Nanocatalysis Synthesis and Applications (Polshettiwar/Nanocatalysis) || Sonogashira Reactions Using...

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SONOGASHIRA REACTIONSUSING NANOCATALYSTS

Rafael Chinchilla and Carmen Najera

INTRODUCTION

The palladium-catalyzed process that can couple a terminal sp-hybridized carbon froman alkyne with an sp2 carbon of an aryl or vinyl halide (or triflate) is termed as theSonogashira coupling reaction (Scheme 4.1). This name arises from the discovery in1975 by Sonogashira, Tohda, and Hagihara that this process could be performed at roomtemperature using a palladium source as catalyst, combined with cocatalytic amount ofCu(I) in an organoamine solvent.1 In the same year, Cassar2 and Heck3 discovered thatit was possible to perform this coupling reaction without the use of copper cocatalysts;however, the reaction in this case worked only at higher temperatures.

The addition of Cu(I) resulted beneficial in terms of increasing the reactivity of thesystem, but added additional problems, the principal being the necessity of avoidingoxidizing conditions (such as the presence of oxygen) in order to block the formation ofthe alkyne homocoupling by-product through a copper-mediated Hay/Glaser reaction.4

Obviously, a way of avoiding this homocoupling side reaction was to eliminate cop-per in the reaction. Although this copper-free process could be perhaps more properlytermed as Heck–Cassar reaction, Heck alkynylation, or Sonogashira–Heck–Cassar cou-pling, it is most frequently called “copper-free” Sonogashira reaction. In fact, the name“Sonogashira reaction” is applied to any palladium (or other metal)-catalyzed couplingof an sp2 (or even sp3) halide or triflate with a terminal alkyne, regardless of whether

Nanocatalysis: Synthesis and Applications, First Edition. Edited by Vivek Polshettiwar and Tewodros Asefa.© 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

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90 SONOGASHIRA REACTIONS USING NANOCATALYSTS

Scheme 4.1. The palladium-catalyzed Sonogashira cross-coupling reaction.

Cu(I) salts are present. Research dealing with the synthetic uses of the Sonogashirareaction has been very intense,5–7 and the resulting products from this process have beenemployed in the most diverse areas of chemistry, such as dyes, sensors, electronics,polymers, guest–host constructs, natural products, and heterocycle synthesis.

Metal nanoparticles have attracted much attention in the last several years owingto their relatively high chemical activity and specificity of interaction.8,9 One of thereasons for the rapidly developing field of nanoparticle research is the distinctly dif-fering physicochemical properties presented by metal nanoparticles compared to theirbulk counterparts due to their large surface-to-volume ratio, providing many highlyactive metal uncoordinated sites. Among these metallic species, palladium(0) nanopar-ticles (Pd-NPs) are particularly interesting due to their applicability to all the array ofpalladium-catalyzed reactions, particularly the C C coupling reactions,10,11 with theSonogashira reaction being no exception. In fact, Pd-NPs can be the real catalysts inmany of the reported Sonogashira reactions as a consequence of decomposition of theused palladium salts or complexes in the reactionmedia. However, this chapter deals onlywith the use of specifically created and identified Pd(0) (or other metal) nanoparticlesor nanostructures for the Sonogashira cross-coupling reaction.

CATALYTIC ACTIVITY, STABILITY, AND REUSABILITY

Transition metal nanoparticles are specially active catalytic systems due to their largesurface area-to-volume ratios.12–15 These catalysts can be considered rather in the borderof homogenous–heterogeneous depending on the particle size and can be named as“semiheterogeneous” systems. Nanoparticles can be stabilized by some additives such astrialkylammonium salts, ionic liquids, or poly(ethylene glycol) (PEG), which can act asligands surrounding the dispersed nanoparticles and therefore minimizing their tendencyto undergo agglomeration.12–15 As the nanoparticle size is associated with reactivity,small nanoparticles would allow, for instance, more favorable oxidative addition of themetal to the carbon–halogen bond at the rim of the nanoparticle.16–18

As mentioned, there are proofs or indications that Pd-NPs can in fact be the real cat-alyst in many of palladium-catalyzed cross-coupling reactions, such as the Sonogashirareaction, as a consequence of decomposition of the original palladium-containing precat-alyst.18, 19 A lot can be inferred about the nature of the active catalysts when consideringthe temperature at which the system operates. Thus, the presence of donor ligands suchas phosphanes can be a component of truly active, soluble palladium complexes in

CATALYTIC ACTIVITY, STABILITY, AND REUSABILITY 91

the coupling process. The condition where these ligands seem to influence the catal-ysis is usually at relatively low temperatures (typically �80 ◦C). At higher reactiontemperatures (such as �120 ◦C), it is likely that many preformed metal ligand com-plexes or mixtures of palladium sources decompose to generate Pd-NPs. However, ithas been demonstrated by transmission electron microscopy (TEM) and kinetic studiesthat soluble palladium species are present when these palladium nanoclusters are usedas catalysts.20–23 Although all these conclusions were usually based on circumstantialevidences, nowadays there are also direct proofs, which add further questions relatedto the nature of the catalytic species in many transition metal-catalyzed cross-couplingreactions. This point is addressed in Section “Mechanistic Aspects.”

Unimmobilized Palladium Nanocatalysts fromPalladium Complexes

Asmentioned previously, the use of ionic liquids as solvents allows stabilization of metalnanoparticles,24, 25 although examples of their use in Sonogashira couplings are ratherlimited. Thus, a basic ionic liquid at room temperature has been explored as a mediumfor the generation of Pd-NPs from PdCl2(PPh3)2 with a small amount of piperidine ormethanol, attempting the coupling of aryl iodides with phenylacetylene, although thehomocoupling of the alkyne as side reaction has been observed in 10–40%.26

The use ofN-heterocyclic carbenes (NHCs) as ligands in palladium-catalyzed cross-coupling reactions is rapidly gaining popularity.27 The resulting complexes exhibit highstability, allowing for indefinite storage and easy handling. For instance, the palladium–biscarbene complex 1 has been characterized after being generated in situ by mixingPdCl2 (2 mol%) and triethylamine as base in the ionic liquid 1,3-di-n-butylimidazoliumtetrafluoroborate during the copper-free Sonogashira coupling of aryl iodides underultrasound irradiation at 30 ◦C in the presence of triethylamine as a base. Once generatedin the reaction media, this complex 1 gives rise to stable, crystalline, and polydispersedPd-NPs as the real catalyst for the reaction between aryl iodides or electron-poor arylbromides and terminal alkynes, as exemplified in Scheme 4.2 with the coupling of1-chloro-4-iodobenzene (2) and 1-ethynylcyclohexanol (3) to give alkyne 4.28 This

Scheme 4.2. Sonogashira cross-coupling reaction carried out using an in situ-generated NHC-

Pd complex as precatalyst.


work again raises the question whether NHC palladium complexes are the real catalyticspecies in the reaction.13,19

Palladium compounds containing at least one metal–carbon bond intramolecularlystabilized by at least one donor atom, termed cyclopalladated compounds or palladacy-cles, are one of the most popular classes of organopalladium derivatives.29,30 Pallada-cycles have emerged as a very promising family of organometallic catalyst precursorsin C C bond-forming processes, often showing interesting mixed characteristics, suchas high catalytic activity and at the same high stability.31–34 It has been proven thatpalladacycles are not the “true” active catalyst, but rather precatalysts that undergo anactivation process and a source of low-coordinate Pd(0) such as Pd-NPs.18,19,29–35

Thus, the carbapalladacycle complexes 5 have been used as precatalysts in severalC C coupling reactions such as the copper-free Sonogashira cross-coupling. Thesecomplexes perform the coupling of aryl iodides and aryl and vinyl bromides withterminal alkynes, working in N-methyl-2-pyrrolidone (NMP) as solvent using tetra-n-butylammonium acetate (TBAA) as base, achieving high turnover numbers (TONs),36 aswell as the coupling of acyl chlorides with terminal acetylenes leading to ynones, usingtriethylamine as base in toluene as solvent.37 Examples of the use of these complexesare shown in Scheme 4.3, where 2-bromobenzonitrile (6) and cinnamoyl chloride (8)reacted with phenylacetylene affording the corresponding coupled products 7 and 9,respectively. It is interesting to note that when performing the Heck reaction employingpalladacycle 5 (R1 = pC6H4 and R2 = Cl), the formation of Pd-NPs was detected.38

Formula 5.

In an attempt to develop a reusable, homogeneous system based on palladacycle 5(R1=MeandR2=OH), its stability against prolonged heating (120 ◦C) in different ionic

Scheme 4.3. Sonogashira and acyl-Sonogashira cross-coupling reactions performed using an

oxime-derived palladacycle as precatalyst.


liquids and PEG was studied.39 It was found that this palladacycle decomposed in water,1-butyl-1-methylimidazolium hexafluorophosphate, and 1-butyl-1-methylimidazoliumchloride to form Pd-NPs in the first two cases and PdCl42− in the third case. The activityof this complex for the copper-free Sonogashira reaction correlates with the stability ofthe complex, the activity in PEG being higher than in any of the ionic liquids tested.Although the carbapalladacycle complex also decomposes in PEG upon reaction, theresulting Pd-NPs (2–5 nm size) are stabilized by PEG acting as a ligand. In this way, areusable, homogeneous system in PEG able to perform the Sonogashira coupling wasdeveloped. Thus, p-iodo-, p-bromo-, and p-chloroacetophenone have been cross-coupledwith phenylacetylene, using cesium acetate as base in the ionic liquid or PEG as solventat 120 ◦C. TEM images of Pd-NPs in PEG after the first and fifth use of complex 5 (R1

=Me and R2 = OH) showed no change in the particle size.

Unimmobilized Palladium Nanocatalysts from Ligand-FreePalladium Compounds

The use of simple palladium salts as catalysts has advantages related to cost and to avoidpossible sensitive ligands. Successful examples of the use of ligand-free palladium saltsas catalysts are the copper-free Sonogashira coupling reaction of aryl iodides and bro-mides using Pd(OAc)2 as catalysts at room temperature in dimethylformamide (DMF)as solvent in the presence of TBAA as basic additive.40 This catalytic system probablygenerates highly reactive Pd-NPs, as carboxylated tetrabutylammonium salts are knownto facilitate the reduction of Pd(OAc)2 to catalytically active Pd(0) species.41 In addi-tion, oil-in-water microemulsions formed by the mixture Triton R© X-100/n-heptane/n-butanol/water/PEG at 80 ◦C have been employed in the fast cross-coupling of veryactivated aryl iodides, such as 10, with phenylacetylene (5 min) catalyzed by Pd-NPsgenerated by combining PdCl2 (0.5 mol%) and sodium hydroxide, yielding the cor-responding alkynes such as 11 (Scheme 4.4).42, 43 However, aryl bromides performedpoorly under these conditions.

Catalytically active Pd-NPs have been synthesized in water by reduction ofNa2PdCl4 with a Fisher carbene complex in the presence of PEG as nanoparticle stabi-lizers. This nanoparticle solution has been used as catalysts (0.01 equivalent with PEG-6000 1.0 equivalent) in the coupling of activated aryl iodides with terminal alkynes,using potassium carbonate as base in water at 55 or 65 ◦C, with no final product beingdetected when starting from aryl bromides.44 In addition, palladium nanowires havebeen obtained by NaBH4 reduction of an aqueous solution of H2PdCl4 seeded by goldnanoparticles and stabilized by a thiol-functionalized ionic liquid.45 These nanowires

Scheme 4.4. Sonogashira cross-coupling catalyzed by Pd-NPs in an oil-in-water

microemulsion.


have been found to catalyze the coupling of iodobenzene and phenylacetylene in thepresence of diisopropylamine as base, in isopropanol at 75 ◦C, although the presence ofcopper cocatalyst and triphenylphosphane is necessary. The catalyst has been recoveredafter the reaction up to three times and reused with no loss of its activity.

Aryl iodides, such as p-iodoanisole, have been cross-coupled with ferroceny-lacetylene (12) to give the corresponding acetylene 13 (Scheme 4.5), using Pd-NPcatalysts generated in situ from PdCl2 (2 mol%) after ultrasound irradiation.46 Thereaction has been performed in the presence of triethylamine as base in acetone atroom temperature. In addition, Pd-NPs have also been created by irradiating Pd(II)acetate (2 mol%) with ultrasounds in the presence of TBAA, and have been usedas catalysts in a one-pot synthesis of substituted benzofurans by the Sonogashiracoupling-5-endo-dig cyclization of 2-iodophenols in acetonitrile at room temperature.47

This one-pot coupling–cyclization process for the preparation of benzofurans has beenperformed using as catalyst Pd-NPs generated in water by reduction of Na2PdCl4 withsodium dodecyl sulphate, which also acted as a stabilizer.48 Thus, benzofurans such as16 have been obtained after coupling of 2-iodophenols such as 14 with terminal alkynessuch as phenylacetylene in the presence of the generated Pd-NPs, and triethylaminein refluxing water at 100 ◦C, the Sonogashira intermediate 15 being cyclized in situ togive the final heterocycle (Scheme 4.5). The aqueous suspension containing the catalystafter the reaction has been recycled for three runs with gradual loss of efficiency due toagglomeration of the nanoparticles after each cycle.

Water has also been the solvent for a Sonogashira reaction catalyzed by �-cyclodextrin-capped Pd-NPs obtained fromNa2PdCl4 and perthiolated�-cyclodextrin.49

Using this catalytic species (10 mol%), the coupling of iodobenzene and 1-iodonaphthalene with aryl alkynes was achieved in high yields, bromobenzene giv-ing moderate results. The process was carried out in the presence of a big excess of

Scheme 4.5. Sonogashira cross-coupling reaction of ferrocenylacetylene catalyzed by Pd-

NPs. Generation of an alkynylated phenol intermediate by a Sonogashira coupling catalyzed

by Ps-NPs generated in water in the presence of a stabilizer, and further internal cyclization

affording a benzofurane.


Scheme 4.6. Sonogashira cross-coupling reaction catalyzed by cyclodextrin-capped Pd-NPs.

diisopropylamine as base in water at room temperature. The role of the cyclodextrin issuggested to be facilitating the inclusion of hydrophobic species inside the cavity, bring-ing themolecules to the vicinity of the palladium surface.Moreover, the other example ofthe use of cyclodextrin (CD)-capped Pd-NPs has been reported. Thus, hydroxypropyl-�-cyclodextrin-capped Pd-NPs have been obtained by addition of �-cyclodextrin partiallyO-hydroxypropylated to an aqueous solution of PdCl2.50 The active Pd(0) generated[Pd(0)/CD] has been used as a catalyst (0.5 mol%) in the coupling of aryl iodides, suchas 4-iodoanisole, or bromobenzene with phenylacetylene or 1-octyne, in the presence oftriethylamine in water at 60–70 ◦C to give the corresponding coupled alkynes such as17 (Scheme 4.6).

Palladium nanoclusters generated by dissolving PdCl2 in a mixed solvent (acetoni-trile/methanol 1 : 1) in the absence of any stabilizer were employed as catalysts (5 mol%Pd) in the presence of potassium carbonate as base at room temperature for the cross-coupling reaction of aryl iodides with terminal acetylenes.51 Leaching of palladium wasobserved by TEM images recorded during the catalytic reaction.51 In addition, Pd-NPswith nanobelt, nanoplate, and nanotree morphologies have been prepared from Pd(II)chloride using vitamin B1 as a reducing agent in water at room temperature without anycapping agent to prevent agglomeration. These palladium species were used as catalystsin the Sonogashira coupling of aryl iodides and bromides in the presence of pyridine asbase in acetonitrile as solvent under microwave irradiation, affording good yields.52

As the surface of the particles is the crucial area in the catalytic activity, recentwork has shown that it is also possible to economize expensive palladium metal in thepreparation of active Pd-NPs by preparing nickel/palladium core/shell bimetallic species,obtained from the consecutive thermal decomposition of their metal–trioctylphosphane(TOP) complexes.53 Whereas the Ni–TOP complex is decomposed at 205 ◦C, the Pd–TOP complex is barely decomposed at this temperature. After aging at 205 ◦C for30 min to decompose the Ni–TOP complex completely, the temperature was increasedto 235 ◦C to decompose the Pd–TOP complex, generating the Pd shell on the top of theNicore. These bimetallic nanoparticles show even higher catalytic activity in Sonogashiracoupling reactions at 2 mol% Pd than nanoparticles containing an equal amount ofpalladium, although copper cocatalysis and the presence of triphenylphosphane arenecessary. The nanoparticle catalyst could be reused at least five times without losingthe catalytic activity.

Hollow palladium–iron nanospheres have also been obtained through a vesicle-assisted chemical reduction method consisting of a mixture of aqueous solutions oftetra-n-butylphosphonium bromide, PdCl2, and FeCl2, followed by their reduction withsodium borohydride. The resulting nanospheres were employed as catalysts in severalpalladium-catalyzed coupling reactions.54 For instance, the Sonogashira coupling of aryl


iodides and terminal alkynes was successfully carried using this material as a catalyst(0.02 mol% Pd) in the presence of CuI, triphenylphosphane, and potassium carbonateas base in water at 80 ◦C. The catalyst could be separated from the reaction mixture bya magnet and reused up to five times without any loss of activity. In addition, bimetallichollow palladium–cobalt nanospheres were also obtained similarly and used as catalysts(0.02 mol%) in the cross-coupling of aryl iodides, as well as bromo- and chlorobenzene,with terminal acetylenes.55 The reaction was also performed using Cu(I) cocatalysisin the presence of triphenylphosphane as ligand, using potassium carbonate as base inwater at 80 ◦C, and the catalyst was separated by centrifugation and reused up to seventimes.

Bimetallic hollow palladium–cobalt nanoparticles were prepared by reduction ofCoSO4 andH2PdCl4 withNaBH4 in polyethylene glycol and used as catalysts in aqueousmedia at 80 ◦C for the coupling of aryl iodides or bromobenzene and terminal alkynes.However, the presence of copper iodide and triphenylphosphane was still required in thepresence of potassium carbonate as base for the reaction to take place.56 After separationfrom the solution, the catalyst was reused three times without any loss of activity. Inaddition, the elemental analysis of the filtrate after the reaction showed no leaching ofpalladium.

Trimetallic Au–Ag–Pd nanoparticle-based catalysts with Au–Ag-rich core/Pd-richshell structure were obtained by mixing solutions of nanoparticles of Au–Ag and Pd.The former were obtained by refluxing an aqueous solutions of HAuCl4 with AgNO3 inthe presence of cetyltrimethylammonium bromide (CTAB), and the latter by refluxingan H2O/EtOH solution of PdCl2 in the presence of CTAB. These trimetallic species wereused as catalysts (0.5 mol%) in the coupling of aryl iodides, bromides, and chloroben-zene with phenylacetylene, the process being performed in the presence of potassiumcarbonate in aqueous DMF as solvent at 120 ◦C.57 The trimetallic nanoparticle catalystwas collected by ultracentrifugation and reused up to three times without losing thecatalytic activity.

Immobilized Palladium Nanocatalysts

Immobilization of the metal on heterogeneous supports allows exploitation of the specialproperties that occur at this size regime. The fusion between porous materials andnanoparticles technology gives the potential for increased efficiency from nanoparticlecatalysis, combined with the advantages of heterogeneous supports concerning possiblecatalyst recovery.58,59 Therefore, research results on the preparation and use of supportednanoparticles as catalysts in C C bond-forming processes such as the Sonogashirareaction have been frequently reported in the very last years.

Palladium Nanocatalysts Immobilized on Polymeric and DendrimericMaterials. Dipyridyl-based poly(styrene-alt-maleimide)-anchored palladium com-plex 18 (1.2 mmol/g of Pd) has been used as a recyclable catalyst in copper-freeSonogashira couplings of electron-rich or electron-poor aryl iodides and electron-pooraryl bromides in refluxing water or under microwave heating using pyrrolidine as baseand tetra-n-butylammonium bromide (TBAB) as additive, achieving TONs up to 105.60


Scheme 4.7. Sonogashira cross-coupling reaction catalyzed by immobilized Pd-NPs generated

from a dipyridyl-based polymer-anchored palladium complex.

Under these conditions, the formation in the polymer surface of stabilized active Pd-NPs was observed with TEM images. The palladium loading could be decreased to0.001 mol% in the coupling of phenylacetylene and 4-chloroiodobenzene (19) to givealkyne 20 (Scheme 4.7), although longer reaction times were needed. This polymericcatalyst was reused up to five times without appreciable loss of catalytic activity.

Polymeric monolithic supports have been prepared by ring-opening metathe-sis polymerization from (Z)-9-oxabicyclo[6.1.0]non-4-ene and tris(cyclooct-4-en-yloxy)methylsilane in the presence of a phase separation-enforcing macroporogen suchas 2-propanol, and a microporogen such as toluene. The porous support was subjectedto pore-size-selective functionalization by hydrolyzing the epoxy groups within poresmore than 6 nm to the corresponding vic-diols using poly(styrenesulfonic acid). Theremaining epoxy moieties located within the small pores (�6 nm) reacted with N,N-dipyrid-2-ylamine, yielding the corresponding dipyrid-2-ylamine-functionalized mono-lithic support 21. These chelating ligands located within the small pores were used byimmobilization of Pd(II), which after reduction with NaBH4 resulted in the formationof Pd-NPs less than 4 nm located in the small pores (Scheme 4.8).61 These Pd-loadedmonoliths 22 were used in the copper-free Sonogashira coupling of deactivated arylbromides and phenylacetylene, using potassium tert-butoxide as base in the presence ofTBAB and a 1/1 (v/v) mixture of tetrahydrofuran (THF) /water as solvent at 50 ◦C. Scan-ning electron microscopy (SEM) measurements on the metal-loaded monoliths showedthat the Pd-NPs were immobilized within the small pores, which was supported by therather low metal content in the coupling products (�40 ppm, �0.13% Pd leaching).

A copper-free triethylamine-promoted Sonogashira reaction of aryl iodides andphenylacetylene in DMF as solvent at 120 ◦C was carried out using as recyclablecatalyst Pd(0) supported on cellulose (1.9 mol% Pd). These immobilized Pd-NPs werecreated by suspending a methanolic solution of PdCl2 with microcrystalline celluloseand reducing the formed solid with hydrazine.62 TEM analysis showed small palladiumnanoparticles along with larger aggregates, with more aggregation being observed in


Scheme 4.8. Preparation of a Pd(0)-loaded polymeric monolithic support.

the recycled catalyst. A 2.22% of palladium leaching was also detected in the reactionmixture after the fourth catalytic cycle.

An oxime palladacycle was anchored to soluble PEG, and the resulting polymer23 was used as a catalyst solubilized in PEG for a copper-free Sonogashira reactionusing cesium acetate as base at 150 ◦C.63 The catalyst was effective in the coupling ofa substrate such as 4-bromoacetophenone and phenylacetylene and can be reused afterprecipitation of the PEG in ether. The PEG-anchored carbopalladacycle was stable onheating in PEG, but largely decomposed during the first catalytic cycle, forming Pd-NPsstabilized by PEG. The catalyst maintained its catalytic properties without leaching fromthe PEG phase.

Formula 23.

Linear polystyrene-stabilized PdO nanoparticles (PS–PdO-NPs) prepared in water bythermal decomposition of Pd(OAc)2 in the presence of polystyrene were used as cat-alysts in the copper-free Sonogashira coupling of electron-rich and electron-deficientaryl iodides and terminal alkynes.64,65 The reaction was carried out in the presence oftriethylamine as base in water at 80 ◦C, and the catalyst was recovered and reused upto five times without loss of activity. Inductively coupled plasma (ICP) atomic emissionspectroscopy analysis of the aqueous phase, after separation of the supported catalyst,showed barely detectable levels of palladium residue, although the size distribution ofthe nanoparticles changed slightly. This catalyst was also employed in the formation ofbenzo[b]furans after reaction of o-iodophenols with terminal alkynes and subsequent


Scheme 4.9. Synthesis of a benzofuran by an alkynylation reaction of 2-iodophenol catalyzed

by linear polystyrene-stabilized PdO nanoparticles and subsequent internal cyclization.

cyclization, as shown in Scheme 4.9 where o-iodophenol was coupled with 1-octyne togive the corresponding final benzofuran 25 through alkynylated intermediate 24.

The use of Amberlite (IRA-67) base resin in the copper-cocatalyzed Sonogashiracross-coupling of 8-bromoguanosine 26 with phenylacetylene to give 27 was examined(Scheme 4.10), both 26 and 27 coordinating to palladium and copper ions.66 X-rayphotoelectron spectroscopy (XPS) was used to probe and quantify the active nitrogenbase sites of the Amberlite resin and the postreaction palladium and copper species.The PdCl2(PPh3)2 precatalyst and CuI cocatalyst added degraded to give Amberlite-supportedmetal nanoparticles (IRA-67-Pd, average size∼2.7 nm), which were observedby TEM analysis. The guanosine product 27 formed using the Amberlite Pd/Cu catalystsystem was of higher purity than the one obtained with the corresponding homogeneouspalladium catalyst.

Colloidal palladium was also stabilized and supported on poly(vinylpyrrolidone)(PVP) by heating Pd(OAc)2 in the presence of PVP. The supported Pd(0) nanoparticlescatalyzed the copper- and ligand-free Sonogashira reaction of aryl iodides and bro-mides with terminal alkynes using potassium carbonate as base in ethanol at 80 ◦C, thepalladium metal being recovered by decantation of the reaction solution and reused.67

One of the main interests in using Pd-NPs in the Sonogashira process relies on theirhigh reactivity, and therefore the suitability of performing copper- and ligand-free cou-plings. However, there are examples where the addition of Cu(I) and a phosphane ligandhas been necessary to perform a Pd-NP-catalyzed homogeneous coupling reaction. Thus,

Scheme 4.10. Alkynylation of 8-bromoguanosine catalyzed by Pd-NPs immobilized on an

Amberlite-based resin.


star-shaped heavily fluorinated aromatic sulfurs were prepared and used as stabilizers forPd(0) nanoparticle-active catalysts for the coupling of 4-iodoanisole and phenylacety-lene.68 The reaction was carried out in the presence of CuI and triphenylphosphane,using potassium carbonate as base in ethanol at 80 ◦C.68

Polymer-stabilized Pd-NPs were shown to be generated by reduction of palladiumnitrate with � -irradiation stabilized in the presence of polystyrene, poly(styrene-co-4-vinylphenylboronic acid), and poly(styrene-co-4-vinylbenzoic acid). The catalytic effi-ciency of these Pd-NPs was tested in the Sonogashira coupling reaction of iodobenzeneor 2-iodothiophene with phenylacetylene. They gave comparable yields as commer-cial 10% palladium on charcoal, although no recycling experiments were reported forthis reaction.69 In addition, Pd-NPs were generated in a solution of Pd(PPh3)4 andstyrene/divinylbenzene under an oxygen atmosphere, followed by radical polymeriza-tion.70 The resulting polystyrene-immobilized Pd-NPs were used as catalysts (1 mol%Pd) in the coupling of methyl p-iodobenzoate with phenylacetylene, using triethylamineas base in DMF at 110 ◦C. The reaction required the presence of Cu(I) iodide as acocatalyst. Unfortunately, recycling experiments were not reported for this system. Pd-NPs have been entangled in resin plugs following a procedure consisting of loading anaminomethylated styrene resin with Pd(II) acetate, reduction to Pd(0) with hydrazineand cross-linking and entanglement by reaction of the amino groups with succinylchloride.71 The resulting plugs were used as supported catalysts (9.8 mol% Pd) inseveral palladium-catalyzed C C bond-forming reactions such as the Sonogashira cou-pling of aryl iodides and phenylacetylene in the presence of potassium carbonate inDMF as solvents at 80 ◦C. Recycling experiments showed that yields remained unal-tered after four runs, and leaching determinations after using this catalyst in a Heckreaction in DMF at 115 ◦C showed 0.37 ppm of Pd(0) content in the solution at thefifth run.

A cross-linked polymer-supported ionic liquid-immobilized palladium catalyst wasprepared by reaction of Pd(OAc)2 with copolymer of 3-butyl-1-vinylimidazolium iodideand divinylbenzene 28 (Scheme 4.11).72 The resulting material [P(DVB-IL)-Pd] showedimmobilized Pd-NPs by TEM analysis, and was used as a catalyst (0.5 mol% Pd) ina copper-free carbonylative Sonogashira cross-coupling reaction of aryl iodides andterminal acetylenes. An example is shown in Scheme 4.11, where m-iodoanisole iscoupled with phenylacetylene under CO pressure (3 MPa) to give ynone 29, the reactionbeing carried out with triethylamine as base, in water as solvent at 130 ◦C.

Pd-NPs embedded into a polymer matrix of poly(1,4-phenylene sulfide) (PPS)were obtained via the thermolysis of Pd(OAc)2.73 XPS studies confirmed the presenceof strong sulfur coordination of PPS to the palladium nanoclusters. These Pd-NPs (Pd-NPs–PPS) were used as an efficient heterogeneous nanocatalytic system for the copper-free acyl Sonogashira reaction, affording ynones, as exemplified in Scheme 4.12, wherethiophene-2-carbonyl chloride (30) reacted with phenylacetylene in the presence ofPd-NPs–PPS and triethylamine as solvent, in MeCN at room temperature, to give thecorresponding ynone 31. The catalyst was recovered and recycled up to four times, TEMimages revealing that the catalyst maintained nanospheric dimensions for four consec-utive catalytic cycles. This protocol was further explored in a one-pot multicomponentsynthesis of 2,4-disubstituted pyrimidines and a tetrahydro-�-carboline derivative whentrimethylsilylacetylene was used as alkyne counterpart.


Scheme 4.11. Preparation of Pd-NPs immobilized in a cross-linked polymer of 3-butyl-1-

vinylimidazolium iodide and divinylbenzene and their use as catalysts in a carbonylative Sono-

gashira reaction.

Poly(methylphenylsilane) was used to immobilize Pd-NPs from Pd(OAc)2, and theresulting material (PSi–Pd) was used as a catalyst in several reactions, such as the modelSonogashira coupling of iodobenzene and phenylacetylene.74 The reaction was carriedout with a 5 mol% of PSi–Pd using potassium carbonate as base and in ethanol as solventat 80 ◦C, although no recycling experiments were carried out in this particular reaction.

Porous materials derived from starch (a polysaccharide formed by a mixture ofamylose and amylopectin) were used for supporting Pd-NPs. The polysaccharide alsoserved as a bioorganic reductant of Pd(OAc)2 after impregnation.75 The resulting sup-ported nanoparticles were used as catalysts in C C coupling reactions, such as inthe Sonogashira reaction. This was performed by coupling iodobenzene and pheny-lacetylene in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) under microwaveirradiation; however, no recycling experiment for this reaction was reported. In addition,gelatin, a water-soluble edible protein derived from partially denatured collagen, wasused as a support material for Pd-NPs generated from PdCl2 after its reduction with thesame biopolymer.76 These gelatin-supported nanoparticles showed catalytic activity forthe cross-coupling of aryl iodides, bromides, and some chlorides, as well as heteroarylbromides with phenylacetylene under copper-, ligand-, and amine-free conditions. Thereaction was carried out in molten TBAB or PEG in the presence of potassium acetate as

Scheme 4.12. Acyl-Sonogashira cross-coupling reaction catalyzed by Pd-NPs embedded into

a polymer matrix of poly(1,4-phenylene sulfide) (PPS).


Scheme 4.13. Formation of an enyne by a Sonogashira reaction catalyzed by gelatin-

supported Pd-NPs.

base. �-Bromo styrene (32) was also coupled with phenylacetylene under these reactionconditions, to afford the corresponding enyne 33 (Scheme 4.13). The supported catalystwas recycled after filtration and reused up to three times, which was accompanied bythe loss of its catalytic activity. According to ICP analysis, 31% palladium leachinginto molten TBAB was observed after the third run, SEM pictures showing aggregationof metal nanoparticles after the first and second runs. However, when the reaction wascarried out in PEG-400, the leaching of the palladium was reduced to 12% after the thirdrun. Probably the strong ionic character of molten TBAB easily removes the particlesof palladium from the surface of the gelatin.

Dendrimers based on polyamidoamine (PAMAM; Figure 4.1) have also been usedto bind Pd-NPs useful for C C coupling reactions. For example, G2 (16 NH2), G3 (32NH2), and G4 (64 NH2) dendrimers were impregnated with PdCl2 and reduced withNaBH4 to achieve immobilized Pd-NPs.77 These Pd(0)-containing dendrimers wereused as catalysts in themodel Sonogashira coupling of iodobenzene and phenylacetylene,using potassium carbonate as base in ethanol at 80 ◦C. However, recycling of the catalystwas not effective, as severe aggregation was shown according to TEM determinations.

Figure 4.1. Chemical structure of PAMAM dendrimer G1.


Palladium Nanocatalyst Immobilized on Carbon Materials. The use ofpalladium on charcoal has found increasing popularity in several of the more commonC C bond-forming reactions, such as the Sonogashira coupling process. Frequently,either Cu(I) cocatalysis and phosphanes78–81 or only phosphanes were necessary for thereaction to take place,82–84 although there were examples of copper- and ligand-freeprocesses.85–87 However, there were issues associated with its use (e.g., levels of leach-ing), which were difficult to address. This result is similar to commercial palladium oncharcoal catalysts, which usually shows highly variable nanoparticle sizes and oxidationstates of the metal that hampers its use in Sonogashira reactions.

A novel form of palladium on charcoal was prepared by dissolving Pd(NO3)2 inwater, and adding activated charcoal into it, followed by treatment with ultrasonicationand drying.88 This palladium on charcoal, named UC Pd, which showed rather largePd-NPs, surprisingly was among the most active catalysts. It gave catalytic activitiesconsistentwithmany commercially sold catalysts for the Sonogashira reactions, allowingthe copper-free coupling of aryl bromides with terminal alkynes (2 mol% Pd), in thepresence of Xphos (34) as a ligand and potassium carbonate as base in ethanol as solventat 50 ◦C. This UC Pd was recycled up to four times with only a small lowering of theactivity, other commercially available Pd/C forms being unreactive after four runs. Afterfiltering the supported palladium, the filtrate showed only traces of leached palladium(2–4 ppm), whereas, interestingly, the addition of CuI diminished the reactivity of thecatalyst by half. The better stability ofUCPd compared to other commercial palladiumoncharcoal catalystswas explained based on the higher levels of reducedmetal at the surfacerelative to other catalysts due to the larger metal nanoparticles in the former. These wouldstabilize oxides on their surface in a lower extent than smaller nanoparticles. The useof this catalytic system allowed the synthesis of complex alkynes from functionalizedterminal acetylenes, such as compound 37, which is produced by coupling of activatedaryl bromide 35 with estrone-derived acetylene 36 (Scheme 4.14).

A carbon aerogel doped with Pd-NPs was used as a catalyst (6 mol%) in theSonogashira cross-coupling of aryl iodides with terminal alkynes, in the presence ofCuI, triphenylphosphane and using diisopropylamine as base in DMF at 100 ◦C.89

Importantly, neither significant leaching of palladium and nor decrease in the catalyticactivity was observed after 15 cycles.

Phthalides were prepared by a ligand-free tandem palladium immobilized on acarbon nanotube (C/CNT)-catalyzed coupling-cyclization process, although no mentionabout recyclability of the supported catalyst wasmade.90 Thus, o-iodobenzoic acids suchas 38 have been coupled with terminal alkynes such as methyl propargylate, using C/C-NTs as catalysts (0.1 mol%) in the presence of DABCO and sodium acetate in wet DMFat 100◦C, to give the corresponding phthalide 40 after cyclization of the Sonogashiraintermediate 39 (Scheme 4.15).

Nitrogen-doped magnetic carbon nanoparticles were prepared using iron-dopedpolypyrrole as the carbon precursor and Pd(II) nitrate as the source of Pd. Aftercarbonization at 800 ◦C followed by calcination in a hydrogen atmosphere, the nitrogen-doped carbon nanoparticles were formed. This material was used as a catalyst (1 mol%Pd) in several C C bond-forming processes such as the Sonogashira reaction, whichwas carried out by coupling 4-bromoacetophenone with phenylacetylene under coppercocatalysis, using sodium carbonate as base in dimethyl sulfoxide (DMSO) as solvent at


Scheme 4.14. Sonogashira cross-coupling reaction catalyzed by a combination of a kind of

palladium on charcoal (UC Pd) and the Xphos ligand.

100 ◦C in the presence of CuI.91 The recovery of the supported catalyst was performedby magnetic separation, being reused up to three times without loss of activity.

Mesoporous cubic carbon containing Pd-NPs formed by reduction of Pd(II) withsodium borohydride was studied as the supported catalyst in the coupling of iodoben-zene and phenylacetylene using different reaction conditions.92 Considerable palladiumleaching was observed, being largely dependent of the base nature. Thus, the use oftriethylamine revealed very poor recyclability, whereas when sodium acetate was used

Scheme 4.15. Synthesis of a phthalide by an alkynylation of 2-iodobenzoic acid catalyzed by

palladium(0) immobilized on carbon nanotubes and subsequent cyclization.


as base, the reusability was much better. This was not due to the extent of palladiumleaching, as it was demonstrated that leaching was more important when using sodiumacetate as base, probably because acetate ions bound strongly to soluble Pd(II) createdby leaching of the Pd-NPs to the solution. Presumably, the Pd(II) complexes were lessprone to aggregation to form inactive palladium black than when low coordinating basessuch as triethylamine were used. Interestingly, the obtained yields were much higherwhen using the supported Pd-NPs than when using suspended nanoparticles. This sug-gests that the Pd(0)-loaded support would be a reservoir for the active catalyst, as itsinterfacial area between the palladium and the reaction mixture results much larger thanin suspended nanoparticles that have tendency to aggregate.93 In addition, Pd-NPs gen-erated similarly have also been deposited on mesoporous carbon formed by pyrolysisof a polymer-coated silica template, this palladium-containing material being used asa catalyst in the cross-coupling of iodobenzene and phenylacetylene.94 The couplingwas performed in the presence of sodium acetate in aqueous DMF as solvent, but theyield of diphenylacetylene obtained was just a 48% with deactivation of the catalyst byformation of large polydisperse crystalline palladium particles.

Multiwalled carbon nanotubes (MWC-NTs)were loadedwith Pd-NPs on the outsidewalls after impregnation with Pd(NO3)2, evaporation, and calcination of the materialat 350 ◦C for 2 h. Finally, the material was reduced under hydrogen gas at 400 ◦C for2 h. This material, labeled as [MWC-NTs-Pd(0)], was employed as a catalyst in thecoupling of aryl iodides with 1-ethynyl-4-methylbenzene to yield the correspondingacetylenes under microwave irradiation in the presence of potassium carbonate as basein a 1 : 1 (v/v) mixture of ethanol–water as solvent at 160 ◦C for 5 min.95 Interestingly,when the reaction was carried out with electron-deficient aryl iodides, such as 1-iodo-4-nitrobenzene, but using piperidine as base in ethanol as solvent at 120◦C, apart from thecorresponding Sonogashira product 41, the unusual formation of an enyne by-product42 was observed (Scheme 4.16). Recovery of the immobilized catalyst and reuse for

Scheme 4.16. Sonogashira cross-coupling reaction catalyzed by Pd-NPs immobilized on mul-

tiwalled carbon nanotubes, showing the unusual formation of an enyne byproduct.


five additional cycles did not lead to a decrease in the catalytic activity. TEM imagesof the catalyst after these cycles did not show evidence of growth of Pd-NPs, althoughdifferent tests revealed a 1.1% palladium leaching. In addition, Pd-NPs supported onimidazolium-functionalized MWC-NTs were employed as a catalyst (5 mol% Pd) in thecross-coupling of p-bromoacetophenone and phenylacetylene using cesium carbonateas base in DMF as solvent at 120 ◦C, although the addition of triphenylphosphane andcopper iodide resulted necessary.96 Reuse of the supported catalyst after 10 times showeda steady decrease in the activity. TEM analysis of the recovered catalysts after 30 timesreuse showed severe aggregation of the Pd-NPs.

Pd-NPs formed from Pd(II) acetate in electrospun polyacrylonitrile nanofibers by acarbonization process were explored (0.5 mol% Pd) in the coupling of iodobenzene andphenylacetylene showing high catalytic reactivity and high leaching resistance.97 Thereaction was carried out in the presence of sodium phosphate as base in refluxing iso-propanol, and recycling experiments showed unaltered yield (85%) of the final coupledproduct after 10 runs, together with 100% retrieval of the nanofibers.

Pd(II)-exchanged graphite oxide has been used as a precatalyst for the formation ofPd-NPs, which are then deposited on the highly functionalized carbonaceous support.98

This ligand-free system was employed as a catalyst (0.25 mol% Pd) in the copper-free Sonogashira coupling of aryl iodides with phenylacetylene in the presence ofsodium phosphate as base, in aqueous isopropanol as solvent at 80 ◦C. A low leachingof palladium was observed at the completion of the reaction, and the catalyst couldbe recovered. Filtration experiments and a three-phase test suggested a homogeneousmechanism. Thus, a solid-phase-bound aryl iodidewas subjected to cross-coupling underthe same reaction conditions, showing high conversion. Since the solid-phase-bound aryliodide is supposed to be unable to attack nanoparticles on graphite oxide, leaching ofpalladium to the solution should be responsible for the catalytic activity.

Palladium Nanocatalysts Immobilized on Inorganic and MixedMaterials. Silica frameworks are interesting support materials for stabilizing Pd-NPsand produce supported palladium catalysts amenable to perform the different C C cou-plings.99 Furthermore, they are usually easy to handle, and their high density makes themsuitable for low-volume work, not requiring extensive washing for high recoveries asthey do not stick to glassware and are stable. In addition, they are robust (mechanicallyand thermally stable), and work well with overhead stirring and stand high temperatures,having low swelling properties, which frequentlymakes them solvent independent. How-ever, the Sonogashira reaction is performed under basic conditions, which sometimesproduces low stability of the silica framework and degradation.

Pd-NPs generated by heating a mixture of Pd(PPh3)4, tetra(ethylene glycol), andtetramethoxysilane, or titanium(IV) isopropoxide, were encapsulated in silica matrix (ortitania matrix) by the subsequent treatment with water. These filtration-recyclable encap-sulated nanoparticles were active as catalysts in the coupling of methyl p-iodobenzoateand phenylacetylene in triethylamine/DMF, although copper cocatalysis and a reactiontemperature of 110 ◦C were necessary.100 In addition, hollow mesoporous silica spheresbearing Pd-NPs residing inside the spheres have been prepared and employed in a model


Sonogashira coupling of iodobenzene and phenylacetylene, the catalyst being recoveredby centrifugation and reused.101

Pd-NPs supported on PEG-functionalized silica gel 43 were obtained by reactionof the corresponding modified silica gel with K2PdCl4 in the presence of the acylmetal salt of the Fischer carbene complex (OC)5W=CMeO−Et4N+.102 These supportednanoparticles were used as catalysts (1 mol% Pd) in the copper-free cross-couplingreaction of iodoaryls with terminal acetylenes, employing potassium carbonate as basein DMF as solvent at 110 ◦C. Recycling and reusing of the immobilized catalyst showeda significative decreasing in the activity after the fifth run. This was justified by observingthe TEM images of the recovered catalyst, which showed that the size of the Pd-NPsincreased by about 2 nm after three catalytic runs, whereas size of the nanoparticlesincreased to 20–25 nm after five runs, indicating that agglomeration to form biggerpalladium clusters was significant.

Formula 43.

Nanostructured silica functionalized with pyridines can form supported palladiumcomplex 44 (X = I, Br, OAc) upon being stirred with palladium acetate.103 This com-plex was used as the recoverable catalyst (10 mol% of Pd) in the Sonogashira reac-tion of iodobenzene, 2-iodothiophene, and 1-iodonaphthalene with phenylacetyleneand p-tolylacetylene in the presence of triethylamine in acetonitrile at reflux. Lowleaching of 0.9 ppm was observed although with a certain catalyst deterioration uponrecycling.

Formula 44.

Perfluoro-tagged Pd-NPs immobilized on silica gel through fluorous–fluorous inter-actions or linked to silica gel by covalent bonds have been used as catalysts (0.1–0.5 mol% of Pd) in the alkynylation of terminal alkynes with a variety of aryl iodides


Scheme 4.17. Sonogashira cross-coupling reaction catalyzed by perfluoro-tagged Pd-NPs

linked to silica gel.

and some aryl bromides in the presence of pyrrolidine in refluxing water as solvent.104

In the case of the nanoparticles supported to the silica by direct fluorous–fluorous inter-actions, high levels of palladium (39–240 ppm) were found in the crude products dueto the relative weakness of the fluorous–fluorous interactions, and reusing was limitedto four runs. However, when the fluorinated system linked to the silica gel 45 was usedas support for the nanoparticles, the catalytic system allowed for a number of recovercycles largely higher (11 runs) than in the previous case. An example of using thissupported system is shown in Scheme 4.17, with the coupling of 4-iodoanisole withterminal alkyne 46 to afford the disubstituted alkyne 47.

Nanostructured mesoporous silica-based materials featuring SBA-15 architecturesand surfaces functionalized with amide–thiol groups have been used for depositionof palladium and employed as catalysts (1 mol% Pd) in the coupling of some arylbromides with phenylacetylene, sodium carbonate being employed as base in aqueousDMF as solvent at 100 ◦C.105 The recyclability of the catalytic system proved possible,although deactivation was observed upon reuse. In addition, the cubic phase of thezeoliteMCM-48 has been impregnatedwith Pd-NPs generated by reduction ofNa2PdCl4with NaBH4 and stabilized by tetra-n-octylammonium bromide as a capping agent.106

This heterogeneous mesoporous Pd(0)–MCM-48 has been used as a reusable catalyst(0.6 mol% Pd) in the copper/amine-free coupling of aryl iodides and bromides withterminal acetylenes, the reaction being performed in the presence of potassium carbonateas base in refluxing ethanol as solvent. The recyclability of this system was investigatedfor the synthesis of diphenylacetylene, the filtered Pd(0)–MCM-48 being reused up tosix times with yields lowering down from 85 to 75%.

Silica gel was also employed for anchoring starch, creating a silica–starch substrate(SSS) suitable for the immobilization of Pd-NPs after impregnation with Pd(OAc)2and further reduction by the polysaccharide.107 This Pd-NP–SSS system 48 was used assupported catalysts in the copper-free Sonogashira coupling of aryl iodides and bromides,as well as electron-deficient aryl chlorides, with terminal alkynes, using potassiumcarbonate as base in refluxing water as solvent. The reusability of this Pd-NP–SSScatalyst was tested using the reaction between bromobenzene and phenylacetylene, thefiltered supported catalyst being reused up to five times without appreciable loss of


activity. ICP analysis of the aqueous phases of the reaction mixture showed that only asmall amount of the palladium (2.2%) was removed from the SSS substrate.

Formula 48.

Air- and moisture-stable Pd/MgLa mixed oxide, prepared by ion exchange ofthe MgLa mixed oxide with Na2PdCl4 and further reduction with hydrazine hydrate,was used as the filtration-recoverable and no-leaching supported Pd(0) catalyst in thecopper-free Sonogashira reaction of aryl iodides, bromides, and even unactivated arylchlorides (1.5 mol% Pd). The coupling reaction took place by heating in DMF at 80 ◦Cin the presence of triethylamine as base.108

A metal–organic framework (MOF) of Zn4O clusters and benzene-1,4-dicarboxylate linkers, forming an open cubic network, has been used for supporting Pd-NPs after soaking theMOFwith Pd(II) chloride and further reduction with hydrazine.109

This nanoparticle-containingmaterial has been used as a catalyst in the Sonogashira reac-tion of aryl iodides and terminal alkynes, performing the coupling in the presence ofpotassium phosphate as base in methanol as solvent at 80 ◦C. The activity of the recycledcatalyst is decreased noticeably after the third run. The deactivation of the catalyst isattributed to palladium oxidation to Pd(II), as determined by XPS, and not to palladiumleaching.

The chromium terephthalate-based mesoscopic metal–organic frameworkMIL-101is one of the most porous materials reported to date, and has been used for immobiliz-ing Pd-NPs created after impregnation with Pd(acac)2 and reduction with a hydrogenatmosphere.110 This Pd–MIL-101 material was used as an immobilized catalyst (3%Pd) in the synthesis of indole systems in refluxing water through the copper-cocatalyzedSonogashira coupling of o-iodoanilines, such as 49, with phenylacetylene, to give thecorresponding indoles such as 51 after cyclization of intermediate 50 (Scheme 4.18).The process was carried out in the presence of triphenylphosphane and potassiumcarbonate as base and the Pd–MIL-101. The catalyst was shown to be recycled by sim-ple centrifugation although a slight reduction in the yield of the coupled product wasobserved. Furthermore, TEM images showed no changes in the structure of Pd–MIL-101 after recycling, and ICP analysis revealed less than 0.9 ppb of Pd content in thesolution.


Scheme 4.18. Formation of an indole by an alkynylation of a 2-iodoaniline catalyzed by

Pd-NPs immobilized in a chromium terephthalate-based mesoscopic metal-organic framework

(MIL-101), and subsequent cyclization.

A chloride-saturated Mg–Al-layered double hydroxide has been employed for theimmobilization of Pd-NPs by an ion-exchange technique using PdCl42− followed byreduction.111 These Pd-NPs have been used as catalysts (1 mol% Pd) in the cross-coupling of chloroarenes with phenylacetylene, the reaction being performed usingtriethylamine as base, in a 1 : 1 THF/water mixture as solvent at 80 ◦C. Heterogeneitytests carried out using this catalyst, although in a Heck reaction, show that this occursat the heterogeneous surface of the Pd-NP. The immobilized catalyst was recovered byfiltration and reused for several runs without loss of integrity.

Impregnation of superparamagnetic Fe3O4 nanoparticles with Pd(0) nanoparticles,generated from a Pd(II) salt and reduction with potassium borohydride, has allowedthe preparation of a magnetically separable palladium catalyst suitable to perform acarbonylative Sonogashira coupling reaction for the synthesis of �,�-alkynyl ketones.112

Thus, aryl iodides such as 52 reactedwith terminal alkynes such as phenylacetylene in thepresence of the palladium catalyst (1mol%Pd) and triethylamine under an atmosphere ofcarbon monoxide (2 MPa) in toluene at 130 ◦C, to afford the corresponding alkynylatedketone 53 (Scheme 4.19). The catalyst was magnetically separated and reused seventimes with a slight loss of activity, the operating mechanism being quasihomogenousand catalyzed by small amounts of palladium species in solution.

Dendritic nanoferrites with a micropine morphology have been prepared, and itsfunctionalization with dopamine, followed by reaction with Na2PdCl4 and reduction

Scheme 4.19. Carbonylative Sonogashira cross-coupling reaction catalyzed by Pd-NPs

impregnated in magnetite.


with hydrazine, has allowed obtaining a material with Pd-NPs at the tips of amino-functionalized micropine ferrites.113 This material is suitable as a catalyst for palladium-catalyzed coupling reactions, such as the Sonogashira cross-coupling, which has beencarried out allowing the coupling of aryl iodides and bromides in good yields in thepresence of potassium carbonate and pyridine, in DMF as solvent at 100 ◦C undermicrowave irradiation. Leaching and recyclability have been analyzed performing Heckcouplings under similar reaction conditions, showing negligible palladium leachingprobably due to the well-defined amine binding sites located on the surface of themicropine ferrites.

The dendritic Pd(II) complex 54 has been prepared by a covalent grafting via a reac-tion between carboxylic acid groups of core–shell � -Fe2O3/polymer superparamagneticnanoparticles and amino groups at the focal point of an amino-terminated dendron.114

Its catalytic activity was investigated in the copper-free Sonogashira coupling (2.4 mol%Pd) of aryl iodides and bromides in methanol or water at 70 ◦C, using Triton X-405as a surfactant and lithium hydroxide as base. The amount of palladium leached to thesolution was 2.3% per cycle. However, the catalysis reactivity reported was not associ-ated with leached palladium (corresponding to 0.05 mol% of Pd of starting palladiumcatalyst per cycle), as leached particles needed to be activated in the reaction medium tobe efficient as catalysts.

Formula 54.

Superparamagnetic nanoparticleswere synthesized fromCoCl2 andFeCl2 followinga microemulsion method with sodium dodecyl sulfate as surfactant and functionalizedwith Schiff base groups on the surface to form immobilized bidentate ligands, whichwere complexed with Pd(OAc)2 to give nanoparticle-supported complex 55.115 Thisnanoparticle-bound complex was employed as a catalyst (1 mol% Pd) in the cross-coupling of aryl iodides with phenylacetylene, the addition of CuI to accelerate thereaction being necessary. The reaction was carried out using sodium phosphate as base,in DMF as solvent at 80 ◦C. The catalyst was recovered by applying an external magnet.The recyclability of the catalyst was investigated after five reaction runs, althoughsignificant decrease in its activity was observed after the first run, no contribution from


leached palladium to the reaction being observed when adding additional amounts ofreactants after separation of the catalyst.

Formula 55.

Immobilization of a Pd(II)�-oxoiminatophosphane complex to amagnetic nanopar-ticle formed by coating commercial iron(III) oxide with silica gives anchored complex56, which have been used as catalysts (0.5mol%) in different cross-coupling reactions.116

Concerning its use in the Sonogashira coupling, when the reaction was performed in thepresence of piperidine and TBAB as additive inwater at 60 ◦C, the usually unreactive arylchlorides were able to cross-couple with terminal alkynes in high yields. An example isshown in Scheme 4.20, where hindered dimethylated chlorobenzene 57 is coupled withphenylacetylene under these reaction conditions to give the corresponding alkyne 58. Thecatalystwas recovered from the reactionmixture bymagnetic separation and reusedwith-out loss of activity after 10 reaction cycles, detecting less than 0.06% palladium leaching.Interestingly, no formation of visible Pd-NPs was observed on the support surface.

Superparamagnetic nanoparticles formed by maghemite nanocrystals have beenformed from supported NHC palladium complex 59 and employed as catalysts(7.3 mol%) in the Sonogashira reaction of aryl iodides and bromides with pheny-lacetylene, although in the presence of CuI as cocatalysts.117 The reaction was carriedout in DMF at 50 ◦C, using sodium carbonate as base. Recycling of the catalyst wasperformed, without observing loss of activity after five consecutive runs.

Scheme 4.20. Sonogashira alkynylation of a hindered and low-reactive aryl chloride cat-

alyzed by a Pd(II) oxoiminatophosphane complex anchored to a magnetic nanoparticle coated

with silica.


Formula 59.

Other Metal-Based Nanoparticles as Catalysts

Different attempts have been made to achieve the Sonogashira reaction in the absenceof the expensive noble metal palladium and using instead a cheaper one, such as copperor iron.118 Nonetheless, behind all these methodologies lingers the question whether theSonogashira cross-coupling reaction has resulted as a consequence of minute amounts ofpalladium contaminants, and extremely caution must be taken considering metal traces.For instance, it was demonstrated that ppb levels of palladium impurities had a dramaticeffect in a reported so-called copper-catalyzed reaction.119

Copper nanoclusters generated by reducing a solution of CuCl2 with tetraoctylam-monium formate in DMF at 65 ◦C were used as catalysts (5 mol%) in the Sonogashiracoupling of aryl iodides and electron-deficient aryl bromides with phenylacetylene, thereaction being performed in the presence of DMF at 110 ◦C.120 These catalysts werereused three times without any loss of catalytic activity when another equivalent of thereactants and base was added. In addition, a solvent-free mixture of octahedral Cu2Onanoparticles (10 mol%), triphenyl-phosphane (20 mol%), and TBAB, using potassiumcarbonate as base at 135–140 ◦C was employed as a reusable system for the cross-coupling of aryl and heteroaryl iodides, bromides and activated chlorides, and terminalalkynes.121 An example of coupling of an aryl chloride is shown in Scheme 4.21, wherethe electron-deficient 1-chloro-4-nitrobenzene is cross-coupled with phenylacetylene togive alkyne 60. In addition, octahedral and rod-like � -CuI nanocrystals were used ascatalysts (10 mol%), combined to triphenylphosphane in the presence of potassium car-bonate, in the cross-coupling reaction of 4-iodoanisole and phenylacetylene performedin PEG-400 as solvent at 130 ◦C.122 Moreover, commercial CuO nanoparticles have beenemployed as catalysts in the Sonogashira coupling of aryl iodides with terminal alkynes,using potassium carbonate as base in DMSO as solvent at 160 ◦C.123 However, the cata-lyst was not reusable as TEM analysis showed that most of the CuO nanoparticles were

Scheme 4.21. Sonogashira cross-coupling reaction catalyzed by octahedral Cu2O

nanoparticles.


Scheme 4.22. Sonogashira cross-coupling reaction catalyzed by paramagnetic magnetite

nanoparticles.

aggregated after the reaction. Interestingly, other nanometal oxides such as nano-Fe2O3,nano-NiO, and nano-In2O3 produced only trace amounts of the Sonogashira productunder the same reaction conditions.123

Paramagnetic magnetite (Fe3O4) nanoparticles were reported to act as efficientcatalysts (5 mol%) for C C bond formation via the Sonogashira reaction under het-erogeneous ligand-free conditions in ethylene glycol at 125 ◦C. By using this catalyst,arylalkynes such as 62 were produced from the reaction of aryl iodides and activatedheteroaryl bromides, such as 5-bromopyrimidine (61), with terminal alkynes, such asphenylacetylene (Scheme 4.22).124 Furthermore, the catalyst was separated after thereaction by an external magnetic field and reused for five consecutive runs without lossof catalytic activity. The addition of different amounts of palladium and copper impu-rities did not affect the final yield significantly, but the addition of different amounts ofthe iron nanoparticles affected noticeably, suggesting that the iron nanoparticles werereally responsible for the catalytic activity.

Copper ferrite (CuFe2O4) nanoparticles were shown to serve as catalysts for thecoupling of aryl iodides, bromides, and chlorides with terminal acetylenes in moderateyields, cesium carbonate being employed as base in refluxing dioxane as solvent.125

The recyclability of the CuFe2O4 catalyst was investigated after removal with a mag-net, which gave the reusable catalyst for three cycles without loss of activity. Atomicabsorption spectroscopy showed a leaching of Cu and Fe of only equal to or less than0.5 ppm in three consecutive cycles.

Nanocatalysts based on cobalt and nickel were also developed for the use inSonogashira reactions. Thus, hollow cobalt nanospheres (3 mol%) in the presence oftriphenylphosphane (10 mol%), CuI (2 mol%), and potassium carbonate in NMP at120 ◦C successfully catalyzed the coupling of aryl iodides or bromobenzene and termi-nal alkynes.126 Furthermore, the cobalt nanoparticles were recovered and successfullyreused up to three times.126

Gold (and its complexes)-catalyzed organic transformations have been focus ofattention in recent years,127,128 and particularly research on gold-promoted cross-coupling reactions has been very active.129 In the particular case of the Sonogashirareaction, some controversy has aroused as it has been reported that Au(I) was unableto perform the oxidative addition of iodobenzene in the first step of a Sonogashira-likecatalytic cycle130; therefore, some observed that Au(I)-promoted Sonogashira reac-tions131–134 could be produced by contaminating traces of palladium. This assertion hasbeen addressed after kinetic and theoretical studies, although DFT calculations showthat the iodobenzene oxidative cleavage on an Au(I) complex is a certainly difficultprocess. Au(I) complexes are converted under the reaction conditions into nascent gold


nanoparticles, and those are in fact responsible of the catalytic activity, making thepresence of traces of palladium to explain the cross-coupling process unnecessary.135

In fact, gold nanoparticles supported on cerium(III) oxide, niobium(V) oxide, and silicacatalyze the Sonogashira reaction of aryl iodides and bromides and terminal alkynes,when reacting in the presence of potassium carbonate as base in DMF under microwaveirradiation.136 In addition, gold nanoparticles have also been supported on chitosan(63), a porous linear polysaccharide produced by deacetylation of chitin, being used ascatalysts in the coupling of iodobenzene and phenylacetylene, working in the presenceof potassium phosphate as base in DMF at 80 ◦C.137

Formula 63.

Concerning the nature of the Au(0) catalyst and the process, studies basedon temperature-programmed reaction measurements supported by scanning tunnelingmicroscopy have shown that phenylacetylene and iodobenzene react on Au(111) (highpurity 99.999%Au) under vacuum conditions to yield biphenyl and diphenyldiacetylenetogether with the corresponding Sonogashira coupling product.138 These studies indicatethat heterogeneous cross-coupling chemistry is an intrinsic property of extended, metal-lic pure gold surfaces. The reagents would be initially adsorbed intact on the surface ofthe gold crystallites until the temperature needed to achieve the C–I bond cleavage ofthe aryl iodide is achieved, which coincides with that required for the Sonogashira cou-pling. Additional studies on the behavior of gold species deposited on lanthana or ceriashowed that gold nanoparticles were highly selective toward the Sonogashira productdiphenylacetylene, although proving active but unselective when supported on silica,alumina, or barium oxide, suggesting an effect of metal-support spillover.139

Finally, an interesting study indicates that the gold nanoparticle-catalyzed Sono-gashira coupling of iodobenzene and phenylacetylene is predominantly a heterogeneousprocess.140 It was observed that large gold particles resulted much more selective towarddiphenylacetylene than small ones, which would be consisting with the hypothesis thatsteric limitations adversely affect the efficiency of the process. Accordingly, an expla-nation in terms of adsorption geometries and steric effects has been offered, and it isillustrated in Figure 4.2. Thus, if iodobenzene activation involves C–I scission, the result-ing phenyl group is expected to be strongly tilted with respect to the gold surface and willhave a relatively small reaction footprint. Phenylacetylene adsorption on gold is stericallymore demanding, as the molecule adsorbs essentially flat through �-interaction with themetal surface. Therefore, homocoupling of two adsorbed iodobenzenemolecules to yieldbiphenyl may be possible on the small facet planes of tiny Au particles, whereas thecoupling of iodobenzene and phenylacetylene may only be accommodated on the largerfacet planes available on bigger Au particles. Moreover, gold leached into the solution


Figure 4.2. Possible origin of gold particle size effect on selectivity when coupling iodoben-

zene and phenylacetylene due to steric demands of reactant adsorption footprint size.

Diphenylacetylene formation resulted inhibited on small gold particles.

phase has exhibited immeasurably low catalytic activity, also pointing to the primacy ofheterogeneous chemistry. These studies have also been extended to the case of metal-lic rhodium nanoparticle catalysts, revealing similar preference for a heterogeneousSonogashira coupling.141

Ruthenium nanoparticles immobilized on alumina (5 mol%) obtained fromRuCl3xH2O and commercial alumina by a calcination–hydrogenation procedure wereable to catalyze the copper-free Sonogashira coupling of aryl iodides and differentacetylenes using triethylamine as base in acetonitrile as solvent at 90 ◦C.142 The het-erogeneous catalyst has been filtered off after the coupling and used in a second cyclekeeping almost the same catalytic activity.

MECHANISTIC ASPECTS

The exact mechanism of the palladium/copper-catalyzed Sonogashira reaction is still notcompletely understood, although it is supposed to take place through two independentcatalytic cycles (Figure 4.3). The first “palladium-cycle” (cycle I) is classical from C Ccross-coupling formations143 and starts in the catalytically active species Pd(0)L2, whichcan be of colloidal nature and/or a low-ligated Pd(0) species stabilized by the ligandspresent, including the base and/or solvent molecules. Once complex [Pd(0)L2] has beenformed, the first step in the catalytic cycle is initiated by oxidative addition of the aryl orvinyl halide, which is considered to be the rate-limiting step of the Sonogashira reaction,the barriers of oxidative addition of ArX (X = Cl, Br, I) increasing in the order ofArI � ArBr � ArCl.144 Highthroughput kinetics and descriptor modeling suggest thatthe initial aryl halides participate in the turnover-determining step of the Sonogashirareaction.145 Presumably, this step is preceded by an end-on ligation of the halogenatom to palladium and therefore could be regarded as an electron-donating step. Thus,the higher the EHOMO of the substrate (electron donor groups), the more stable thecomplex should be and, the higher the rate determining activation barrier for subsequent

MECHANISTIC ASPECTS 117

Figure 4.3. The proposed mechanism of the copper-cocatalyzed Sonogashira reaction.

steps. On the contrary, a low EHOMO (electron-withdrawing groups) would facilitate theoxidative addition reaction. The formed [Pd(II)R1L2X] adduct, shown in Figure 4.3,is then transformed into a [Pd(II)L2R1(C≡CR2)] species after transmetalation with acopper acetylide formed in a “copper cycle” (cycle II). This adduct suffers reductiveelimination, after cis/trans-isomerization, to the final alkyne, regenerating the catalyst[Pd(0)L2].

The “copper cycle” (cycle II) is poorly known. The base (organic or inorganic) isbelieved to assist the copper acetylide formation with the help of a �-alkyne–coppercomplex, which would make the alkyne terminal proton more acidic. However, it hasbeen shown that CuI–polyphosphane adducts can be formed and ligands can be trans-ferred from one metal to another, showing that copper–ligand interactions might also belikely in tandem palladium/copper cross-coupling reactions.146,147

The processes involving the copper-free Sonogashira reaction have been investigatedmore deeply, even theoretically,148,149 and the suggested mechanism is depicted inFigure 4.4a. This proposed catalytic cycle is initiated, as usual, by the oxidative additionof the aryl or vinyl halide to the catalytic species [Pd(0)L2]. The following step would bea reversible �-coordination of the alkyne, producing an alkyne–Pd(II) complex wherethe acetylenic proton is acidified, facilitating its removal by the base with coordinationof the acetylene ligand to the metal. This [Pd(II)R1(C≡CR2)L2] complex releases thecross-coupled product by reductive elimination, reforming the catalytic species.

Recent theoretical calculations carried out on the copper-free Sonogashira couplingof iodobenzene and several 4-substituted phenylacetylenes considering all the reportedmechanistic proposals150 suggest that in this process (like in other cross-coupling reac-tions) there are several reaction pathways that may have competitive rates and a changein the reaction conditions might favor one over the other. In addition, calculations carriedout considering the coupling of bromobenzene and phenylacetylene, using Pd(PPh3)4as catalysts and sec-butylamine as base,151 suggested that the catalytically active palla-dium species would be Pd(PPh3)3 and the process would consist of a oxidative addition


Figure 4.4. (a) Proposed mechanism for the copper-free Sonogashira reaction if a possibly

present amine is a less good ligand for Pd(II) than the alkyne. (b) Mechanism for the Sono-

gashira reaction if a present amine is a better ligand than the alkyne for the Pd(II) center.

through biligated species, followed by cis/trans-isomerization, deprotonation, and bili-gated reductive elimination. The amine present can also inhibit the oxidative addition byforming stable complexes with palladium, confirming that amines can playmultiple rolesin the copper-free Sonogashira reaction.152 Thus, experimentally it has been shown that,besides their expected function as deprotonating agents, amines may be involved in dif-ferent steps preceding the deprotonation. Amines can interfere in the oxidative additionby an accelerating effect due to the formation of more reactive [Pd(0)L(amine)] com-plexes, and they can also substitute one ligand in the complex formed after the oxidativeaddition. Depending on the rate of the competition between amine and alkyne in the sub-stitution of one ligand in this complex, other mechanism could also operate (Figure 4.4a)together with the one presented. Thus, the mechanism in Figure 4.4a can be consideredpreferential if the amine is a less good ligand than the alkyne for the Pd(II) center in[Pd(II)XR1L2] (i.e., L = PPh3, amine = piperidine or morpholine). However, a mecha-nism, as depicted in Figure 4.4b, would be preferred if the amine is a better ligand thanthe alkyne for the Pd(II) center in [Pd(II)XR1L2] (i.e., L=AsPPh3, amine= piperidine).

A particular consideration concerning the mechanism of metal-catalyzed C C cou-pling reaction whenmetal nanoparticles are involved is whether the coupling is catalyzedby the nanoparticles themselves or bymolecular species.153 Thus, when Pd-NPs are usedas catalysts, the leaching and formation of catalytically active molecular species cannotbe ruled out, and therefore three possible scenarios have been proposed (Figure 4.5): (a)Pd-NPs can act as real heterogeneous catalysts, the reaction occurring in their surface;(b) Pd-NPs act as a reservoir of molecular species, and Pd(0) atoms can leach from thenanoparticles and enter into a homogeneous catalytic cycle; c) the oxidative addition canoccur at the nanoparticle surface followed by leaching of the formed [Pd(Ar)X] species,which then initiate another homogeneous catalytic cycle.

SUMMARY AND FUTURE OUTLOOK 119

Figure 4.5. The three possible mechanisms for the Pd-NPs-catalyzed C C coupling reactions.

The presence of catalytically active molecular species in solution has been directlyaddressed by using a simple approach based on using a special built-in-house mem-brane reactor. This reactor consists of two stainless steel compartments separated by amembrane that allows the passage of palladium atoms and ions, but not of species largerthan 5 nm, such as palladium clusters.154,155 Therefore, if a suspension of palladiumclusters is placed on one side of the membrane, and the reaction mixture on the other,monitoring the reaction over time on both sides would give direct information on thetrue catalytic species. Using this procedure, it has been shown that palladium atoms andions do leach from palladium clusters under Heck and Suzuki coupling conditions (andmost probably under Sonogashira conditions). Thus, according to TEM and ICP analysisand in absence of any reactant, small clusters do not form on one side and then diffuseto the other, but Pd(0) species (i.e., palladium atoms) do transfer across the membranebecause there are no oxidizing agents present to oxidize Pd(0) to Pd(II). Conversely, inthe presence of an aryl halide such as iodobenzene, Pd(II) complexes can be formed byoxidative addition, either on the cluster surface or through reaction with Pd(0) atomsthat have already leached into solution. Thus, fast atom bombardment mass spectrom-etry measurements showed polymeric species of oxidative complexes on the other sideof the reactor after some time. Both Pd(0) atoms and Pd(II) complexes can then enterthe cross-coupling homogeneous catalytic cycle, and the remaining palladium clusterswould not be catalytically active species. These two possible scenarios are illustratedin Figure 4.6, where the Pd(0) atoms or Pd(II) complexes are shown leaching from thepalladium clusters across the membrane.

SUMMARY AND FUTURE OUTLOOK

The Sonogashira cross-coupling reaction is a process of an enormous synthetic utility inthe preparation of compounds of interest. It seems that many of the palladium catalysts


Figure 4.6. Suggested mechanisms for palladium transfer from side A to side B of a membrane

reactor: (a) Pd(0)-atom leaching and transfer under nonoxidizing conditions; (b) formation and

subsequent transfer of Pd(II) complexes.

employed in this transformations are in fact just precatalysts, nanoparticles formed aftertheir decomposition being the real catalytic species, which opens new possibilities forreactivity based on their higher or lower stabilization. High reactivity, which avoids thenecessity of Cu(I) cocatalysis, is desirable for environmental, economic, and cleanerprocedures. Among the catalytic systems developed, those suitable to be recycled andreused are particularly interesting. Thus, many different ways of immobilizing Pd-NPson polymers, carbon structures, or inorganic materials have been reported in the lastyears, although their activity and recyclability are limited sometimes. In addition, manyof these catalytic systems or procedures still lack a broad applicability and are effectiveonly for the coupling of “easy” aryl iodides and terminal alkynes, some of them onlybeing assayed in a model coupling between iodobenzene and phenylacetylene. Thegeneral use of aryl chlorides, activated or not, as coupling partners still remains a notsufficiently resolved matter that surely will be subject of interest in next future, as wellas the development of procedures based on the use of aqueous systems or neat water assolvents.

Particularly interesting in recent years has been the use of non-Pd-NPs as catalysts inthe Sonogashira reaction. Thus, copper, iron, ruthenium, or gold nanoparticles have beenreported to act as catalysts in this process, sometimes arousing controversies about therole of traces of metal contaminants in reagents or glassware. It seems that nanoparticlesof some of other transition metals have an effective catalytic activity in the Sonogashirareaction, and therefore this is going to be an area where research will focus in next future.

REPRESENTATIVE EXPERIMENTAL PROCEDURES

Sonogashira Reaction Catalyzed by Unimmobilized Pd-NPs from aLigand-Free Palladium Salt48

To a mixture of Na2PdCl4 (12 mg, 0.0408 mmol) and sodium dodecyl sulfate (144 mg,0.5 mmol) in water (3 ml) was added iodobenzene (204 mg, 1 mmol), phenylacetylene(123 mg, 1.2 mmol), and NaOH (120 mg, 3 mmol). The mixture was stirred at roomtemperature for 9 h (thin layer chromatography). The reaction mixture was extractedwith ethyl acetate (3×10 ml). The extract was washed with water and brine and dried

REPRESENTATIVE EXPERIMENTAL PROCEDURES 121

with Na2SO4. Evaporation of the solvent left the crude product, which was purifiedby column chromatography over silica gel (hexane) to afford pure diphenylacetylene(153 mg, 86%).

Sonogashira Reaction Catalyzed by Pd-NPs Immobilizedon a Polymer67

Pd(OAc)2 (50 mg) was added to a solution of PVP (MW 40,000, 2.5 g) in MeOH(150 ml), and the mixture was refluxed under nitrogen for 3 h. The resulting brownliquid was filtered through 0.2 �m Teflon Millipore, and MeOH was removed underreduced pressure to give Pd/PVP. Under nitrogen atmosphere, an oven-dried round-bottomed flask was charged with Pd/PVP (0.106 g of 1% Pd on PVP, containing 1.06 mgPd), K2CO3 (272 mg, 2.0 mmol), aryl halide (1.0 mmol), terminal alkyne (1.0 mmol),and ethanol (4 ml). The reaction mixture was refluxed at 80 ◦C for 6 h. After coolingto the room temperature, diethyl ether (10 ml) was added and stirred for 10 min toensure product removal from Pd/PVP. As Pd/PVP and other inorganic s precipitated andagglomerated to the bottom of the flask, the organic layer was decanted and the residuewas washed using diethyl ether (2×5 ml). The combined organic layers were dried overNa2SO4, filtered, concentrated, and the residue was purified by flash chromatographyon silica gel to give the desired cross-coupling product.

Sonogashira Reaction Catalyzed by Pd-NPsImmobilized on Carbon88

Darco KB activated carbon (100 mesh, 25% H2O) was dried overnight under vacuumat 150 ◦C. The dry activated carbon (3.6 g) was added to a 100 ml round, bottom flaskcontaining a stir bar. A solution of Pd(NO3)2 · H2O (Pd ≈ 40%, 1 g, 3.7 mmol) indeionized H2O (50 ml) was added to the activated carbon, and additional deionized H2O(30 ml) was added to wash down the sides of the flask. The flask was stirred vigorouslyat room temperature for 1 h and then submerged in an ultrasonic bath for 20 h. It wasthen attached to a distillation setup and placed in a preheated (175–180 ◦C) sand bathwhile stirring. As the distillation ended, the sand temperature began to rise and washeld below 200 ◦C. After cooling the charcoal to room temperature, it was washed withtoluene (50 ml) and then Et2O (50 ml), and the resulting solid filtered in vacuo in afritted funnel. The fritted funnel was turned upside down under vacuum overnight untilthe Pd/C fell from the frit into the collection flask placed in a preheated 80 ◦C sandbath. The impregnated charcoal (∼3.94 g) was transferred to, and stored in, separatevials. Thus, 10.2 wt% Pd/C (calculated by ICP analysis) or 0.93 mmol Pd/g catalyst wasobtained and used as a catalyst for the Sonogashira coupling. Thus, in a 10 ml round,bottom flask under argon containing Pd/C (42 mg, 0.93 mmol g−1,∼0.04 mmol), XPhos(18 mg, 0.04 mmol) and potassium carbonate (552 mg, 4 mmol) was added 95% ethanol(6 ml) followed by the aryl bromide (2 mmol) and then the terminal alkyne (4 mmol).The flask was submerged in a preheated 50 ◦C water bath and stirred vigorously for theindicated time. Themixture was then poured into a flask containing silica (3–4 g), and thesides of the reaction flask were washed with diethyl ether. Solvents were removed under


vacuum, and the resulting residue was introduced on top of a silica gel chromatographycolumn to purify the product.

Carbonylative Sonogashira Reaction Catalyzed by Pd-NPsImmobilized on Paramagnetic Nanoparticles112

Commercial Fe3O4 nanoparticles were impregnated with a Na2PdCl4 (1.0%) aqueoussolution and stirred for 1 h. After impregnation, the suspension was adjusted to pH12 by adding sodium hydroxide (1 M) and stirred for 6 h. The solid was washed bydistilled water and the catalyst precursors were reduced by adding 0.2 M KBH4 solutiondropwise under gentle stirring in an ice water bath for 30 min until no bubbles wereobserved in the solution. The resulting Pd/Fe3O4 was washed thoroughly with distilledwater and subsequently with ethanol (Pd content 1.04%), being employed as catalystsin carbonylative Sonogashira reactions performed in a 100 ml autoclave equipped withmagnetic stirring and automatic temperature control. Thus, iodobenzene (2.5 mmol),phenylacetylene (3.0 mmol), Pd/Fe3O4 (50 mg Pd, 1.04 wt%), Et3N (7.2 mmol), andtoluene (5 ml) were charged into the reactor. The autoclave was closed, purged threetimes with CO, pressurized to 2 MPa with CO, and then stirred at 130 ◦C for 4 h. Aftercompletion of the reaction, carbon monoxide was purged carefully and the catalyst wasobtained by magnetic separation. The catalyst could be directly reused for the next runafter washed several times with ethanol and dried under vacuum; the base should befreshly added before the next carbonylation reaction. The crude product was purified bycolumn chromatography on silica gel to give the corresponding 1,3-diphenylprop-2-yn-1-one.

Sonogashira Reaction Catalyzed by Magnetite Nanoparticles124

To a 5 ml flask, which contained ethylene glycol (3 ml), were added nanoparticles ofmagnetite (Fe3O4, 0.05 mmol, 11 mg), K2CO3 (2 mmol, 276 mg), iodobenzene (204mg,1 mmol), and phenylacetylene (205 mg, 2 mmol), and the mixture was heated at 125 ◦Cfor 35 h. After completion of the reaction, the catalyst was separated magnetically andthe reaction mixture was extracted with ethyl acetate (5×1 ml). The organic phase wasseparated, evaporated, and purified by column chromatography (EtOAc/n-hexane) toobtain diphenylacetylene (164 mg, 92%).

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