Prospects and Applications of Palladium Nanoparticles in the Cross-coupling of (hetero)aryl Halides and Related Analogues.

Discovering efficient methods for the formation of carbon-carbon bonds is a central ongoing theme in organic synthesis. Cross-coupling reactions catalysed by metal nanoparticles are attractive alternatives to the traditional use of metal counterparts due to the catalytic tunability, selectivity, recyclability and reusability of the nanoparticles. The ongoing search for sustainable processes demands that reusable and environmentally benign catalysts are used. While the advantages of nanoparticles catalysts over bulk catalysts cannot be overemphasised, the problem of sintering, agglomeration and leaching are drawbacks to their full industrial applications. Hence, efforts are being made towards advancing the efficiency of the catalytic nanoparticle systems over the years. This review presents the progress, the challenges and the prospects of palladium nanoparticle with focus on Heck, Suzuki, Hiyama and Sonogashira cross-coupling reactions involving (hetero) aryl halides and the analogues.

Introduction

The use of nanomaterials for solving critical issues in many scientific fields, including catalysis, has attracted the interest of various research groups. The large‐scale applicability and the outstanding physical and chemical properties of nanomaterials have had a significant impact on recent efforts in the research and development of modern technologies.[ , ] It is well established that there are certain limitations to using solid‐supported ligand‐free metal catalysts in cross‐coupling reactions despite their numerous advantages over homogeneous ligated catalysts such as metal leaching, lack of recyclability, product contamination, and recovery as well as economic and environmental issues. Consequently, the use of highly efficient, economical and recoverable catalysts, with low or null toxicity is essential from a green chemistry and sustainability perspective.[ , ] The synthesis of transition metal nanoparticles and their application in C−C bond formations has received considerable attention in the past few dates.[ , , , ] Due to their high surface area, they often show remarkable catalytic performance and are considered to be on the borderline between the homogeneous and heterogeneous catalysts. However, in practice, their separation and recovery from the reaction medium using standard techniques is cumbersome, and this hurdle has been overcome by stabilising metal nanoparticles over a variety of organic and inorganic supports. Several stabilising agents such as thiols, phosphines synthetic polymers and silica derivatives have been designed and described. Recently, magnetic nanoparticles have been widely applied as solid supports for the catalyst. Magnetic nanoparticle‐supported catalysts can be simply and efficiently separated from the reaction system by a permanent external magnet, thus avoiding the complex operating process. Organic polymer‐coated magnetic nanoparticles can be stabilised in reaction media to prevent nanoparticle aggregation. Moreover, it is easier to functionalise the polymers by introducing various kinds of ligands as well as immobilise the metal catalysts efficiently. Nevertheless, the prevention of sintering of nanoparticle in the metal nanoparticle‐catalysed reaction is paramount so that the nanoparticles retain their size, structure, and most importantly, their catalytic efficiency. The direct consequence of sintering might be particle growth and coalescence, shape deformation, and change in the composition of the active nanoparticles, which eventually results in altered activity or total deactivation of the nanocatalysts. However, Pd‐leaching probably poses a more significant challenge in the practical application of immobilised palladium nanoparticles in catalysing C−C bond construction than sintering. This is because most recent cross‐coupling reactions are conducted in relatively mild temperature conditions. Consequently, an appropriate selection of stabiliser is the most critical parameter for the design of metallic nanoparticles with minimal leaching or sintering effects. Over the last two decades, the attention of many research groups has been directed towards catalytic activation/functionalisation of aryl and heteroaryl halides using metal nanoparticles catalysis despite the tremendous success recorded in using ligand‐supported palladium homogenous catalysts in the transformation due to its economy, environmental friendliness and industrial application.[ , ] This review provided an overview of the application of palladium nanoparticle catalysed cross‐coupling over the past two decades with particular focus on Heck, Suzuki, Sonogashira, and Hiyama reactions.

Heck Cross‐Coupling Reactions

The Mizoroki‐Heck reaction, independently discovered by Mizoroki and Heck in the early 1970s, is one of the most efficient methods for alkenylation of aryl, vinyl, and alkyl halides. It has been implicated in the synthesis of several drugs and intermediates such as naproxen (an anti‐inflammatory agent), prosulfuron (herbicide), Singulair,[ , ] Eletriptan,[ , , ] BVDU (antiviral), Axitinib (antitumour), 2‐ethylhexyl‐p‐methoxycinnamate (UV sunscreen B agent), and comonomers of styrene polymers. Due to the recyclability and reusability of catalytic nanoparticle systems; various supported catalytic systems are being developed for Heck reactions.

Heck Coupling Catalysed by Polymer Stabilised Pd Nanoparticles

Polymers have been widely utilised as a support/stabiliser for nanoparticles.[ , ] Their extensive application is attributed to their availability, enhanced stabilisation properties of metal nanoparticles and resistance to particle sintering/agglomeration. Jin and co‐workers reported ligand‐free Heck reaction catalysed by in situ generated Pd nanoparticles stabilised by PEG‐400 (Figure 1).

Figure 1

TEM micrographs of Pd nanoparticles (a) 30 min after the reaction, (b) 180 min after the reaction, (c) prepared Pd nanoparticles (Pd(OAc)2 1 mol%) in PEG‐400 at rt under N2. Adapted from Lui et al. with permission.

The cross‐couplings between aryl iodides (1) with electron‐withdrawing groups or electron‐donating groups and styrene or acrylic acid methyl ester (2) were achieved in good yields using a 1 mol% Pd loading of the catalyst in short times (Scheme 1).

Scheme 1

PEG‐400/Pd(OAc)2 catalysed Heck reaction of aryl halides with olefins

In this reaction, the reactivity of styrene was faster than that of acrylic acid methyl ester when using the same aryl bromide; However, reaction failed for the reaction of 4‐bromobenzaldehyde and acrylic acid methyl ester.

Recently, the use of novel engineered polymers such as polyorganophosphazenes with an inorganic backbone, polyvinyl pyridines,[ , ] fibres and dendrimers[ , , ] as supports has become increasingly popular. In a related development, palladium nanoparticles supported on triazine functionalised mesoporous covalent organic polymers (Pd@MCOP) was used as an effective catalyst for the cross‐coupling reaction of various substituted aryl halides (4) with styrenes 5–6 and acrylate 7 respectively (Scheme 2). The catalyst was effective in cross‐coupling aryl bromides containing electron‐withdrawing and electron‐donating groups aryl bromide as well as hindered substrate coupled readily with styrene to give excellent yields (86–98 %).

Scheme 2

Heck reaction of substituted aryl halides with styrenes and acrylate catalysed by Pd/MCOP.

Yang et al reported a novel heterogeneous Pd catalyst by attaching Pd(II) onto poly(undecylenic acid‐co‐N‐isopropylacrylamide‐co‐potassium 4‐acryloxyoylpyridine‐2,6‐dicarboxylate)‐coated Fe3O4(Fe3O4@PUNP) magnetic microgel. The Fe3O4@PUNP−Pd catalyst was used for the cross‐coupling reaction between substituted aryl halides (11) with acrylic acid (12) under argon atmosphere. It was found that only 0.1 mol% quantity of the catalyst was sufficient to attain 89–96 % yield of the required cinnamic acid derivatives 13 (Scheme 3). Pleasingly, all the catalysts could be used for several cycles with negligible loss of their activities.

Scheme 3

Fe3O4@PUNP−Pd‐catalyzed Heck reaction of substituted aryl halides with acrylic acid in water under argon atmosphere.

Heck Coupling Catalysed by Pd Nanoparticles Supported on Biopolymers

Biopolymers and biomass‐related polymers have been recently employed for the preparation of supported metal nanoparticles. Biopolymers have drawn attention for use as supports for catalytic applications due to their several advantages compared to traditional supports including low toxicity and cost as well as high biocompatibility, availability and abundance. Keshipour and co‐workers prepared palladium nanoparticles supported on ethylenediamine‐functionalised cellulose as stabilising material (PdNPs@EDACs) for the Heck reaction of styrene (15) and methyl acrylate (18) with several halobenzenes (14 and 15) (Scheme 4). It was observed that NMP and H2O were the best solvents but the water was used from the green chemistry perspective. By maintaining the temperature at 100 °C, the best‐desired cross‐coupled products (91–99 % yield) were obtained with K2CO3 in the presence of the relatively higher catalyst loading (0.30 mol % of Pd(0)) in H2O at a short time of 8 h.

Scheme 4

Heck reaction of styrene and methyl acrylate with halobenzenes catalysed by PdNPs@EDACs.

These remarkable results were comparable to those obtained by Reddy et al. and Morres et al. using Pd impregnated on cellulose and nano‐cellulose in an organic solvent and organic solution, respectively.

Green synthesis of palladium nanoparticles supported on pectin was explored in Heck reaction between activated and non‐activated aryl halides (20) and n‐butyl acrylate (21) under solvent‐free conditions to obtain the products in good to excellent yields of 57–94 % (Scheme 5). Interesting, the Pdnp/pectin catalyst was highly stable and insensitive to oxygen that the reaction did not require an inert atmosphere.

Scheme 5

Heck reaction of aryl halides with n‐butyl acrylate catalysed by Pdnp/pectin.

In 2015, Shen et al. reported a novel D‐glucosamine‐derived pyridyltriazole@palladium catalyst (Figure 2) for solvent‐free Heck reactions between different aryl halides (23) and olefins (24) under solvent‐free conditions (Scheme 6). Besides finding application in the facile synthesis of the marketed drug Axitinib, the catalyst can retain its activity for at least six times of separation and reuse.

Figure 2

TEM images of (a) D‐glucosamine‐derived pyridyltriazole@palladium catalyst, and (b) recovered catalyst after the sixth run. Reproduced from Zhang et al with permission from The Royal Society of Chemistry.

Scheme 6

Heck reaction of substituted aryl halides with olefins catalysed by D‐glucosamine‐derived pyridyltriazole@palladium catalyst.

High interest in cyclodextrins in the present era reveals their extensive applications in organic synthesis and stabilization of transition metal nanoparticles for C−C bond formations.[ , , , , ] In this regard, Zhao and coworkers investigated β‐cyclodextrin‐capped palladium nanoparticle‐catalyst, which provided yields of coupled products according to the relative strength of the C−X bond of the aryl halide substrates (Scheme 7). While the reaction of aryl iodides with styrenes (27 and 28) provides 90–96 % yields within 2 h, treating aryl bromides (26) with methyl or ethyl acrylates (29) gave products 32 in 55–76 % yield at a much longer time (10 h). Pd nanoparticles/β‐CD/NMU was consistently reused with dynamic stability after four times.

Scheme 7

Heck reactions between substituted aryl halides with styrenes catalysed by PdNPs/β‐CD/NMU.

Heck Coupling Catalysed by Carbon‐Supported Nanoparticles

Carbon materials present great merits as supports for the nanoparticle‐catalysed cross‐coupling. The contemporary advancement in this aspect has allowed the preparation of carbon nanostructures with well‐defined porosities and high surface areas. Heck reaction catalysed by palladium supported on carbon was successfully used for the synthesis of stilbene (Scheme 8). Pleasingly, the relatively high yield of stilbene (34) obtained using autoclave was remarkable, coupled with high reusability of the catalyst without significant loss of the activity.

Scheme 8

Pd/C catalysed cross‐coupling of chlorobenzene with styrene.

In a related study involving allylic acetates (36), Mariampillai et al. observed that Palladium on carbon gave increased reactant conversion with tetrabutylammonium chloride akin to a discovery made by Jeffery. The coupling of various aryl iodide partners (35) with allyl acetates (36) proceeded well to give the olefinic products (37) under low catalyst loading (Scheme 9).

Scheme 9

Intramolecular Heck‐type coupling of allyl acetate with various aryl Iodides catalysed by Pd/C.

Mechanistically, the authors posited that an initial oxidative insertion of palladium into the aryl halide 35 followed by carbopalladation of olefin 36 would give the intermediate that undergoes β‐acetoxy elimination leading to the product 37. Whereas substrates bearing electron‐withdrawing groups required a shorter reaction time, those with electron‐donating substituents had extended reaction time, probably due to slower oxidative addition. This procedure gives rapid access to a range of both terminal and internal olefins, which can easily be further functionalized.

Heck Coupling Catalysed by Graphene Supported Pd Nanoparticles

Sharavath and Ghosh made a novel contribution towards Heck cross‐coupling reaction by employing palladium nanoparticles supported on noncovalently functionalised graphene using PCA−GNS−Pd. They coupled several aryl bromides and aryl chlorides (38) containing a wide range of functional groups with styrene and olefin 39 using water as the solvent and with low catalyst loadings (0.2 mol%) in pure water (Scheme 10). By optimising the coupling reaction between p‐bromobenzaldehyde and styrene in the presence of TBAB as phase transfer catalyst (PTC)), the coupling of various aryl halides (38) with styrenes and olefins 39 was achieved to obtain the coupled products 40 in good to excellent yields (41–92 %). Good to excellent yields were afforded with different aryl chlorides having varied substituent groups. Aryl chlorides and bromides with hydrophilic substituents also produced higher yields, whereas chlorides with hydrophilic substituents gave excellent yields due to high solubility of substrates in water.

Scheme 10

Heck coupling of aryl halides with styrene catalysed by PCA−GNS−Pd.

The incorporation of cyclodextrin (CD) molecules into graphene oxide (GO), before GO is fully reduced results CD−GNS hybrids exhibiting high dispersibility and stability in water, and do not aggregate for a long time. Because of these versatile properties, CD−GNS supported Pd NPs have been investigated as recyclable heterogeneous Pd catalysts in pure water (Figure 3).

Figure 3

TEM images of CD−GNS (a), fresh Pd@CD−GNS (b), reused catalyst for Suzuki‐Miyaura reaction (after 2 runs). Adapted from Ghosh et al. with permission from the Royal Society of Chemistry.

In 2014, Ghosh et al. described the use of palladium nanoparticle‐β‐cyclodextrin‐graphene nanosheet (Pd@CD−GNS) and used them for Heck reaction in water. The reaction gave 60–95 % yield of the related products at 90 °C in sodium carbonate, TBAB and 0.05 mol% catalytic mixture.

Heck Coupling Catalysed by Surfactant (TX‐100) Stabilised Palladium Nanoparticles in Ionic Liquid

Research has shown that Imidazolium ionic liquid ([BMIM]PF6) is an ideal medium for the preparation and stabilisation of transition metal nanoparticles. To illustrate of this property, Kuang and co‐workers investigated the catalytic performance of the greener ionic liquid H2O/TX‐100/[BMIM]PF6 microemulsion containing the Pd nanoparticles for the reaction of iodobenzene (41) with methyl acrylate, ethyl acrylate and styrene (42) (Scheme 11).

Scheme 11

Product yields for other Heck reactions of aryl iodide with alkenes in H2O/TX‐100/[BMIM]PF6 microemulsion ionic liquid.

The nanoparticles were prepared by dissolving palladium chloride first in water before mixing with surfactant (TX‐100) in the ionic liquid [BMIM]PF6. On addition of the palladium chloride, reduction of the palladium chloride by the surfactant (TX‐100) in the ionic liquid microemulsion occur rapidly in situ without any further reducing agents to produce the nanoparticles composite (Figure 4). Interestingly, the H2O/TX‐100/[BMIM]PF6 microemulsion containing Pd nanoparticles was found to decrease the reaction time for the Heck reaction compared with the conventional solvent system and the catalytic activity of the Pd nanoparticles only decreased after the fourth cycle. Notably, compared with an organic liquid base (Et3N), the catalytic activity of the system greatly decreased with the use of an inorganic solid base such as Na3PO4, NaOAc and Na2CO3. This is because inorganic solid bases destroy the stability of microemulsion and cause the agglomeration of Pd nanoparticles.

Figure 4

a) TEM image, b)HRTEM image of Pd nanoparticles separated from the [BMIM]PF6 microemulsion. Adapted from Kuang et al. with permission from the Royal Society of Chemistry.

Heck Coupling Catalyzed by Zn/Fe3O4 Supported Pd Nanoparticles

Nargakar and co‐workers employed palladium supported on zinc ferrite nanoparticles for the Heck coupling reactions of aryl halides (44) with alkenes (45) under ligand‐free condition (Scheme 12).

Scheme 12

Heck reaction of aryl halides with alkenes catalysed by Pd−Zn/Fe3O4 nanoparticle under the ligand‐free condition.

The efficient superparamagnetic solid catalyst was prepared by loading Pd (0) species during the synthesis of zinc ferrite nanoparticles by ultrasound‐assisted co‐precipitation in the absence of surface stabiliser or capping agent (Figure 5). The advantage of the protocol stems from the fact that an external magnet could quickly separate the nanocrystal catalyst from the reaction mixture, and the catalyst can be recycled six times without a significant loss in its activity. The most appealing feature of the strategy is that the materials can be quickly recovered using a permanent magnet in the reactor and can be reused in up to 20 runs without a significant loss in catalytic activity.

Figure 5

SEM image of Pd−ZnFe2O4 MNPs. Adapted from Nagarkaret et al with permission from the Science Direct.

In a related reaction, Kim and co‐workers carried out the reaction using Pd−Fe2O4 heterodimeric nanocrystal catalytic system at a temperature of 110 °C within 24 h (Scheme 13). The catalytic system showed good yields (85–94 %) of coupled products from the reactions with aryl iodides having electron‐rich or electron‐poor substituents, except for the case of electron‐rich 1‐iodonaphthalene that gave 46 % yield. Besides, the reactions of styrene with aryl bromides (47) gave a very poor yield of a product as a result of the weak conversion of the starting material by the catalyst.

Scheme 13

Heck reaction of aryl iodide with alkenes catalysed by Pd−Fe3O4 nanocrystals.

Suzuki‐Miyaura Cross‐Coupling Reactions

Suzuki cross‐coupling reaction is one of the highly versatile and utilised reactions for the selective construction of carbon‐carbon bonds. Suzuki reaction is a palladium or nickel‐catalysed cross‐coupling of an organoboron reagent and an organic halide or pseudohalide in the presence of a base.[ , ] The success of this reaction can be associated with the generally mild reaction conditions required and the versatility of the boron species as organometallic partners. Compared to related C−C bond formations, the environmentally benign nature, high functional group tolerance, wide commercial availability of the reactants, and compatibility with aqueous conditions are expedient. Consequently, it is majorly used in the formation of biaryls compounds, substituted aromatic compounds and alkene derivatives which are structural components several natural products, nucleosides. agrochemicals, pharmaceuticals, and advanced materials. Quite many improvements have been made in recent years.[ , ] From a green chemistry perspective, metal nanoparticle catalysis immobilised on solid supports has been adapted for several Suzuki cross‐coupling reactions.

Suzuki‐Miyaura Coupling Catalysed by Pd Nanoparticles Supported on MIL‐101‐NH2

In 2015, Pascanu and co‐workers successfully prepared a diverse set of heteroaromatic and highly functionalised biaryls through the Suzuki‐Miyaura cross‐coupling reaction catalysed by Pd nanoparticles supported in a functionalised mesoporous MOF (8 wt % Pd@MIL‐101(Cr)‐NH2). They investigated the coupling of boronic acids or pinacolate esters with heteroaryl iodides (51) using K2CO3 as the base (2 eq) in a mixture of H2O/EtOH (1 : 1) (Scheme 14). The majority of the functionalised (hetero)aromatic halides, including hindered aryl iodides, less reactive aryl bromides and lengthy substrate, reacted in excellent yields at mild temperatures (20 or 50 °C) and in short reaction times (0.5–4 h), leading to pharmaceutical relevant intermediate biaryl products despite the presence of one or several heteroatoms.

Scheme 14

Suzuki cross‐coupling of (hetero)aromatic halides with aryl boronic acids or pinnacolate ester catalysed by Pd@MIL‐101(Cr)‐NH2.

The coupling of 2‐bromobenzonitrile (53) with p ‐tolyl boronic acid (54) occurred at ambient temperature in only 30 min to afford a quantitative yield of 55, an intermediate used in the synthesis of the cardiovascular drug Valsartan (Scheme 15).

Scheme 15

Suzuki cross‐coupling of 2‐bromobenzonitrile with p ‐tolyl boronic acid catalysed by Pd@MIL‐101(Cr)‐NH2.

Superior results and better tolerance towards multiple co‐ordinating heteroatoms were obtained when the heterocyclic moiety was located on the boron transmetallating partners. A large variety of exciting (hetero)aromatic or vinyl boronic acids of pyridines, indoles, furans and thiophenes (56) were coupled with aryl iodides and aryl bromides (57) and afforded biaryls 58 (Scheme 16).

Scheme 16

Suzuki coupling of halobenzene with various (hetero)aryl boronic acids catalysed by Pd@MIL‐101(Cr)‐NH2.

Suzuki Coupling Catalyzed by GO/Fe3O4/PAMPS/Pd Nanoparticles

Metal oxides offer high thermal and chemical stabilities combined with a well‐developed porous structure and high surface areas (>100 m2 g−1), meeting the requirements for most applications. They can also be easily prepared and further functionalised, adding value to their use as support or catalyst. Asadi and co‐workers designed and prepared novel, and recyclable catalytic system based on palladium nanoparticles (Pd‐NPs) immobilised onto the surface of graphene oxide (GO) modified by poly 2‐acrylamido‐2‐methyl‐1‐propane sulfonic acid decorated with magnetic Fe3O4 (GO/Fe3O4/PAMPS/Pd). They modelled the reaction on bromotoluene and the best conversion of 4‐bromotoluene to the corresponding biphenyl occurred with 0.4 mol% of catalyst in 2 h in a mixture of H2O and EtOH as the solvent (Scheme 17).

Scheme 17

Optimisation Suzuki reaction of 4‐bromotoluene with phenylboronic acid catalysed by GO/Fe3O4/PAMPS/Pd.

The Suzuki reaction of a variety of aryl halides with aryl boronic acids catalysed by GO/Fe3O4/PAMPS/Pd provided low to quantitative yields of biaryls depending on the nature of electrophilic substrates and the substituents on the phenylboronic acids. As usual, the coupling with aryl iodide gave quantitative yields which decreased to 60 % as aryl bromide and aryl chlorides with the corresponding reduction of TONs/TOFs. The lowest yield (30 %) recorded with the catalytic system occurred when activated 4‐bromotoluene was coupled with activated 4‐methyl phenylboronic acid.

Superparamagnetic oxides, such as Fe3O4, have recently emerged as new materials for the immobilisation of metal nanoparticles with improved separation capabilities. Elazab and Baran independently studied Suzuki reaction on a diversity of different substrates using Pd nanoparticles deposited on Fe3O4. and pectin‐carboxymethyl cellulose composite (Pct−CMC/Fe3O4) (Scheme 18) respectively The PdNPs was an easily recyclable and highly efficient catalyst for the fabrication of various biaryl compounds and can be used in different catalytic systems due to its notable features such as easy workup, high reaction yields, easy separability, and excellent reusability.

Scheme 18

Suzuki‐Miyaura reaction of halobenzene with phenylboronic acids catalysed by Pd NPs@Pct−CMC/Fe3O4.

In another front, Nehlig and co‐workers used highly efficient and retrievable immobilised Pd on magnetic nanoparticles bearing proline as a catalyst (Figure 6) for Suzuki‐Miyaura catalyst in aqueous media (Scheme 19).

Figure 6

Structure of Pd on Fe2O3 nanoparticles bearing proline as a catalyst. Adapted from Nehlig et al. with permission from The Royal Society of Chemistry.

Scheme 19

Suzuki reaction of (hetero)aryl halides with phenylboronic acids catalysed by g‐F2O3@Cat‐Pro(Pd).

The optimised reaction conditions were applied in the cross‐coupling of aryl halides with various boronic acids. The excellent catalyst yields and conversions were obtained with low Pd loadings (down to 0.01 mol% Pd), and the catalyst was stable up to 6 months in water under aerobic conditions and efficiency remained unaltered even after 7 repeated cycles.

Suzuki Coupling Catalyzed by PVP Stabilized Pd Nanoparticles

Li and co‐workers applied palladium nanoparticles stabilised by poly(N‐vinyl‐2‐pyrrolidone) (PVP) as an efficient catalyst for the Suzuki reactions of phenylboronic with iodobenzene in an aqueous medium to give the biaryl in 95 % yield (Scheme 20).

Scheme 20

Suzuki‐Miyaura reaction of iodobenzene with phenylboronic acid catalysed by PVP−Pd Catalyst.

It was observed that the Pd metal precipitated during the reaction, thus decreasing the catalytic during the reaction. Therefore, further improvements on the catalyst stability are necessary for practical applications. Narayanan and El‐Sayed on an investigation of the effect of the catalysis and recycling on the stability and catalytic performance of the nanoparticles observed that refluxing the nanoparticles for 12 h during the reaction increases the average size and width of the distribution of the nanoparticles. This was linked to Ostwald ripening in which the small nanoparticles dissolve to form larger nanoparticles. However, the average size of the nanoparticles decreased in size when recycled for the second cycle (Figure 7). This could be due to the large nanoparticles aggregating and participating out of solution which explains the observed loss of the catalytic efficiency of the nanoparticles during the second cycle.

Figure 7

Left: nanoparticle size and distribution before catalysis; Right: nanoparticles size and distribution after the first cycle of catalysis. Reproduced from Narayanan and El‐Sayed with permission. with permission from American Chemical Society.

Suzuki Coupling Catalyzed by PHEMA/KIT‐6 Supported Pd Nanoparticles

Kalbasi and Mosaddegh investigated the Suzuki reactions of different aryl halides and phenylboronic acid with Pd nanoparticle‐poly(2‐hydroxyethyl methacrylate)/KIT‐6 (Pd‐PHEMA/KIT‐6) composite as the catalyst (Scheme 21). The reaction condition was optimised with phenylboronic acid and aryl iodide with a satisfactory yield and was extended to other aryl halides.

Scheme 21

Suzuki‐Miyaura reaction of aromatic aryl halides and phenylboronic acid‐catalysed by Pd‐PHEMA/KIT‐6.

They observed that the coupling reactions with aryl bromide and aryl chloride required a higher temperature (95 °C) to obtain excellent yields. However, it can be concluded that Pd‐PHEMA/KIT‐6 exhibits excellent catalytic activities for Suzuki‐Miyaura cross‐coupling reactions of aryl chloride, bromide and iodides in aqueous medium and under aerobic conditions Notably, the catalyst was reused for nine cycles stability and no significant loss of activity/selectivity performance.

In a related development, Calo and co‐workers explored Pd nanoparticles as efficient catalysts for Suzuki and reactions of aryl halides in ionic liquids. The optimised reaction was applied to the substituted chloroarenes to obtain unsymmetrical biphenyls. In this protocol, the ionic liquid, THeptAB is better stabilising agent than TBAB for Pd NPs because it consistently provided better yields of biaryls than TBAB irrespective of the electrophilic substrates used. While excellent yields of biaryls were obtained from the coupling of chlorobenzene with phenylboronic acid, higher temperatures (at least 110 °C) were required in the case of deactivated electron‐rich aryl chlorides. Recycling experiments, carried out on p‐bromotoluene with Na2CO3 as a base, showed that the catalytic system could be reused for three runs with a slight decrease in product yields.

Suzuki Coupling Catalyzed by Graphene Supported Pd Nanoparticles

Many researchers have investigated the catalytic activity of the graphene‐based nanocatalysts in Suzuki cross‐coupling reaction. In 2018, Nasrollahzadeh and co‐workers reported a comprehensive review graphene‐based nanocatalysts in Suzuki cross‐coupling reaction. García‐Suárez et al efficiently used palladium nanoparticles supported on graphene platelets as a catalyst in the Suzuki‐Miyaura coupling between aryl bromides and potassium aryltrifluoroborates using 0.1 mol% of Pd and potassium carbonate as a base in MeOH/H2O as solvent at 80 °C by Gómez‐Martínez and co‐workers (Scheme 22). They modelled the reaction between 4‐bromoanisole and potassium trifluoroborate to study the catalytic activity of the palladium supported catalysts.

Scheme 22

Suzuki reaction between aryl bromide and potassium phenyl trifluoroborate catalysed by palladium nanoparticles supported on graphene platelets.

Brinkley and co‐workers developed the analogous reaction. The Pd/G prepared by this strategy was useful in Suzuki‐Miyaura cross‐coupling reactions with a broad range of substrates (Scheme 23). Reactions were carried out by combining an aryl halide (0.27 mmol), a substituted boronic acid (0.32 mmol), K2 CO3 (0.9 mmol), and the Pd/G catalyst (2 mol%) in 4 ml of H2O : EtOH (1 : 1) and microwave irradiation at 80 °C for 10 min. The carbon‐based materials employed as active catalyst supports portray vast promise in organic reactions, which is linked to their structural resemblance with organics, large specific surface area, chemical stability, and photocatalytic properties.

Scheme 23

Suzuki‐Miyaura reaction of aromatic aryl halides and phenylboronic acid‐catalysed by Pd/G.

In 2014, Sharavath and Ghosh made a novel contribution towards Suzuki cross‐coupling reaction by using noncovalently functionalised grapheme‐supported palladium nanoparticles (PCA−GNS−Pd) (Scheme 24). The reaction between various aryl halides with phenylboronic acids gave good to excellent yields of the coupled product (65–97 %) by using 0.2 mol% PCA−GNS−Pd, Na2CO3 and H2O. Notably, there were no apparent effects on yield when aryl bromides containing electron‐donating or electron‐withdrawing substituents were used. However, moderate to good yields were afforded when the reaction was carried out with electron‐rich and electron‐poor aryl chlorides as well as with the sterically hindered aryl halide substrates at longer reaction times. However, it was observed that Pd‐reduced graphene oxide and Pd−GO nanocomposites have lower catalytic activity towards chloro‐ and bromo‐ arenes in water than the PCA−GNS−Pd nanocomposites.

Scheme 24

Suzuki‐Miyarua coupling of aryl halides with phenylboronic acid by PCA−GNS−Pd.

Suzuki Coupling Catalyzed by Nano‐Silica Triazine Dendritic Polymer (nSTDP) Supported Pd Nanoparticles

In 2013, Isfahani and co‐workers developed a new thermally stable, oxygen insensitive, phosphine‐free, air‐and moisture‐stable, and reusable palladium nanoparticles immobilised on nano‐silica functionalised triazine dendritic polymer (Pd‐nSTDP) catalyst and applied it for the Suzuki‐Miyaura cross‐coupling under conventional conditions and microwave irradiation. The catalytic system showed high activity in the Suzuki‐Miyaura cross‐coupling of aryl iodides, bromides and chlorides with aryl boronic acids (Scheme 25). These reactions were best performed in a DMF/water mixture (1 : 3) in the presence of only 0.006 mol % of the catalyst under prevailing conditions and microwave irradiation to afford the desired coupling products in high yields (80–96 %). The Pd‐nSTDP was also utilised as an active catalyst for making a series of a star‐ and banana‐shaped molecule with a benzene, pyridine, pyrimidine or 1,3,5‐triazine unit as the central core.

Scheme 25

Suzuki cross‐coupling reaction of substituted aryl halides with different substituted phenylboronic acids catalysed by Pd‐nSTDP.

Further in 2014, they reported the preparation of a series of di‐ and trisulfides with benzene, pyridine, pyrimidine, or 1,3,5‐triazine as the central cores by one‐pot multi C−S cross‐coupling reactions of aryl/heteroaryl halides with aromatic/heteroaromatic thiols in the presence of the Pd ‐nSTDP as the reusable catalyst under thermal conditions and microwave irradiation.

Suzuki Coupling Catalyzed by Bio‐Supported Pd Nanoparticles

Sarkar and co‐workers prepared waste corn‐cob cellulose supported poly(amidoxime) palladium nanoparticles (PdNs@PA) by the surface modification of waste corn‐cob cellulose through graft co‐polymerization and subsequent amidoximation. The supported nanoparticles showed high catalytic activity (45–400 mol ppm) towards Suzuki‐Miyaura cross‐coupling of aryl bromides/chlorides (84) with organoboronic acids (85) and (86) using 0.03 mol% of palladium at 80 °C to give the corresponding biaryl products 87 and 88 up to 99 % yield with a high turnover number (TON) 19777 and turnover frequency (TOF) 4944 h−1 (Scheme 26). Moreover, the PdNs@PA was easily recovered from the reaction mixture and reused several times without significant loss of its catalytic activity.

Scheme 26

Suzuki reaction of substituted aryl halides with aryl boronic acids catalysed by PdNPs@PA.

In a related development, Baran and co‐workers designed a green chitosan/starch composite as support material for stabilisation of palladium nanoparticles. They employed it in the synthesis of a series of biphenyl compounds via Suzuki‐Miyaura cross‐coupling reactions with an unconventional technique. In 2019, Dhara and co‐worker used glucose stabilised palladium nanoparticles (PdNPs) as a catalyst for Suzuki reactions of both electron‐rich and electron‐deficient aryl halides with a variety of boronic acids to access a wide variety of biaryl compounds and substituted alkenes in good to excellent yields. Contrarily, Baruah et al used nanoparticles supported on cellulose (Scheme 27). The catalyst can be recycled up to ten times without losing its activity significantly.

Scheme 27

Suzuki reaction of substituted aromatic aryl halides with phenylboronic acids catalysed by glucose stabilised palladium nanoparticles.

In another related research, Firouzabadi et al described a newly developed material composed of magnetic Fe3O4 nanoparticles modified with agarose‐supported palladium nanoparticles (Pd@agarose−Fe3O4). They investigated the catalytic properties of Pd@agarose−Fe3O4 for Suzuki‐Miyaura coupling reaction by modelling the reaction of 4‐iodotoluene with phenylboronic acid in the presence of K2CO3 for cross‐coupling of different aryl halides with organoboronic boronates and boronic acids to obtain the coupled product in 67–97 % yield. While it took half of 30 min to record >90 % yields of biaryl with aryl iodide substrates, 24 h was needed to obtain biphenyls from both activated and deactivated aryl chloride with lower yields.

Suzuki Coupling Catalyzed by Pd Bimetallic Nanoparticles

Several reports have demonstrated the application of two nanoparticulate palladium‐based catalysts in cross‐coupling including Suzuki reaction. Kim and co‐workers explored the application of carbon‐supported bimetallic Pd−M (M=Ag, Ni, and Cu) nanoparticles made by γ‐irradiation in Suzuki cross‐coupling. They applied it for cross‐coupling of an organohalide (92) with phenylboronic acid (60) in ethanol (Scheme 28).

Scheme 28

The Suzuki reaction of (hetero)aryl halides with phenylboronic acid catalysed by Pd−Cu bimetallic system supported on carbon.

Applying the yield of the reaction to determine catalytic efficiency, it was observed that the carbon‐supported Pd−Cu bimetallic system was the most efficient.

In another study, Singh and coworkers prepared Bimetallic Ni−Pd alloy nanoparticles (99 : 1 or 95 : 5 Ni to Pd atomic ratios) and explored it for Suzuki C−C coupling reactions under moderate reaction conditions. Expectedly, significantly enhanced catalytic activity was achieved with the studied Ni−Pd nanoparticle catalysts for the C−C coupling reactions and products were obtained in moderate to high yields.

Hiyama Cross‐Coupling Reactions

Hiyama cross‐coupling reactions have emerged as possible substitutes to the Suzuki‐Miyaura cross‐couplings.[ , , ] It is a cross‐coupling reaction of organosilicon partner with organic halides.[ , ] It has gained popularity for asymmetric biaryl compounds synthesis or construction of multi‐substituted alkenes that are components of various functional materials. Its wide applications are attributed to the low cost, low toxicity, commercial availability, as well as high functional group tolerance, relative to organomagnesium and organocopper. Besides, the high moisture and air stability organozinc compounds in comparison to other organometallic reagents (Zn, Al, B, and Zr) used in cross‐coupling reaction is highly expedient.[ , ] Following the original report by Shibata and co‐workers, reactive aryl bromide and iodide had been majorly used instead of the relatively cheap and commercially available aryl chloride for Hiyama coupling[ , ] due to several drawbacks associated with the cheap aryl chloride in Hiyama coupling.[ , , , , , ] Below are some of the recently supported Hiyama couplings.

Hiyama Coupling Catalyzed by Carbon Immobilised Nanoparticles

Sajiki and co‐workers reported the first active palladium on carbon catalysed ligand‐free Hiyama cross‐coupling of a variety of electron‐rich and electron‐poor aryl halides (95) with aryltriethoxysilane (96) in good to excellent yields at 0.5 mol% Pd/C catalytic loadings in refluxing toluene within 24 h (Scheme 29). The use of fluoride sources such as TBAF.3H2O or metal fluorides is critical for the reaction to proceed. The reaction was also extended to phenytrimethoxysilane derivatives, and good yields were obtained within 48 h.

Scheme 29

Hiyama cross‐coupling of substituted aryl halides with aryltriethoxysilanes catalysed by Pd/C.

In the same vein, Brindaban and co‐workers reported a simple one‐pot fluoride‐free operation using in situ generated palladium (0) nanoparticles for efficient Hiyama cross‐coupling of a wide variety of substituted aryl bromides and iodides with aryl silanes in water (Scheme 30). The reaction proceeded very fast and was performed in air with excellent chemoselectivity and high yields.

Scheme 30

one‐pot fluoride‐free palladium (0) nanoparticles Hiyama coupling of aryl halides with aryl siloxane catalysed by in situ generated palladium (0) nanoparticles.

A similar reaction was independently reported by Sarkar and co‐workers using colloidal palladium nanoparticles (1 mol%) generated from Fischer carbene complex of tungsten as the reductant and PEG as the capping agent in water. Like every other cross‐coupling reaction, the catalytic efficiency depended on the nature of the bases and the ratio of PEG and Pd. Here, NaOH and Pd/PEG ratio 1 : 1 provided the optimal yields. While excellent isolated yields of biphenyls were recorded by cross‐coupling with arrays of electron‐rich and electron‐poor aryl bromides; no example of coupling of aryl chlorides was demonstrated, probably because the catalytic system was inactive to these substrates. Although the high surface to volume ratios and very active surface atoms which increase the reactivity as well as the recyclability make metal nanoparticles desirable catalysts compared to bulk catalysts, only very few heterogeneous Pd catalysts were found to convert aryl chlorides even at elevated temperatures except for microwave heating.

Hiyama Coupling Catalysed by Pd Nanoparticles

The cross‐coupling of allyl acetates and aryl and vinyl siloxanes proceeds readily by the catalysis of in situ generated palladium (0) nanoparticles. In 2008, Brindaban and co‐workers demonstrated that several structurally substituted allyl acetates (100) underwent regio‐ and stereoselective couplings with phenyl, tolyl, and vinyl siloxanes (101) to produce the corresponding allylated products (102) in high yield and purity (Scheme 31). The coupling with vinyl siloxanes was a novel method for the synthesis of 1,4‐pentadiene.

Scheme 31

one‐pot fluoride‐free palladium (0) nanoparticles Hiyama coupling of aryl bromide/iodide with aryl siloxane catalysed by Pd(0) nanoparticles.

Hiyama Coupling Catalysed by Pd Bimetallic Nanoparticles

As alloys or core‐shell states, bimetallic nanocatalysts are proven to show superior catalytic performance compared to that of its monometallic analogous for many catalytic reactions. The enriched catalytic performance of bimetallic systems is attributed to the favourable synergistic interactions between the metals, for which strong metal‐metal interactions presumably tune the bonding pattern of the reactants and stabilise the vital reaction intermediates on the catalyst surface.[ , ] These distinctive features are principally due to their composition and structure, causing specific electronic effects and in particular singular catalytic behaviour, which is distinguished by the synergy between both metals. Rothenberg and co‐workers reported the application of stable and highly mono‐dispersed core‐shell bimetallic Ni−Pd nanoparticles in the cross‐coupling reaction of different haloaryl (103) and phenylmethoxysilane (104) (Scheme 32). With a variety of iodo‐ and bromoaryl, good product yields were obtained; thus acting as a good source of biaryl‐containing compounds which are vital intermediates for preparing biologically active molecules, organic semiconductors and liquid crystals. Further study of the catalytic activity of Ni/Pd core/shell cluster visa‐vis Ni(OAc)2, Ni(0) clusters, Pd(OAc)2, Pd (0) cluster, Ni(0)/Pd(0) alloyed cluster in the Hiyama cross‐coupling revealed that the activity of the nanoparticle palladium could be increased by combining it with non‐reactive metal like Nickel in the following order Pd (0) cluster < alloy Ni−Pd clusters < core‐shell Ni−Pd clusters. The substrate scope of the catalyst was not expanded to involve aryl chlorides probably because of the inactivity of the catalyst to convert the substrates.

Scheme 32

Bimetallic Ni−Pd nanoparticles Hiyama cross‐coupling reaction of phenyl(triethoxy)silane with various haloaryls catalysed by Ni/Pd core/shell cluster.

Sonogashira Cross‐Coupling Reactions

Sonogashira cross‐coupling is the formation of carbon‐carbon bonds by cross‐coupling of terminal alkynes with aryl halides or vinyl halides.[ , , ] Sonogashira reaction has been applied in the synthesis of alkyne‐containing aromatic compounds,[ , ] natural products,[ , ] medicinal products,[ , ] oligomers,[ , ] and polymers. The air sensitivity of copper co‐catalyst which results in oxidative homocoupling of acetylenes to give diacetylenes as potentially explosive copper acetylides is the major setback of the reaction. Difficult removal of high boiling point solvents from the reaction mixture increases cost due to low homogeneous Pd catalyst reusability as well as product contamination by toxic Pd metal during the reaction.[ , ] However, recent improvements have been made.[ , , ] including the development of supported Pd for heterogeneous catalysis which simplifies separation and recyclability of the catalyst. Several catalysts support such as perovskites, carbon,[ , ] zeolites, hydrotalcite, silica, celluloses, and polymers have been employed. In the development of supported catalysts, the use of the right amount of catalyst loading on the supporting material to ensure catalyst reactivity and reducing catalyst leaching is a significant consideration.[ , ] To date, most of the supported catalysts developed still have ample room for further improvement. From the green chemistry point of view, using recyclable supported catalysts in aqueous media is desirable.

Sonogashira Coupling Catalysed by Carbon‐Supported Pd Nanoparticles

The application of Pd on carbon was also exploited by Stoltz and co‐workers. They explored the Pd/C and Amberlite IRA‐67‐mediated ligand‐free Sonogashira coupling of several deoxynucleoside derivatives 107 with trifluoroacetyl (108) and phthalimido reagents 109. They modelled the strategy employed by the Kotschy and co‐workers replacing the Pd/C for Pd(PPh3)4, lowering the catalyst loading to 5 % and carrying out the reaction at 50 °C to afford deoxyuridine, uridine, dideoxyuridine and deoxycytidine derivatives 110–111 (Scheme 33). The dideoxyuridine derivatives are particularly crucial as a critical intermediate in the synthesis of conventional Sanger DNA sequencing reagents. On the other hand, nucleic acids are advantageous biomaterials because they are non‐toxic, environmentally friendly, readily available and biodegradable; that is why the successful preparation of bio‐nano particles such as DNA−NPs has recently emerged.

Scheme 33

Solid‐supported Sonogashira coupling of deoxynucleoside derivatives mediated by Pd/C/Amberlite IRA‐67.

The condition was extended to the synthesis of 2‐deoxyadenosine and 2‐deoxyguanosine derivatives 112 (Scheme 34). Although the coupling of 8‐bromo‐2‐deoxyadenosine and 8‐bromo‐2‐deoxyguanosine derivatives was sluggish under Pd/C‐catalysis, the use of Pd(PPh3)4/Amberlite IRA‐67 system gave good to excellent yields of cross‐coupled products 113.

Scheme 34

Solid‐supported Sonogashira coupling of deoxynucleoside derivatives mediated by Pd/C/Amberlite IRA‐67.

Sajiki and co‐workers reported the cross‐coupling of a variety of aryl iodides (114) with aromatic and aliphatic terminal alkynes (115) to give the corresponding 1,2‐disubstituted aromatic alkynes (116) in good yields by using only 0.4 mol% of the heterogeneous 10 % Pd/C as the catalyst (Scheme 35). They explored the scope and limitations of the substrates under the optimised reaction conditions (10 % Pd/C and Na3PO4.12H2O (2.0 eq) in 50 % iPrOH at 80 °C). Iodobenzene and the aryl iodides containing an electron‐withdrawing group on the aromatic ring, such as nitro and acetyl functionalities and 3‐iodopyridine, a π‐deficient heteroaryl iodide, were smoothly coupled with a variety of both aliphatic and aromatic terminal alkynes. While the coupling of 4‐iodoanisole containing an electron‐donating methoxy group produced relatively lower efficiencies (38–72 % yields), the coupling products were smoothly obtained. They also demonstrated the application of the wet‐type Pd/C to catalysis of Sonogashira coupling reaction, and the reaction proceeded efficiently under argon and aerobic conditions.

Scheme 35

Copper‐, ligand‐, and amine‐free Sonogashira coupling reactions of various substituted aryl iodides with aliphatic and aromatic terminal alkynes catalysed by Pd/C.

Sonogashira Coupling Catalysed by Polymer‐Supported Nanoparticles

Zang and co‐workers in 2012 employed Pd(0) loaded polymethyl methacrylate (PMMA) microspheres for Sonogashira cross‐coupling of a variety of terminal acetylenes (117) with different phenyl iodides, bromides and chlorides (118) in aqueous media (Scheme 36). The coupling of phenyl iodides with electron‐donating or electron‐withdrawing groups proceeded readily with phenylacetylene in excellent product yields.

Scheme 36

Sonogashira cross‐coupling of aryl halides with phenylacetylenes catalysed by Pd(0)/PMMA in water.

In a related development, Shunmughanathan et al. developed melamine‐based microporous network polymer‐supported palladium nanoparticles (Pd/SNW1) as a stable and efficient catalyst for the Sonogashira coupling reaction in water (Scheme 37). Preliminary studies were performed using iodobenzene and phenylacetylene as model substrates in the presence of catalysts under various conditions to optimise the reaction yield. The optimised reaction condition was applied in the coupling of bromobenzene with phenylacetylene to afford various phenylethynyl benzene in good yields.

Scheme 37

Cross‐coupling of different substituted aryl halides with phenylacetylenes catalysed by Pd/SNW1 in water.

Sonogashira Coupling Catalysed by Copper Clusters or Pd Nanoparticles

Rothenberg and co‐workers first reported substituted diphenylalkynes prepared in good isolated yield and high selectivity for Palladium‐free and ligand‐free Sonogashira cross‐coupling of phenylacetylene (121) with various aryl halide (45) under stable Copper cluster catalysis (Scheme 38). Phenylacetylene and aryl halide (1.5 : 1 eq) were reacted in the presence of the base and the metal clusters at 110 °C. The stable copper cluster was prepared by reducing solutions of the chloride salt precursor with tetraoctylammonium formate (TOAF) in DMF at 65 °C. In this reaction, the nature of the base is critical to obtaining a high yield of the product. TBAA is more effective than TBAF, Et3N and NaOAc providing 100 % conversion.

Scheme 38

Cu2O catalyse cross‐coupling of phenylacetylene and iodobenzene.

In a related reaction, Wei and co‐workers applied an in situ generated palladium nanoparticles catalyst supported on Al(OH)3 for the Sonogashira cross‐coupling reactions of (hetero)aryl bromides and chlorides. The optimised reaction conditions were harnessed in cross‐coupling of various (hetero)aryl halides (45) bearing neutral, electron‐withdrawing or electron‐donating substituents on the phenyl ring with phenylacetylene (120) bearing electron‐donating and electron‐withdrawing groups in the benzene ring to afford the 1,3‐diyne products 123 in good to excellent yield (Scheme 39).

Scheme 39

Cross‐coupling of substituted aryl halides with phenylacetylene catalysed by Pd nanoparticles supported on Al(OH)3.

Heteroaryl bromides derived from pyridines, thiophenes, quinolines, and pyrimidines (124) were converted to the corresponding cross‐coupled products 125 in modest to high yields (Scheme 40). In this reaction, DMSO was the best form of solvent than DMF and H2O. Also, K2CO3, K3PO4, KOAC provided lesser yield than NaOAc in the reactions while KOH gave no yield at all.

Scheme 40

Pd(0)/Al(OH)3 cross‐coupling of (hetero)aryl acetylenes with bromobenzene.

In another development, Turimala and co‐workers investigated the Sonogashira‐type cross‐coupling reaction between phenylacetylene and iodobenzene in DMF solvent and K2CO3 as a base using Cu2O nanoparticles (NPs). The Cu2O nanoparticles (NPs), prepared by a microemulsion synthesis method, successfully catalyse C−C coupling reactions. The catalytic protocol is under ligandless and base‐free conditions and it was suggested to follow a truly heterogeneous pathway.

Sonogashira Cross‐Coupling Catalysed by EDACs Supported Nanoparticles

Shaabani et al synthesized and characterized Pd nanoparticles supported on ethylenediamine‐functionalized cellulose as an efficient novel bio‐supported heterogeneous catalyst for the Heck and Sonogashira couplings in H2O at 100 °C. The catalytic activity of PdNPs@EDACs for the Sonogashira coupling reaction was assessed with halobenzene (45) and phenylacetylene (120) in the presence of CuI (Scheme 41). At first, the influence of the solvent, the temperature, amount of catalyst and different kinds of bases on the reaction was studied. The optimal results were obtained in the presence of 0.40 mol % of catalyst and 100 mol % of K2CO3 in H2O after 7 h.

Scheme 41

Sonogashira reaction of iodobenzene with phenylacetylene catalysed by PdNOs@EDACs.

The optimal reaction condition was applied for the coupling of various electron‐neutral, electron‐rich, or electron‐poor aryl halides (127) reacted with phenylacetylene (126) to generate the corresponding cross‐coupling products 128 (Scheme 42). Pleasingly, the catalyst could be easily recovered by simple filtration and reused for at least 4 cycles without losing its activity.

Scheme 42

Cross‐coupling of different substituted aryl halides with phenylacetylene catalyse by PdNOs@EDACs.

Sonogashira Coupling Catalysed by Pd Bimetallic Nanoparticles

Increasing interest has been focused recently on bimetallic nanoparticles due to their unique physicochemical properties compared to their corresponding monometallic counterparts. These distinctive features are principally due to their composition and structure, causing specific electronic effects and in particular singular catalytic behaviour, which is distinguished by the synergy between both metals. A wide variety of Pd bimetallic nanoparticles have been reported and used for Sonogashira and other named‐cross‐coupling reactions because of their unique advantages over a monometallic one such as catalytic control, selectivity, stability and synergistic effects.[ , ] After the pioneering work of Silvert et al. in 1996 on the synthesis of PdAg nanoalloys by polyol methodology using EG as a solvent, several contributions of palladium bimetallic nanoparticles (BMNPs) have been described in the literature, mostly involving noble metals, such as gold, platinum and ruthenium, but also BMNPs, including first‐row transition metals such as iron, cobalt, nickel, and copper. Hyeon and coworker synthesised Pd−Ni bimetallic nanoparticles with a Ni‐rich core and Pd‐rich shell structure from thermal decomposition of palladium and nickel salts at a temperature of 205 °C and found out that the catalytic activity of Pd/Ni showed much better catalytic activity than similarly sized Pd nanoparticles (Figure 8). The nanoparticle catalyst was active for bromoaryl but conspicuously showed no activity for chloroaryl.

Figure 8

Comparison of Pd/Ni catalytic activity with similarly sized Pd nanoparticles. Reproduced from Hyeon et al. with permission from the American Chemical Society.

The catalyst was recycled and reused for at least five times without losing its catalytic activity. It was noted solvent polarity and concentration of the stabilisers are important factors in optimising the stability and activity of nanoparticle clusters; and that the deposition of the Pd shells on Ni cores is driven by variation standard potentials which allowed Ni(0) to reduce Pd(II) to Pd(0). Similarly, Evangelistic and co‐workers reported a poly‐4‐vinyl pyridine‐supported bimetallic Cu/Pd nanoparticles (d=2.5 nm) synthesised by metal vapour synthesis (MVS) technique and supported on poly‐4‐vinyl pyridine (PVPy) resin that showed significantly higher catalytic activity in Sonogashira‐type cross‐coupling reactions compared to the related monometallic Cu and Pd systems. While Pd/Ni nanoparticle catalysts provided a synergistic catalytic effect, Gadi and co‐workers observed metal nanocluster prepared by reduction of bimetallic Cu/Pd with tetrabutylammonium acetate (TBAA) in DMF at 65 °C were less active than either monometallic Pd or Cu nanoparticle catalysts in Sonogashira cross‐coupling of aryl halides. While in the presence of 5 mol% of Cu cluster variety of aryl iodides gave quantitative yields of coupled products, aryl bromides supplied good to moderate yields and no conversion of chloroarenes.

Reactions Mechanism

The precise mechanism for metal nanoparticle C−C cross‐coupling of aryl halides is controversial as a result of the various hypothesis that been postulated.[ , ] It was posited that palladium nanoparticles on a solid support are a reservoir from which active palladium atoms are leached out to involve in the catalytic cycle; and after that, regenerated Pd(0) is redeposited into the palladium cluster.[ , ] This is called dissolution‐redeposition theory. Whether the mechanism for the nanoparticles cross‐coupling reaction is to be regarded as homogeneous or heterogenous has also been debated. However, in 2011 study by Perez‐Lorenzo proposes both mechanisms for palladium nanoparticle catalysed Suzuki reactions may be regarded as mutually complementary and depended on the mobilisation degree of the nanoparticles (Figure 9).

Figure 9

The proposed mechanism for nanoparticles cross‐coupling reaction of aryl halides. Adapted from Perez‐Lorenzo et al. with permissions from American Chemical Society.

In heterogeneous nanoparticle catalysis, the catalytic transformation (oxidative addition to reductive elimination) of substrates (aryl halides) take place in the surface of the palladium cluster. In another way, the mechanism may become homogenous if the leached out active palladium atoms initiate and complete the catalytic transformation of the substrate in the solution. These heterogeneous and homogenous mechanisms are generally followed by other named palladium nanoparticle catalysed cross‐coupling reaction, e.g Heck, Sonogashira, Hiyama etc. Eight years after Prez‐Lorenzo study on homogenous/heterogeneous nature of the mechanism of Pd catalysed C−C bond formation, an interfacial surface‐enhanced Raman spectroscopic study of the same mechanism unveiled clear evidence of only heterogeneous catalysis which occurs by direct contact of aryl halides with the Pd metallic surface. Furthermore, increasing the electrical attraction between the nanoparticle surface and the substrate molecules enhanced the turnover frequency (TOF) of the catalyst. Conversely, the inactivity of soluble Pd species that leached out of the cluster into the solution suggests the exclusion of homogeneous catalysis. Detailed discussion on the status of the mechanism of palladium nanoparticles C−C cross‐coupling reaction can be found in the reviews by Knight et al and Friedrich et al.[ , ]

Conclusions and Outlook

Pd nanoparticles have higher surface to volume ratios than the analogous bulk catalysts. This relatively increased surface area leads to a higher proportion of active surface atoms and, ultimately, to enhanced catalytic performance. The tunability, recyclability and environmentally benign nature of immobilised nanoparticles on solid supports and the ones suspended in colloidal solutions account for their wide acceptability as a heterogeneous and homogeneous catalyst in varieties of named‐cross‐coupling reactions, unlike the bulk catalyst. However, the major setbacks to the efficient usability catalysing electron‐rich and sterically encumbered substrates are rooted in their often agglomeration and leaching. Therefore, a variety of supports and capping agents have been investigated to circumvent these undesirable effects. Besides, catalysts involving two (bimetallic) and multimetallic have been introduced because they provide catalytic synergism, selectivity and thermal stability. Though the reviewed articles are limited to Heck, Suzuki, Hiyama and Sonogahira, the observations from applications of palladium nanoparticles to other named cross‐coupling reaction are similar to the ones discussed. For example, several bioactive compounds such as allocolchicines, stegnacine and eupomatilones have been prepared from 2‐bromo‐3,4,5‐trimethoxy benzaldehyde using of Fe3O4 supported Pd(0) nanoparticles (Pd/Fe3O4) by Stille cross‐coupling. The scope of the catalytic strength excluded the unreactive aryl chloride substrate. The efficient adaptability of nanoparticles for the catalytic transformation of aryl halide substrates is still far from being accomplished, particularly, the inefficiency of the catalyst for activation of aryl chlorides like homogeneous bulk Pd(0) complexes containing electron‐rich bulky ligands such as phosphine. Hence, the main concern in nanoparticles catalysis is still finding a catalytic system to effectively activate C−Cl and the development of reusable catalyst with minimal or no loss of activity of variety.

List of Abbreviations

bromovinyldeoxyuridine

polyethene glycol

mesoporous covalent organic polymers

poly(undecylenic acid‐co‐N‐isopropylacrylamide‐co‐potassium 4‐acryloxyoylpyridine‐2,6‐dicarboxylate)

ethylenediamine‐functionalised cellulose

β‐cyclodextrin/N‐methyl urea

1‐Butyl‐3‐methylimidazolium Hexafluorophosphate Microemulsions

1‐pyrene carboxylic acid

β‐cyclodextrin‐graphene nanosheet

poly 2‐acrylamido‐2‐methyl‐1‐propane sulfonic acid

pectin‐carboxymethyl cellulose

poly(N‐vinyl‐2‐pyrrolidone)

poly(2‐hydroxyethyl methacrylate)

Nano‐Silica Triazine Dendritic Polymer

polymethyl methacrylate

pinacolate

poly‐4‐vinyl pyridine

turn over frequency

tetra‐n‐butylammonium acetate

tetra‐n‐butylammonium fluoride

Conflict of interest

The authors declare no conflict of interest.

Biographical Information

Jude I. Ayogu obtained a B.Sc (first‐class honours) in Pure and Industrial Chemistry in the University of Nigeria, Nsukka in 2011. He proceeded with a masters degree (Organic Chemistry) at the same University where he made a parallel distinction (GPA 5/5) in 2015. He is a recipient of the Outstanding Academic Excellence Award (2011), among others. He started his teaching career as a graduate assistant in 2013 at University of Nigeria Nsukka. Besides other contract appointments such as laboratory demonstrator, teaching assistant, senior teaching assistant, Bentham Science Ambassador; he is currently a lecturer II in the Department of Pure & Industrial Chemistry, University of Nigeria.

Efeturi A. Onoabedje completed his PhD in Organic Chemistry (2014) from the University of Nigeria, with a research stint at Cardiff University, Cardiff, Wales, UK (2013). His PhD research focused on the application of palladium catalysis in functionalisation of phenothiazine and phenoxazine scaffolds. He is a recipients of the Petroleum Technology Development Fund (PTDF) PhD Scholarship (2012) and CSIR‐CDRI TWAS Post‐Doc Fellowship (2017) awards. He is presently a Senior Lecturer in the Department of Pure & Industrial Chemistry, University of Nigeria, where he teaches courses in organic chemistry and does research in the design and synthesis of anti‐infective agents.