration and confirm reused that at least the for palladium ﬁve times supported without losingcatalysts its activity.are responsible However, for it the was observed observed catalytic that Pd(0) activity species and leached not the from leached the hybridmaterial. support Hence, during at the themoment reaction it is and hard were to re–depositedsay what the onto nature the of support the true at thecatalyst end of is, the due reaction. to the dynamic Therefore, nature the reaction of the mechanismreported catalytic is homogeneous systems for in cross nature‐coupling and the reactions. leached palladium species are the “true active species”.

8.Author Conclusions Contributions: P.P.M. and Z.P.V. prepared this manuscript under the guidance and supervision of G.E.M.M. and H.B.F. In conclusion, the literature survey shows that remarkable progress has been made regarding the Funding: This research was funded by Mintek. activity and recyclability of heterogeneous palladium based catalytic systems for C–C cross coupling reactions.Acknowledgments: However, We thorough would like leaching to express and our recyclability gratitude to testsMintek are and still the needed Department for most of Science reported and heterogeneousTechnology South catalytic Africa (Advanced systems to Metals unequivocally Initiative program) conﬁrm thatfor financial the palladium support supportedfor our work catalysts in this area. are responsibleConflicts of forInterest: the observed The authors catalytic declare activity no conflicts and of not interest. the leached material. Hence, at the moment it is hard to say what the nature of the true catalyst is, due to the dynamic nature of the reported catalytic systemsReferences for cross-coupling reactions.

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