Nanocatalysis Synthesis and Applications (Polshettiwar/Nanocatalysis) || Nanocatalysts for Hiyama,...

5NANOCATALYSTS FOR HIYAMA,STILLE, KUMADA, AND NEGISHI

C–C COUPLING REACTIONSAbhinandan Banerjee and Robert W. J. Scott

INTRODUCTION

In the last century, the synthetic organic chemist had formidable resources available forthe design and preparation of new complex molecules.1, 2 However, in the twenty-firstcentury, it is essential for a successful synthetic strategy not only to yield new, pureproducts selectively but also to develop processes that are environmentally friendly,cost-effective, and dependent on renewable feedstocks rather than on fast-depletingfossil fuels or their derivatives.3–5 The burgeoning field of catalytic nanomaterials, ornanocatalysts, offers an opportunity to the modern synthetic chemist to follow the tenetsof green chemistry without compromising on crucial factors such as yield and selectivityof products.6 Current emphasis on catalysis using nanomaterials, which straddles theboundaries of homogeneous and heterogeneous catalysis, often combining the benefitsof both, underscores the quest for recyclable catalytic materials.7 In this field of research,the formation of new C C bonds using nanomaterials has emerged as a challenging newproblem that is being studied across the globe.8 C C couplings are now a staple ofmodern organic chemistry, as evidenced by the recent Nobel Prize award in chemistryto Heck, Negishi, and Suzuki in 2010. A recent Web of Knowledge R© search showsthe almost exponential growth in the number of literature reports related to interdisci-plinary research involving nanochemistry and organic synthesis during the past decade(Figure 5.1).

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.

133

134 NANOCATALYSTS FOR HIYAMA, STILLE, KUMADA, AND NEGISHI C C COUPLING

0

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

10

20

30

40

50

60

70

80

Figure 5.1. Publications on nanoparticle-catalyzed C C couplings from 2000 to 2011: the

number of publications dealing exclusively with C C bond formations using nanocatalysts

plotted as a function of year.

The reasons for this increase in research directed toward nanocatalyzed C C cou-plings are several. First of all, C C couplings form one of the most significant classesof organic synthetic strategies, and they find application in the synthesis of materialsas diverse as capparatriene (a drug used to treat leukemia),9 tazarotene (an antiacneagent),10 altinicline (effective for the treatment of Parkinson’s disease and Alzheimer’sdisease), (+)-papulacandine D (an antifungal compound),11 liquid crystals,12 Lightemitting diodes, organic conductors,13 dendrimers,14 supramolecular species, and soon. Second, nanomaterials represent a continuum between discrete atoms and macro-scopic objects, and in doing so, possess unique physical, chemical, and electrical prop-erties, which bestow upon them special catalytic abilities that may be harnessed for“green” chemical transformations under benign reaction conditions.6 Third, propertiesof nanomaterials (such as dispersibility, tolerance of high temperatures, and resistance toagglomeration) are very often greatly dependent on their local environment or support,so these can be suitably tailored to suit individual reactions.6, 15 Most importantly, how-ever, it has been the realization by many researchers that the harsh conditions neededfor many homogeneous catalysts (�100 ◦C temperatures, strong bases, and so on) areoften needed for the activation of the homogeneous “precatalyst” into the actual clusterand/or nanoparticle catalyst that is responsible for the high C C coupling efficiencies.16

This realization has inspired many researchers to predesign nanoparticle catalysts (bothmonometallic and bimetallic) that are quite active at much lower temperatures (andin some cases at room temperature) for C C coupling reactions that typically had tobe done at much higher temperatures.17 In differentiating between homogeneous andheterogeneous catalysis mechanisms in a seminal review, Crabtree mentions what hecalls “suspicious circumstances” such as harsh reaction conditions.18 If a so-called

INTRODUCTION 135

homogeneous catalysis reaction can proceed successfully only above 100–150 ◦C, orin the presence of harsh reagents such as powerful oxidants or reductants, then theactive catalytic material may well be nanoparticles. Inversely, however, in some casesthe nanoparticle is simply a reservoir for the catalytically active homogeneous species,which can leach from the nanoparticle surface and be redeposited during reductive elim-ination steps.19 The ability to lower reaction temperatures also has major ramifications inthe importance of catalyst recyclability; lower temperatures can also allow for catalyticspecies to be reused over many catalytic cycles.4 This cannot be stressed enough—notonly is it worthwhile to recover precious metals such as Pd, Pt, Ru, and Rh (whichare often the catalytic species of choice) from an economic point of view but also toensure that the products are not contaminated by the presence of residual heavy metalspecies. Since most transition metals are cytotoxic even in trace amounts, it is of crucialimportance to ensure that organic molecules formed by metal-catalyzed reactions inthe pharmaceuticals industry are free from traces of heavy metals.20 Nanoparticles canpotentially be of immense benefit in this area; however, it must be noted that leachingof metals from nanoparticle catalysts has been observed in many coupling reactions,and thus can be problematic for product purity in liquid-phase catalytic applications ofnanoparticles.21 Finally, in recent times, the concept of “tandem catalysis” involvingthe nanoparticle stabilizer (such as an oxide support or an ionic liquid (IL), describedin detail in the following section) in the reaction strategy as well has been developed,thereby designing a sort of “one–two punch” approach that makes multistep synthesesredundant.22 In the synthesis of pharmaceuticals and natural products—where overallyields can increase and costs of production can go down drastically if the number ofsteps involved in the total synthesis is reduced—this strategy is of immense importance.

While there are many C C cross-coupling reactions developed, the following cou-pling reactions find maximum application in industrial processes: Heck, Sonogashira,Suzuki–Miyaura, Kumada–Corriu, Negishi, Stille, Hiyama, and Fukuyama coupling.23

While some of these have been studied so intensively from a nanocatalysis point of viewthat other chapters in this book have been dedicated to them (see Chapters 2, 3, and 4,on Heck, Sonogashira, and Suzuki–Miyaura coupling), others such as Kumada–Corriucoupling, Negishi coupling, Stille coupling, and Hiyama coupling have been studied toa lesser extent for the purpose of establishing a nanomaterial catalyst protocol; thoughtremendous research progress on these coupling reactions has been noted in the past10 years. A general schematic representation of the reactions explored in this chap-ter (excluding modifications, mentioned separately for each reaction) can be seen inScheme 5.1. The main goal of this chapter is to introduce stabilized nanoparticles ascatalysts for these coupling reactions, and to disclose the mechanistic aspects of suchcouplings, in order to investigate reactions in which precatalysts undergo in situ conver-sions to yield the actual zerovalent catalytic metal clusters, as well as newer syntheticstrategies where nanocatalysts are designed and synthesized in advance, keeping in mindthe demands for a particular reaction sequence. We also intend to discuss the rapidlyfading boundaries between conventional homogeneous and heterogeneous catalysis inthis context, and comment on the role of nanoparticles as applied to C C couplingreactions in transcending such boundaries.


R'ZnX

R'MgX

R'SnR"3

R'SiR"3

R-R'

R-R'

R-R'

R-R'

(Negishi)

(Kumada–Corriu)

(Stille)

(Hiyama)

Metal catalystR-X

(X can be a halide, or a pseudohalide, such as a triflate)

Scheme 5.1. Metal-catalyzed C C cross-coupling reactions.

CATALYTIC NANOPARTICLES FOR C C CROSS-COUPLINGS

Synthesis

While nanoparticle synthesis approaches can often be broadly classified as top-down(via breaking down a bulk material by physical/chemical methods such as laser ablationor ball milling) or bottom-up (via the agglomeration of atoms to form well-defined clus-ters and/or nanoparticles), catalytic metal nanoparticles are mostly synthesized by thelatter approach, primarily because better synthetic reproducibility and uniformity in themonodispersity of size and shape of particles are the hallmarks of the bottom-up strat-egy.24 As there is a cornucopia of literature focusing on the various bottom-up strategiesfor nanoparticle syntheses, we only discuss selective aspects of such reactions. Greaterattention is paid toward methods used to stabilize metal nanoparticles, both against pre-cipitative agglomeration and metal leaching. Synthesis of multimetallic nanoparticles isalso briefly discussed.

Among the various metal nanoparticle synthesis protocols available, metal saltreduction is perhaps the most commonly used. Typically a reducing agent is used,which can range from ordinary chemical reductants such as alkali metal borohydrides,elemental phosphorus, ascorbic acid, citrate, or hydrogen, to such novel reductants ascarbenes, organoaluminiums, alfalfa extracts, beverage extracts, proteins, vitamins, andbiowaste.25–27 The reducing agent is typically reacted with a metal salt in the presence ofthe stabilizer to generate zerovalent metal atoms, which then collide with other atoms,or metal ions, to produce metal nanoclusters and/or nanoparticles, which remain stableas long as they are protected by the stabilizer (Scheme 5.2).24 Note that the size of thesenanoparticles depends strongly on the difference in the redox potentials of the metal saltand the reductant of choice, the strength of the intermetallic bonds, and the nature of thestabilizer used. With controlled conditions, metal nanoparticles having any diameterswithin the definition of the “nanoscale regime” (1–100 nm) can be generated, as well as

CATALYTIC NANOPARTICLES FOR C C CROSS-COUPLINGS 137

Reduction

Ion–atom collision Polyatomic collision

Mx + cation

M0 atom

50 nm

Nucleation

Metal cluster

TEM image of Au-NPs

Scheme 5.2. Steps involved in the formation of metal nanoparticles by reduction of salt

precursors.

multiatomic clusters below 1 nm in dimension. For example, Sawoo et al. have used cat-alytically active palladium nanoparticles (Pd-NPs) prepared by the reduction of K2PdCl4in water by (CO)5W = C(Me)ONEt4 in the presence of polyethylene glycol (PEG) asa stabilizer, and used the protected metal nanoparticles for Suzuki, Heck, Sonogashirsa,and Stille couplings.28 Meier et al. synthesized star-shaped block copolymer-stabilizedPd-NPs for efficient Heck cross-coupling by sodium borohydride reduction of Pd(OAc)2in dimethylformamide (DMF) in the presence of the copolymer, leading to stabiliza-tion of Pd-NPs of defined size within five-arm star-shaped block copolymers consistingof a poly(ethylene oxide) core and a poly(ε-caprolactone) corona.29 Aqueous garde-nia extracts were used by Jia et al. to reduce PdCl2; the nanoparticles thus generatedwere small (3–5 nm) and highly active in catalyzing the reduction of p-nitrotoluene,with 100% yields at 150 ◦C. The catalysts remained unagglomerated for five cycles ofreaction, possibly due to the plant antioxidants protecting the nanoparticle surfaces.30

Thermal and photochemical degradations are also often used in syntheses where thepresence of a reductant and/or its by-products is not desired. A labile metal complex,often with olefinic ligands such as cyclooctadiene or cyclooctatetraene, is subjected tothermal, microwave, or photolytic conditions, under which the ligands are removed, andzerovalent metal nanoparticles are formed.31 Radiolytic methods subject an aqueoussolution of a metal salt to X-rays, � -rays, or ultraviolet-visible (UV-Vis) radiation fromHgorXe lamps, generatingmetal nanoparticles via a radical pathway.32 Radical initiatorsare often used to reduce the irradiation time, and the presence of stabilizers is usuallyessential to prevent particle aggregation and broad particle size distributions.33


Electrochemical methods are also used in metal nanoparticle synthesis. One ofthe earliest strategies in this field was to oxidize a sacrificial anode in the presenceof a stabilizer to generate metal ions that are then reduced at the cathode to generatewell-dispersed metal nanoparticles.34 This method also simplifies problems such asmetal nanoparticle isolation and purification. Other, more elegant, electrochemical metalnanoparticle synthetic strategies have been developed in the last few decades. DuranPachon et al., for instance, used an electrochemical protocol to generate Ni seedsthat were then encapsulated in Pd shells via a “wet chemical method” to generatemonodisperse core–shell nanoparticles active in Hiyama coupling.35 In a recent studyby Deshmukh et al., Pd(OAc)2 was electrochemically reduced in the IL [BMIM](OAc)to form approximately 6 nm nanoparticles; these were seen to catalyze Suzuki couplingin water in the presence of KOH and tetrabutylammonium bromide (TBABr), the latterpresumably stabilizing the nanoparticles.36

Biogenesis of metal nanoparticles is a very important trend that has been devel-oped within the last decade; biological materials ranging from simple prokaryotes tocomplex eukaryotic organisms including higher angiospermic plants and viruses areincreasingly being used for nanoparticle synthesis.37 Application of bacterial strains,viral lines, yeast, fungi, plants, and algae for the synthesis of monometallic, bimetallic,and chalcogenide nanoparticles is currently being studied extensively, not only becausethese methods can lead to monodisperse nanoparticles of unusual morphologies butalso because biologically generated nanoparticles are believed to be more suitable forbiological applications such as drug delivery.25 Nanoparticles have been developed bothin vivo (within living organisms) and in vitro (in extracts of plants, fungi, animal tissues,and so on).38 While there are not many experimental studies on C C cross-couplingscatalyzed by biologically generated nanoparticles, the fact that such nanoparticles arecatalytically active is undeniable. Sharma et al., for instance, grew Sesbania seedlingsin chloroaurate solution, which led to accumulation of gold in the form of stable goldnanoparticles in plant tissues. These biomatrix-captured nanoparticles were proposed tobe catalytically active, and this claim was substantiated by facile reduction of aqueous4-nitrophenol on nanoparticle-rich biomass.39 Bimetallic AuPd-NPs were synthesizedby Stevens and coworkers via an environmentally benign method of bioreductive pre-cipitation by the microorganism Shewanella oneidensis, and these were seen to catalyzeSuzuki coupling reactions of different aryl iodides and arylboronic acids with variableactivities (Figure 5.2).40

Bimetallic nanoparticles, which are currently being studied for their unique catalyticproperties, have also found application in C C cross-coupling reactions. Concurrentthermal decomposition of Ni and Pd surfactant precursors by Son et al. in 2004 generateda Pd shell on a Ni core, and these nanoparticles were seen to be extremely efficient (notonly from the point of yield but also from the point of atom economy) in Sonogashiracoupling.41 Such nanoparticles can be formed inmany different structures, themain onesbeing random alloy, core–shell, phase-segregated (or “cluster on cluster”), intermetallic,and multiple shells (Figure 5.3).42 Bimetallic clusters can be generated in a variety ofways, in the gas phase, in solution, supported on a substrate, or in a matrix. For a detailedaccount of bimetallic nanoparticle synthesis, the reader is directed to extensive reviewson the subject.42,43


(HO)2BR2

I

Pd/Au

R2

R1

0.5 um

R1

Figure 5.2. Suzuki coupling catalyzed by AuPd bimetallic nanoparticles biologically precipi-

tated on the cell wall of the metal-respiring bacterium S. oneidensis. (Reprinted from Ref. 40,

Copyright 2012, with permission from Elsevier.)

Protection of Catalytic Nanoparticles against Agglomeration

It is a well-documented fact that nanoparticles, in the absence of stabilizers, formmacroscopic ensembles, which typically precipitate out of the solution.44 The functionof stabilizers and/or supports is to prevent this course of events. While the sheer numberof chemical entities that have found application as nanoparticle stabilizers or supportswould justify an entire review devoted to the topic, here we briefly introduce the differentcategories of metal nanoparticle stabilizers; a detailed treatment of each species can befound in the relevant references.

(a) (b)

(d) (e)

(c)

Figure 5.3. Types of bimetallic nanoparticles: (a) alloy, (b) core–shell, (c) phase-segregated,

(d) multiple shells, and (e) intermetallic.


While a precise and systematic classification of metal nanoparticle stabilizers is yetto be worked out, for the purposes of this chapter, we can roughly group the supportson the basis of the nature of catalytic activity of the protected nanoparticles. Two broaddivisions that emerge from such a differentiation are “polysite” (a variety of activecatalytic sites as is the norm in heterogeneous catalysts) and “oligosite” (catalysts witha limited number of active sites, with each active site “motif” repeated over and over;characteristic of stable, monodisperse nanoparticle suspensions).45 Each category hasbeen discussed here in some detail.

“Quasi-homogeneous catalysis” resides at the interface between the traditional dis-ciplines of homogeneous and heterogeneous catalysis.45 Metal nanoparticles are oftendispersible in traditional solvents (unlike conventional heterogeneous catalysts), and itis possible to characterize them using spectroscopic and electrochemical techniques.Additional benefits of “quasi-homogeneous” catalysis with metal nanoparticles includeselectivity, efficiency, and facile catalyst regeneration leading to reusability.46 Tradi-tionally, many of the first stabilizers used in quasi-homogeneous nanocatalysis werepolymers, not only because of the steric bulk of their framework but also becausethey ligate weakly to the nanoparticle surface through a heteroatom, such as N inpoly(vinylpyrrolidone) (PVP), and act as a bulky ligand conglomerate.47 Shi and Zhang,for instance, found PEG-stabilized Pd(OAc)2 to be an efficient catalytic system forHiyama coupling, whereas the catalytic activity decreased in the absence of the PEG,which presumably stabilizes the nanoparticles formed in situ.48 Special types of poly-mers, such as dendrimers, bioploymers (polysaccharides, nucleic acids, and so on), andblock coploymers, have also been used successfully as nanoparticle stabilizers.49 Therehave been detailed studies on dendrimer-stabilized nanoparticles as highly efficientC C cross-coupling catalysts. Crooks and coworkers investigated poly(amidoamine)(PAMAM) dendrimer-encapsulated Pd-NPs as catalysts for Stille C C coupling reac-tions, and found that the resulting particles were active catalysts even at room tem-perature conditions.50 Bernechea et al. further studied this system and found that thedendrimer-stabilized Pd-NPs were precursors for molecular Pd species, which leachedfrom the nanoparticle upon oxidative addition of the aryl halide, but were still boundto the dendrimer, as shown in Figure 5.4.19 Borkowski and coworkers used similardendrimer-stabilized Pd-NPs system for Suzuki–Miyaura, Hiyama, Heck, and Sono-gashira reactions.51

Ligand-stabilized nanoparticles are another important class of oligosite catalyststhat have been found to be catalytically active; however, some very strong ligandssuch as thiolates may actually either completely or partially passivate metal nanopar-ticle surfaces and reduce or shut down their catalytic activities.52 Supramolecularspecies such as cyclodextrins and polyoxoanions, as well as chelating ligands suchas 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), have also been used for metalnanoparticle stabilization.53 Stille coupling, in particular, has been carried out usingPd-NPs stabilized by an octyl-tagged bisphosphine ligand by Tatumi et al.54 This ligandstabilized highly monodisperse 1.2 nm Pd-NPs, which were active catalysts for Stillecoupling, and were immune to deactivation by thiol additives. An additional advantageof BINAP ligands is their ability to impart asymmetry to the catalytic reactions, lead-ing to stereoselectivity. Keggin-type polyoxometallates have also been used to stabilize


Figure 5.4. Suggested mechanism for the Stille reaction in water using the Pd dendrimer

system as a catalyst. The reaction is catalyzed by Pd species leached from the nanoparticle and

coordinated to the dendritic interior. (Reprinted with permission from Ref. 19, Copyright 2009,

American Chemical Society.)

nanoparticles for Stille C C coupling reactions.55 Micellar and reverse micellar stabiliz-ers, such as tetraalkylammonium halides and fluorinated surfactants, have also been usedextensively as nanoparticle-stabilizing agents in C C cross-coupling reactions.56 Thesestabilizers have been used in a wide variety of liquid media including water, organic sol-vents, and supercritical solvents. Peptide fragments have been used by Pacardo et al. tostabilize Pd-NPs for Stille coupling (Figure 5.5) in a pioneering study on the interactionbetween inorganic interfaces and biological molecules.57 Further investigations havebeen carried out by the same group in order to identify the structural motifs present inthe peptides that actually prevent the nanoparticles from agglomerating, and to fine-tunethe size, surface structure, and functionality of single-crystal Pd-NPs between 2 nm and3 nm using materials directing peptides.58,59

A special class of compounds thatmerits separatemention is solvents known as ionicliquids (ILs): ionic compounds that exhibit fluidity at ambient temperatures.60 ILs canstabilize metal nanoparticles by different mechanisms, intrinsically as well as throughthe addition of secondary stabilizers. Intrinsic stabilization can be performed throughbinding of the anion to the metal surface, functional groups present in the cation ofthe IL (often known as task-specific ILs), polymeric moieties added to the structureof the IL, and so on.45,61 Fei and coworkers, for instance, synthesized imidazoliumILs with one or two cyanoterminated alkyl substituents, and noted that the stability of


NaBH4

PhSnCl3

XSnCl3

Pd2+

Peptide

ArX

ArX

Oxidativeaddition

Ar

X

Ar

Ar

PhArPh +

X

Pd ionabstraction

Transmetalation

Reductiveelimination

Nanoparticledeposition

Pd0

Figure 5.5. Biomimetic synthesis and catalytic application of peptide-capped Pd-NPs.

(Reprinted with permission from Ref. 59.)

Pd-NPs in these ILs was due to the interaction between the cyano-moieties and thecoordinatively unsaturated nanoparticle surface.62 Calo and coworkers, on the otherhand, used tetraalkylammonium bromide ILs for the stabilization of Pd-NPs, whichwere then used for Stille and Suzuki C C couplings without any functionalizationof the IL.63 Many neat ILs themselves owing to their high viscosities, well-definedstructural domains, and presence of precursor impurities can intrinsically stabilize metalnanoparticles; however, such stabilization may be short-lived.64 Extrinsic stabilization isachieved through the addition of stabilizers mentioned previously; a crucial factor hereis the solubilities of those stabilizers in the IL, and this is where instrinsic stabilization ispreferred over additive-induced stabilization. We have, for example, showed that PVP-stabilized nanoparticles can be successfully dispersed in [BMIM][PF6] for catalysis;however, the presence of trace amounts of 1-methylimidazole can also be used tostabilize nanoparticles in these ILs.65,66

Nanoparticles tethered onto a solid support are popular catalysts for C C cross-couplings. Some of the supports that have been explored in this context include meso-porous carbon, metal oxides (both Lux-Flood acids and bases depending on catalyticapplications), zeolites, hydroxyapatite, clays, silica gel, foams, cellulose, functionalizedmultiwalled carbon nanotubes (CNTs), and graphene.67–73 Lipshutz for instance, hasreviewed the development of nickel-on-charcoal as a “dirt-cheap” catalyst for C Ccross-coupling reactions.74 Multiwalled CNTs decorated with Pd-NPs have been foundto catalyze Stille C C couplings.75 Magnetic supports deserve special mention in thiscontext, since they are easily separable from the reaction medium, and have been used ascores in Pd/Fe3O4-catalyzed Hiyama coupling reactions; the magnetite particles them-selves have shown catalytic activities in Sonogashira–Hagihara cross-coupling reac-tions.76 Pd(II) salts or complexes have been tethered onto fluorous silica gels, and theorganic–inorganic hybrid material has been reduced to generate the active catalyst. Tsai


et al. have used this approach to graft a Pd–bipyridyl complex onto nanosized meso-porous silica, and used the resulting material to catalyze Kumada–Corriu couplings.77

Nanocomposites have also been used for similar purposes.Other siliceousmaterials, suchas mesocellular foams, ordered mesoporous materials, and mesoporous spheres, havebeen similarly used for nanoparticle stabilization.78,79 Choudhary et al., for instance, hasused layered double hydroxides for encapsulating Pd-NPs that are active for Stille C Ccoupling reactions.80 Merrifield resins, usually used for automated peptide synthesis,have also been used as metal nanoparticle supports, albeit with added functionalities.81

Perovskites and other inorganic matrices have also been used successfully for encap-sulating catalytic metal nanoparticles. Kiss et al. immobilized Ni on various inorganicsupports such as hydrotalcite, mixed MgLaO, and 4 A molecular sieves, and came to theconclusion that MgLaO, where the Ni was incorporated into the surface structure of thesupport, was the best support for the Kumada–Corriu catalyst.82 The catalysts describedin these examples exhibit different turnover numbers (TONs), extent of leaching, andcatalytic efficiencies, but, in general, are of considerable scientific interest.

Characterization of Catalytic Metal Nanoparticles

It is essential to characterize nanoparticles in order to gain insight into their struc-tures, and predict their properties, including (but not limited to) catalytic behaviour; forinstance, many nanoparticles larger than 10 nm in diameter would most likely be poorlyactive in coupling reactions. There are numerous techniques for nanoparticle character-ization, some of them simple yet elegant, others highly complex and technologicallychallenging. Some of the more usual techniques have been summarized as follows:

1. Spectroscopic techniques: UV-Vis spectroscopy can be useful in the study ofmetal nanoparticles if the metals show localized surface plasmon oscillationsin the visible range. This is of immense significance in bimetallic nanoparticlesin which Au or Ag is a major component; an Au core, for instance, would notshow any visible absorptions if it is successfully coated with another metal,which does not have a surface plasmon resonance at similar wavelengths, whilea gold coating will generate a new surface plasmon band. Fourier transforminfrared (FTIR), Raman, and nuclear magnetic resonance (NMR) spectroscopytechniques have also been used successfully in the field of nanocatalysis, primar-ily to investigate attachment of a support or a ligand onto a metal nanoparticlesurface. Duran Pachon and coworkers confirmed the formation of Pd-coatedNi-NPs by using, among other techniques, UV-Vis spectroscopy.35 The peptide-encapsulated Pd system prepared by Pacardo et al.was also characterized byUV-Vis spectroscopic analysis. Pd(II)-impregnated peptides showed an absorbanceshoulder at approximately 224 nm. This absorbance was attributed to the Pd–amine ligand-to-metal charge transfer band, confirming that Pd(II) bound to thepeptide. After reduction of Pd(II) to Pd(0), a color change from yellow to brownwas observed, with an increase in absorbance at lower wavelengths. Circulardichroism techniques were also used in the same study to probe changes inthe peptide motifs.57, 83 Wu et al. applied31 P NMR to study phosphine-based


(a)

(b)

(c)

Figure 5.6. TEM micrographs of (a) pristine MWCNTs, (b) free Pd-NPs, and (c) MWCNTs dec-

orated with Pd-NPs, nano-Pd–MWCNTs. (Reprinted with permission from Ref. 75, Copyright

2008, American Chemical Society.)

dendrimers stabilizing Pd-NPs, both in order to understand the Pd-NP–P(ligand)linkage and to investigate a ligand oxidation process that generated phosphineoxide.84

2. Electron microscopy: In this technique, a beam of electrons is focused onto asurface to illuminate it and generate a highly magnified image of a specimendeposited on the surface. Different types of electron microscopy (EM) used fornanoparticle imaging include scanning EM, transmission EM (TEM), scanning-TEM (STEM), and low-voltage EM. Spectroscopic information about the spatialcomposition of nanoparticle catalysts can often be obtained via energy dispersivespectroscopy (EDS) and electron energy loss spectroscopy on many modernEMs. Almost all the studies mentioned in this chapter use one or the other ofthese imaging methods to confirm the formation of nanoparticles, and to studytheir morphological peculiarities. Figure 5.6 shows a relevant example of Pd-NPs decorated on multi-walled carbon nanotube (MWCNT) supports.62 Wileyand coworkers applied high-angle annular dark-field scanning TEM (HAADF-STEM) technology to obtain images of Au core and Pd petal nanoflowers capableof Suzuki cross-coupling reactions (Figure 5.7). The images clearly show thecontrast between the Au core (due to its higher atomic number) and the Pd petalsof the as-synthesized nanoflowers. In the same study, energy dispersive X-ray


(a) (b)

(c) (d)

Figure 5.7. (a) HAADF-STEM image of nanoflowers consisting of an Au core and Pd petals.

(b–d) Elemental maps obtained with EDX spectroscopy showing the distribution of Au and

Pd in the nanoflowers. (Reprinted with permission from Ref. 85, Copyright 2009, American

Chemical Society.) (See color insert.)

(EDX) spectroscopy in a STEM was applied to map the elemental compositionof the particles, and similarity between the sizes of the Au core in the nanoflower(14.0 ± 0.7 nm) and the starting Au seed (14.0 ± 1.3 nm) was taken as a proofthat significant alloying between the Au core and the Pd shell did not occur.71

3. Atomic force microscopy: Also called scanning force microscopy, this techniqueutilizes a cantilever probe that travels across a sample landscape and generatesinformation about the nature of the surface. For example, well-defined sphericalPd-NPs grafted onto chemically modified silica gel supports by Dutta and Sarkarfor Stille coupling were studied by Atomic force microscopy (AFM) to gainsome information about the topography of the catalyst and true diameter of theparticles.86

4. X-ray spectroscopy: X-ray spectroscopy can be used for nanoparticle charac-terization not only after their isolation but also in real time, as they catalyze areaction (in situ or in operando). X-ray photoelectron spectroscopy (XPS) cangive valuable information about catalyst composition and oxidation states, whileother techniques such as X-ray absorption near-edge structure and extended X-ray absorption fine structure (EXAFS) spectroscopy can provide a wealth ofinformation about the oxidation state of the metals, and their atomic coordina-tion sphere, respectively, and are typically carried out at modern synchrotronfacilities. For example, a recent quick-scanning EXAFS study of supported Pdcatalysts for Heck coupling shed considerable light on the role of colloidal Pd(0)clusters (∼2 nm) that were seen to form in operando.87


5. Miscellaneous techniques: Other techniques that have been used extensively fornanoparticle characterization are optical microscopy, powder X-ray diffraction,porosity measurements via nitrogen absorption isotherms, dynamic light scat-tering, X-ray microtomography (3D imaging), and Matrix assisted laser desorp-tion/ionization time of flight (MALDI-TOF) mass spectrometry. Ohtaka et al.,for instance, used optical microscopy in order to assess the colloidal stability ofthe synthesized polypyrrole–Pd nanocomposite-coated latex particles. The opti-cal microscopy evaluation indicated darkening of the particles after being coatedwith the PPy–Pd nanocomposite due to the black color of the PPy component.88

In conclusion, it is evident from the literature cited previously that the scientificcommunity today possesses sufficient know-how to synthesize, protect, and characterizecatalytically active metal nanoparticles, either in a quasi-homogeneous medium or astraditional heterogeneous catalysts. The following section focuses on the use of suchsystems as catalysts inHiyama,Negishi, Kumada–Corriu, and Stille C C cross-couplingreactions.

HIYAMA COUPLING

Ever since its discovery in 1988 by Tamejiro Hiyama and Yasuo Hatanaka, the Hiyamacross-coupling reaction has been a powerful method for the generation of new C Cbonds with chemo- and regioselectivity.89 The Hiyama cross-coupling reaction, inits original form, involves Pd-catalyzed cross-coupling of organosilanes, activated inthe presence of fluoride ions, with organic halides, and was promoted as an effi-cient method of cross-coupling without the use of ultrareactive (such as organomagne-sium), toxic (such as organotin), or moisture-sensitive (such as organozinc) main grouporganometallic compounds. The organosilane is activated with fluoride (as some sortof salt such as tetrabutylammonium fluoride (TBAF) or tris(dimethylamino)sulfoniumdifluorotrimethylsilicate (TASF) or a base to form a pentavalent silicon center, which islabile enough to allow for the breaking of a C–Si bond during the transmetalation step.90

A mechanistic representation of this sequence of events is depicted in Scheme 5.3. Asshown in Scheme 5.3, a Pd(0) precursor (PdL2) is typically identified as the active speciesfor the reaction, followed by transmetalation at the Pd center and reductive eliminationof the final product.

Since the 1990s, considerable work has been done by several research groups toexpand the scope of this reaction. A significant modification is the Hiyama–Denmarkcoupling, where a Brønsted base is used as an activator, making the use of fluoride ionsunecessary.48,91–93 The reaction has been optimized with the use of various Brønstedbases and/or phosphine ligands attached to the Pd center to accommodate many sub-strates to form various Csp2–Csp2 and Csp2–Csp bonds. Other modifications to the originalscheme involve the use of silylcyclobutane rings and a fluoride source that is hydrated,generating a silanol, and eventually a pentacoordinated “activated” silicon center that islikely the reactive species.94 Variations include judicious applications of organochlorosi-lanes and alkoxysilanes, which make it possible for the reaction to proceed in the

HIYAMA COUPLING 147

R-X

X

R

R-R′Reductiveelimination

transmetallation

Oxidative addition

R′-SiF4+

F4SiR′+

NBu4F

R

R’

X-SiF4+NBu4

-

LnPd(II)

LnPd(II)

LnPd(0)

NBu4-

Scheme 5.3. Mechanistic representation of the Hiyama coupling reaction.

presence of environmentally benign and inexpensive activating agents such as NaOHor even water. Lewis acid additives such as alkali metal phosphates and cocatalystssuch as Cu salts chelated to fluorinated acetylacetonate ligands have also been appliedto facilitate “sans-fluoride” Hiyama couplings.92 Several excellent reviews exist on thescope and utility of the Hiyama coupling, and the interested reader is referred to someof these for a detailed account of the various substrates, ligands, solvents, and so on, thathave found application in the Hiyama cross-coupling reactions. Greater stability andsmaller eco- and cytotoxicity of organosilicon species coupled with the range of possi-ble substrates make the Hiyama coupling an attractive alternative to the more prevalentSuzuki coupling for C C bond formations, and it finds extensive use in the synthesisof antifungals and natural products of medicinal and commercial worth. The utiliza-tion of Pd-NPs in the Hiyama coupling can be broadly divided into two categories: the“serendipitous” category, in which the precatalyst (a Pd salt, such as Pd(OAc)2, or apalladacycle) generates catalytically active Pd-NPs during the course of the reaction,and the “deliberate” category, where either Pd-NPs are intentionally generated in situor presynthesized Pd-NPs are applied for the coupling. While the early literature tendsto focus more on the serendipitous generation of Pd-NPs from precursors during thecourse of the reaction, recent research attempts to synthesize and protect the catalyti-cally active Pd-NPs in a deliberate attempt to heterogenize an erstwhile homogeneouscoupling reaction.

The scientific community has been aware for a long time that some of the exoticmetal–ligand complexes used in C C coupling only serve as precatalysts; the actualcatalytic species can be the colloidal metal (as clusters or nanoparticles) generatedfrom the precatalyst under reducing conditions, or, less often, the bulk metal film orpowder formed by the agglomeration of such colloidal particles.95 Several reports ofearly Hiyama coupling reactions make a passing mention of the probability that theactual catalysts may be colloidal metal particles.96 Presence of an induction periodduring the course of the reaction, or drop in catalytic activity owing to poisoning by Hg,strengthened this argument; however, most of the earlier studies could, at best, identifythe Pd-NPs formed, but not comment on their catalytic contributions.97


One of the earliest examples of Pd-NPs playing a role in Hiyama coupling waspublished in 2007 by Shi and Zhang, where Pd(OAc)2-catalyzed fluoride-free cross-coupling between the aryl bromides and arylsiloxanes was studied in water containingthe polymer PEG-200 under ambient conditions.48 However, it was observed that thereaction was significantly less successful (74% yield of cross-coupled product in purewater as opposed to 92% in a 3 : 3 water/PEG-200 mixture) in the absence of the PEGnanoparticle-stabilizing agent. Thus, the combination of water and PEG was found tobe an efficient medium for the reaction, and the authors concluded that PEG functionedas a stabilizer for Pd-NPs in the reaction process. The authors also conducted recy-clability studies on this system, and found that after extraction of the product(s) thePd(OAc)2−PEG−H2O mixture could be subjected to the next cycle by charging it withthe same substrates in the remnant. It was shown that the catalytic system could berecycled eight times with a small decrease in activity without the need for activation oraddition of the catalyst or PEG.

In 2008, Alonso and Najera studied the coupling of aromatic halides and alkenyltrioxysilanes under conventional and microwave heating in the presence of NaOH as anactivator to generate styrenes and unsymmetrical stilbenes.98 Ligandless Pd(OAc)2 or4-hydroxyacetophenone oxime-derived palladacycles acted as precatalysts under low Pdloadings, but they generated Pd-NPs during the heating. The catalysts gave moderate-to-high yields (60–99%), and a certain degree of regio- and diastereoselectivity in theproducts, although this tended to vary with different substrates. While investigating thepossibility of catalyst regeneration, they found that the palladacycle was catalyticallyactive for six cycles, whereas Pd diacetate gave good yields for fewer cycles. Whilevery low levels of leached Pd could be detected in the crude products for the first fewcycles, this value eventually increased to over 50 ppm after four consecutive runs. Alonsoand Najera have also reviewed the advantages and limitations of oxime palladacyclesas a source of highly active Pd-NPs for high-turnover catalyzed cross-couplings, andproposed the development of supported oxime-derived palladacycles (such as Kaiseroxime palladacycles) in order to facilitate precatalyst recovery and reuse in cross-coupling reactions, especially under aqueous reaction conditions.96 Skarzynska andGniewek synthesized unsymmetrical H-spirophosphorane-coordinated Pd precatalystsfor Heck and Hiyama cross-couplings, and detected the presence of Pd-NPs in thecatalytic reaction mixture. TEM micrographs of the postcatalysis liquid phase showedthe formation of spherical Pd-NPs of approximately 8 nm size, along with irregularaggregates. Darkening of the reaction mixture after one catalytic cycle also indicatedthe formation of nanoparticles.97

There are many studies in the recent literature on the Pd-NP intermediates as theactive species in Hiyama coupling reactions. In 2009, Bauerlein et al. devised an elegantsynthesis of an electron-deficient alkene functionality (such as chalcone and benzylideneacetone) doped common ILs, which were shown to be very promising reaction mediafor Hiyama coupling in the presence of a Pd(OAc)2 precatalyst.89 Imidazolium ILssuch as 1-pentyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide and 1-pentyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide were doped with these lig-ands, and used in what was the first instance of Hiyama coupling in ILs. Cyclohexenylethyl carbonate was coupled with aryl siloxanes in the presence of a fluoride activator,

HIYAMA COUPLING 149

showing conversions over 90%. Products were isolated by Kugelrohr distillation andwere free from the chalcone ligands as well as leached Pd (�50 ppm from elementalanalysis). However, initial recycling experiments suggested that the IL/catalyst systemwas rendered inactive after the vacuum extraction of the products. The Pd-NPs generatedin situ were examined by TEM, and it was found that the substituents present in thephenyl ring of the chalcone dopants played a definite role in controlling the nanoparticlessizes; electron withdrawing groups led to 1–3 nm nanoparticles, while 4–5 nm nanoparti-cles were seen for electron donating groups. The smaller nanoparticles had significantlyincreased coupling rates due to their higher surface areas. In 2011, Penafiel et al. gener-ated N-heterocyclic carbene–Pd complexes from hydroxyl-functionalized imidazoliumsalts, and showed that under microwave irradiation in the presence of aqueous NaOH,these could serve as active precatalysts for fluoride-free Hiyama cross-coupling of arylhalides with trialkoxy(aryl)silanes.90 TBABr was seen to be a necessary additive foraryl chloride activation. Again, the presence of Pd-NPs is a likely prospect under theseconditions.

Deliberate synthesis of metal nanostructures for Hiyama couplings began around2005, with the seminal work by Duran Pachon et al., in which a combined chemical/electrochemical cluster synthesis approach was adopted to make core–shell NiPd-NPs,which proved to be catalytically active for Hiyama coupling, and superior to monometal-lic nanoparticles in their catalytic efficiency.35 Electrochemically preparedNi seeds werecoated with Pd via a wet chemical method to generate monodisperse core–shell nanopar-ticles having a mean diameter of 4.9 nm, with tetraoctylammonium bromide (TOAB)as a protecting agent, in dimethylformamide (DMF) or tetrahydrofuran (THF). Thesecore–shell catalysts could promote complete conversion of iodotoluene to substitutedbiphenyl, with only 1–2% of the homocoupling by-product. After several control reac-tions, the authors conclude that that by combining Pd with another nonreactive metal(in this case, Ni), it is possible to increase the activity per Pd atom. This was reflectedin the following trend for catalytic efficiency and degree of conversion: Pd(II) salts �segregated Pd clusters � alloy NiPd clusters � core–shell NiPd clusters. Ni(II) andNi clusters were catalytically inactive under the reaction conditions. The authors didnot conduct any recyclability study on the system, but it was noted that the core–shellnanoparticles remained unagglomerated for weeks in DMF.

Sawoo et al. prepared stable Pd-NPs in water fromK2PdCl4 using a Fischer carbenecomplex of tungsten as the reductant and PEG-600 as the capping agent.28 The Pd-NPswere seen to be stable in air for a month and extremely active in Hiyama cross-couplingreactions for a variety of substrates with excellent yields. The particle sizes and thereactivity were correlated, with relatively larger particles (9.7 nm) generated in thepresence of smaller amounts of PEG, which showed greater reactivity as well as lowerstability against agglomeration. It is pointed out that the catalytic reaction is fluoride-free, needs no additional ligands for Pd, and uses the most benign solvent (i.e., water).However, no comments were available on the recyclability potential of the catalyticsystem. The same group used PEG-600 as both reductant and capping agent for themanufacture of polycrystalline Pd-NPs, which were then used for coupling benzylhalides with phenyltrimethoxysiloxane in THF. TBAF was used as an activator, and itproduced good yields (�75% in all cases) as well as complete chemoselectivity. Again,


Figure 5.8. Proposed mechanism for nanocatalyzed Hiyama coupling reaction. (Reprinted

with permission from Ref. 99, Copyright 2010, American Chemical Society.)

no recyclability studies were mentioned in the communication. Benzyl and allyl halideswere coupled with aryltrialkoxysiloxanes by the same group in 2010 using PEG-600-stabilized Pd-NPs.A tentativemechanismwas proposed for the “nano”-Hiyama couplingas shown in Figure 5.8,99 in which oxidative addition of the allyl halides occurs on thesurface of the particles.

Pd black, or Pd/C, a widely used solid-supported catalyst, has been studied exten-sively in recent years as a potential catalyst for Hiyama coupling.91 In the presence of 1%Pd/C and 4% PPh3 as a ligand, iodobenzene could be arylated with phenyltrimethoxysi-lane in DMF at 100 ◦C with the addition of TBAF as an activator. Different commercialas well as “in-house” varieties of Pd/C have been compared for their catalytic activitiesin the Hiyama coupling, and it is shown that the source and type of palladium on charcoalcatalysts strongly determine the efficiency of cross-coupling reactions. Pd on MWCNTcatalysts showed enhanced catalytic activities for C C cross-coupling reactions.91 Morerecently, Yanase et al. used Pd/C in the presence of tris(4-fluorophenyl)phosphine [(4-FC6H4)3P] to catalyze Hiyama cross-coupling reactions that only needed small amountsof 10% Pd/C (0.5 mol%) and phosphine ligands (1.0 mol%) for efficient reaction.100

This work was continued in another study by the same group where Pd/C was usedfor ligand-free Hiyama coupling.92 In the presence of a fluoride donor such as TBAFand acetic acid, 0.5 mol% of 5% Pd/C (K-type, N.E. Chemical Corporation, Japan) wasseen to catalyze the Hiyama cross-coupling of various aryl halides and aryltriethoxysi-lanes. Regeneration of the catalyst after a few runs was poor owing to Pd leaching; afterhot-filtration studies, the investigators determined that the coexistence of the substratesand acetic acid enhanced the leaching of the Pd species from 5% Pd/C, and the leachedPd itself possessed catalytic activity toward the Hiyama cross-coupling reaction. It wasconcluded that the Pd/C was a Pd source for the ligand-free Hiyama cross-coupling reac-tion. Pd catalysts containing 4–10 nm metal nanoparticles deposited onto multiwalledCNTs were also seen to be efficient catalysts for the Hiyama coupling. Kim and cowork-ers anchored 6 nm Pd-NPs onto the surface of thiolated multiwall CNTs, as shownin Figure 5.9. TEM, XPS, and Raman spectroscopic studies revealed the formation

HIYAMA COUPLING 151

Figure 5.9. TEM image of Pd-NP/MWCNT catalyst. (Reprinted with permission from Ref. 91,

Copyright 2010, Elsevier.)

of approximately 6 nm Pd-NPs adhering strongly to the side walls of the CNTs. Thepristine Pd(dba)2, CNTs, the mixture of CNTs and Pd(dba)2, and a commercial Pd/Ccatalyst were shown to be catalytically inactive, while the Pd-grafted CNTs catalyzedthe Hiyama coupling reaction of 4-iodotoluene and trimethoxysilylbenzene in the pres-ence of TBAF as an activator in p-xylene at 50 ◦C to produce approximately 98% ofthe desired cross-coupling product.93 This result indicates that surface thiolation is aneffective way to obtain highly dispersed metal nanoparticles on the surface of CNTs,and markedly improves their catalytic activity for Hiyama cross-coupling.

Pd/Fe3O4, a magnetically recoverable nanocatalyst containing approximately0.023 mmol of Pd per gram of the catalyst, also catalyzed the coupling of aryl bromideswith aryl siloxanes under fluoride-free conditions.101 It was unambiguously shownthat the reaction occurred via heterogeneous catalysis, and the filtrate after the cata-lyst removal was neither catalytically active nor significantly enriched in dissolved Pdspecies. Five catalytic cycles did not deactivate the catalyst, with the average yieldremaining 86%, and the last cycle producing 82% product. It is expected that Pd embed-ded on various forms of supports will remain an attractive subject of future research asrecyclable catalysts for Hiyama coupling.

Surfactant stabilizing agents have been used in the synthesis of Pd-NPs for Hiyamacross-coupling byRanu and coworkers, who obtainedmoderate-to-good yields for a one-pot reaction between allyl acetates and organosiloxanes in THF at 65 ◦C in the presence


Nanopalladium

Ar1-X

X

Ar1Ar2

Ar1

Ar1-Ar2

HOSi(OMe)3 + X- Ar2-Si(OMe)3 + OH-

Figure 5.10. Proposed mechanism for Hiyama coupling catalyzed by sodium dodecyl sulfate

(SDS)-protected Pd clusters. (Reprinted with permission from Ref. 103, Copyright 2008, Elsevier.)

of PdCl2, TBABr, and TBAF.102 The Pd-NPs were generated in the reaction vessel byreduction of the Pd salt by allyl acetates, and were protected by the tetrabutylammoniumgroups of the added TBABr. TEM studies revealed these nanoparticles to be between3 nm and 5 nm in size. Products were obtained in high purities; Pd-NPs were recoveredafter reaction and were reused for subsequent runs. It was found that for up to threeruns the catalysts were appreciably active, but every cycle led to a slow increase inagglomeration, leading to increase in size and catalyst deactivation upon repeated use.In another study by the same group, 2–3 nm Pd-NPs were detected as the catalyticallyactive species in the synthesis of dienes and trienes via Hiyama cross-coupling in thepresence of PdCl2 and TBAF in THF under ambient conditions, where the TBAF servedas a fluoride supplier and nanoparticle stabilizer at the same time. Compatibility withbase-sensitive functional groups such as esters and nitriles, general applicability for awide range of aryl and heteroaryl halides, good yields, and excellent stereoselectivityby providing only trans-products were some of the advantages of the reactions exploredin this study. Surfactants such as SDS and sodium dodecylbenzene sulfonate were alsoused by Ranu and coworkers to prevent the agglomeration of Pd-NPs generated in situfrom Na2PdCl4, and these nanoparticles were then used in a one-pot Hiyama couplingof a number of substituted aryl bromides and aryl siloxanes in water at 100 ◦C toproduce the cross-coupled products in excellent yields (Figure 5.10).103 The aqueouslayer containing the catalyst after product extraction was used for three cycles withgradual loss of efficiency; however, it is not mentioned if this was due to agglomerationor leaching.

Polymer-supported Pd-NPs have also proved to be effective catalysts for Hiyamacross-coupling, a representative example being 3.5 nm Pd-NPs protected by PAMAM

NEGISHI COUPLING 153

dendrimers by Borkowski et al., who then applied these catalysts in a variety of C Ccross-coupling reactions, including the Hiyama reaction, for which they got moderate-to-low yields and very little catalytic recyclability. It was proposed that the entrapmentof dendrimer-protected Pd-NPs in mesoporous frameworks could potentially improveyield and recyclability of these reactions.51

The first example of a nanoparticle-catalyzed Hiyama reaction in a continuous-flow microreactor was published in 2010. Silica gel was reacted with ClPPh2 in thepresence of pyridine in THF at room temperature, and after washing with ether, thediphenylphosphine-tagged silica gel was reacted with Pd(acac)2 in THF to obtain Pd-enriched silica gel.104 The amount of Pd in the silica gel was determined to be 5.92 wt%by inductively coupled plasma-mass spectrometry (ICP-MS) analysis. This Pd-enrichedsilica gel was then used for the construction of a microreactor that gave excellent yieldsfor the fluoride-activated Hiyama coupling of aryl bromide and arylsiloxanes. The Pd-enriched silica gel was independently shown to be catalytically active with only slightlyreduced yields for three cycles of catalysis in a batch reactor.

It thus becomes evident from a survey of the relevant literature that Hiyama couplingand its modifications (Hiyama–Denmark coupling, and so on) are eminently suitablecandidates for “greening,” in the sense that nanoparticle catalysts can be used for thesereactions, thereby facilitating catalyst recovery, minimizing metal contamination ofproducts, and generally improving the yields and selectivity of these reactions.

NEGISHI COUPLING

Some of the first organometallic reagents used by scientists for the formation of newC C bonds included organozinc compounds. In particular, a seminal work by King,Okukado, and Negishi laid the groundwork for this elegant reaction system, as shownin Scheme 5.4.105 Although organozinc compounds were, for a length of time, over-shadowed by more reactive organomagnesium and organolithium compounds, the lowchemoselectivity and high activity of these compounds soon renewed the scientificcommunity’s interest in organozinc compounds. Facile transmetalation of organozinc

R-X

X

R

R-R′


Oxidative addition

R′-ZnX

R

R’

X-ZnX

LnPd(II)

LnPd(II)

LnPd(0)

transmetallation

Scheme 5.4. Representation of the Negishi coupling reaction.


compoundswith a variety of transitionmetal complexes followed by cross-coupling reac-tions with organic electrophiles opened new reaction pathways and led to widespreadapplications of this reaction protocol in synthesis.106

A cursory study of the literature on C C cross-couplings involving organozincspecies would reveal that there have been less attempts to synthesize nanoparticulatecatalysts for this process compared to, say, the Hiyama protocol. Reasons for thisapparent exclusion are several. Unlike the Hiyama reaction, which, in some of itsvariations, can be carried out in open air, with water as a solvent, and in the presenceof recyclable Pd-NP catalysts, the Negishi reaction needs an inert atmosphere for itssuccess. This is partly because organozinc compounds are pyrophoric and thus unstablein the presence of air and water, and react with most protic solvents. Diorganozinccompounds are even more reactive than organozinc halides. In many reactions theyare prepared in situ, not isolated, and reacted further. All reactions require an inertgas (nitrogen or argon) blanket. Under these circumstances, it is of course of little useto develop an ambient condition catalyst for such reactions. However, the question ofcatalyst recyclability is still an important concern. However, a number of organozinccouplings are catalyzed by cheaper metals such as Ni rather than noble metals such as Pdor Pt, and this in turn may have somewhat quenched the search for recoverable catalysts.However, in the synthesis of pharmaceutical products, for instance, it must be ensuredthat the isolated compound is free from the heavy metal catalyst, and this, among otherreasons, has led to research into Negishi nanocatalysts.

The following section deals with the use of Ni and Pd nanocatalysts in Negishicouplings, including reactions where metal nanoparticles are suspected to be the actualcatalytic species. Other types of organozinc cross-couplings such as those catalyzed bycopper salts, those that proceed in the absence of any catalysts, and those that also includean organotin reagent in a double cross-coupling reaction are beyond the scope of thischapter, and the interested reader is referred to an excellent general review on organozinccoupling reactions in synthetic organic chemistry for a detailed overview of the topic.23

One of the first examples of heterogeneous Ni catalysts in Negishi coupling wasreported in 1999, when Lipshutz and Blomgren developed in situ generated Ni nanopar-ticles on charcoal as an inexpensive and highly effective catalyst for mediating Negishicouplings between functionalized zinc reagents and substituted aryl chlorides.107 Avariety of substituted zinc halides and aryl chlorides, most notably with each partnerbearing electrophilic functionality (e.g., ketones, esters, nitriles, and aldehydes), wereseen to readily and efficiently couple in refluxing THF in the presence of Ni/C, withmoderate-to-good yields. The issue of catalyst leaching was carefully examined, but anICP-MS study could detect only trace amounts (0.0015% vs ArCl) of Ni, which wasnot likely to be sufficient for catalysis. In addition, upon halting an ongoing couplingby removal of the Ni/C via filtration followed by re-exposure of the clear reaction solu-tion to the original catalytic conditions did not lead to additional cross-coupling to anysignificant degree. It was explicitly pointed out that retention of Ni on the solid supportoffers control over such critical parameters as waste disposal, toxicity, and presumablycatalyst recyclability. The true heterogeneity of the systemwas later called into question,and it was suggested that the Ni/C served as a reversible reservoir for homogeneous Nispecies in solution, involving a release/capture mechanism. It is proposed that a dynamic

NEGISHI COUPLING 155

equilibrium exists for the Ni located inside and outside the pore system of the char-coal, and this equilibrium strongly favors the former, thus leaving only traces of metaldetectable in solution. This would account for virtually complete recovery of Ni onthe charcoal following filtration of a reaction mixture and allows for recycling of thecatalyst. A combination of microwave heating and use of Ni/C was later reported to bea successful and efficient procedure for Negishi coupling, leading to 87% isolated yieldof the product.108 Interestingly, even ultrasonication of the reaction aliquot for mixingpurposes (no microwave irradiation, with prereduced Ni0/C, bath temperature up to only40 ◦C) afforded the same high yield of coupled product. Ni/C thus offers advantagespeculiar to both homogeneous and heterogeneous catalysts, and can act as an efficient andrecyclable catalyst for Negishi couplings. There are also some examples of zirconium-Negishi coupling (reactions involving organozirconium rather than organozinc reagents)catalyzed either by “ligandless” Pd or by Ni/graphite systems, which have TEM imagesthat are representative of nanoparticles. The “ligandless Pd” catalysts are poisoned byHg, indicating the presence of a catalytically active heterogeneous species.109 Similarly,Ni/graphite could catalyze cross-couplings between vinylic zirconocenes, derived fromterminal alkynes, and aryl halides under microwave irradiation leading to stereodefinedstyrenes in good yields.110

The use of ligandless “homeopathic” Pd catalysts obtained in situ fromPd(OAc)2 was a definite attempt to use Pd-NPs as the active catalysts in Negishi cou-pling. It was noted in the study by Alimardanov and coworkers that the use of ligand-freePd was possible only when the Pd–substrate ratio was kept low, typically from 0.01 to0.1 mol%. By lowering the Pd concentration, the oxidative addition of the aryl bromidecould compete against the formation and growth of the Pd-NPs, and moderate-to-goodyields of the cross-coupled products were obtained at 50 ◦C.111

A recent investigation by Liu and coworkers proved conclusively that Pd-NPs wereformed from Pd(OAc)2 and TBABr under the reaction conditions employed.112 It iswell-known that agglomeration and precipitation of nanoparticles can be preventedby the presence of a nanoparticle-stabilizing additive such as TBAX (X = halide)in the reaction medium. Thus, a combination of Pd(OAc)2 and TBABr catalyzed thecross-coupling between aryl iodide and alkylzinc efficiently at room temperature aswell as at −20 ◦C in excellent yields within 1 h. A possible mechanism involved thereduction of Pd(OAc)2 to Pd(0) by the alkylzinc reagent under the reaction conditions,stabilization of the in situ generated nanoparticles by TBABr, and catalysis by thesePd-NPs (Figure 5.11). Upon following the reaction between ethyl-2-iodobenzoate andcyclohexyl-ZnCl by in situ FTIR spectroscopy, it was noticed that the reaction reached60% completion after 30 s and 100% after 2 min. An additional observation suggestedthat PPh3 acted as a catalyst poison, presumably by ligating irreversibly to the activesites of the Pd-NPs. The role of tetraalkylammonium halide additives was also exploredin the context of organozinc-mediated coupling in a series of articles published byGiovannini and coworkers from 1999 onwards.113 An initial study demonstrated thatthe addition of TBA iodide significantly accelerated the Pd(0)-catalyzed cross-couplingbetween benzylic zinc bromides and alkenyl or aryl triflates, and also allowed a wholenew reaction pathway involving Ni(0)-catalyzed cross-coupling between alkyl iodidesand benzylic zinc reagents. A subsequent study showed that in the presence of TBA


R

R

RR

R

RR

Br

Br

RN

R

RR

BrR

N

N

R

RR

RB

r N R

Ar

X

R

RR

R

RR

Br

Br

RN

R

RR

BrR

N

N

R

RR

RB

r N

R

Ar

Ar′

Ar′ZnX

Ar-Ar′(coupled product)

Ar-X

R

RR

R

RR

Br

Br

RN

R

RR

BrR

N

N

R

RR

RB

r N

Figure 5.11. A tentative mechanism for nanocatalyzed Negishi coupling reactions in the

presence of tetraalkylammonium salts.

iodide and 20mol% 4-fluorostyrene, unreactive primary and secondary alkylzinc iodidesunderwent Ni-catalyzed cross-couplings with primary alkyl iodides or bromides. It wasnoted that the presence of excess TBA iodide was essential for rate enhancement, andthe involvement of a low-valent Ni center was suspected.114 While nanoparticles are notexplicitly mentioned, their involvement appears to be a definite possibility.

While organozinc compounds are notoriously moisture-sensitive, there appears toa route to conduct Negishi reactions in water without decomposition of the organoz-inc halide or the diorganozinc compounds.115 This route involves the in situ formationof the organozinc species on the surface of zinc dust from an alkyl or vinylic halide,which then couples with the organic halide under Pd catalysis within the hydrophobiccore of a micelle. In the presence of a stabilizing ligand for the transient RZnX species(e.g., tetramethylethylenediamine), this sequence can occur in an aqueous medium, gen-erating products that can subsequently be recovered. The relative rates of organozinc

STILLE COUPLING 157

halide formation, transmetalation to Pd, and aqueous protonation of RZnX must all becontrolled in such a way that RZnX is not formed in situ too rapidly, so as to avoidquenching by eventual exposure to water. It is pointed out that the surfactant likelyplays dual critical roles by helping to insulate the nascent organozinc species fromwater, thereby extending its lifetime, as well as by acting as a general solubilizing agent.In 2009 and 2010, a number of detailed studies were conducted on this topic, basedon the concept of micellar catalysis using nanoparticle reactors. In the most signifi-cant of these, Pd-catalyzed, Zn-mediated Negishi-like cross-coupling reactions betweenaromatic bromides and alkyl iodides in the absence of a stoichiometrically preformedorganometallic coupling partner were performed in water at room temperature in thepresence of 2% polyoxyethanyl �-tocopheryl sebacate (PTS), a commercially availableamphiphile.116 The lipophilicity of the reactants influenced the yield significantly, pos-sibly because greater lipophilicity led to facile dissolution of reactants and promotedtheir entry into the lipophilic core of a nanomicelle for catalysis. Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) [Pd(Amphos)2Cl2] was used aprecatalyst, and it could be surmised that this was reduced by the organozinc to generatesurfactant-stabilized Pd(0) centers entrapped within micelles, where the actual reactiontook place. This method was also seen to be of use in zinc-mediated stereoselectivesp3−sp2cross-couplings between an alkyl and alkenyl halide in the presence of a Pd(II)precatalyst and PTS. Only 2 equivalent of the corresponding alkyl halide and 1 mol% ofPdCl2(Amphos)2 were required for high levels of conversion and good isolated yieldsunder mild, ambient temperatures. The concept of a “designer” surfactant was furtherexplored in 2011, when Lipshutz et al. fabricated an environmentally benign surfactant(TPGS-750-M), a diester composed of racemic �-tocopherol, MPEG-750, and succinicacid (Figure 5.12).117 This surfactant was found to possess a high hydrophilic/lipophilicbalance (∼13), and formed micelles of optimal shape and size to facilitate Pd-catalyzedC C cross-couplings, which led the authors to suggest that micelles on the order of50+ nm best accommodate the components associated with Pd-catalyzed couplingsdescribed to date. Figure 5.12 shows images of PTS and TPGS-750-M polymers.117

High product yields and improved stereoretention in this medium were noted.In conclusion, while there are not as many examples of nanocatalyzed Negishi

reactions as there are for other C C coupling reactions, ongoing modifications of thisreaction protocol, such as carbonylative Negishi coupling (where CO is directly used asone of the reactants, to generate a carbonyl center in the coupled product), and zirconium-Negishi coupling, will likely, in all probability, be explored for heterogeneous andnanoparticulate catalysis in the near future.118 Furthermore, application of nanocatalystsmay also enable scientists to carry out these coupling reactions in or “on” water, whichnot only eliminates the need for environmentally damaging organic solvents but alsoreduces the overall cost of these reactions.

STILLE COUPLING

The use of organotin derivatives in cross-coupling reactions has been studied exten-sively as there are very few limitations as to which groups can be coupled via such a


OMe

(a) (b)

TPGS-750-M

enables reactions in water at room temperature

Heck, Suzuki–Miyaura, aminations,borylations, silylations, Negishi-like,

olefin metathesis reactions

n(n=∼16)

OO

O

O3

O

Figure 5.12. Novel surfactants for micelle-mediated Negishi coupling: (a) PTS and (b) TPGS-

750-M. Structure of TPGS-750-M is shown below. (Adapted with permission from Ref. 117,

Copyright 2010, American Chemical Society.) (See color insert.)

protocol, and thus the Stille reaction finds immense application in natural products andpharmaceutical synthesis, as well as in the manufacture of supramolecular structures,polymers, and inorganic target molecules.119–121 Scheme 5.5 shows a general mecha-nistic representation of Stille coupling. It should be noted that Pd(II) species can alsoundergo direct transmetalation reactions with organotin species to give homocouplingproducts upon reductive elimination. While the comparatively greener Suzuki couplinghas replaced Stille coupling as the synthetic reaction of choice in a number of applica-tions, it still remains a very useful cross-coupling protocol, and attempts to make it more

R-X

X

R

R-R′


Oxidative addition

R′ Sn(R″)3

R

R′X-Sn(R″)3

LnPd(II)

LnPd(II)

LnPd(0)

Transmetallation

Scheme 5.5. Mechanistic representation of Stille coupling reaction.

STILLE COUPLING 159

“eco-friendly” have produced some positive results. Of course, the most importantconcern about organotin compounds is their possible inherently high toxicity; adversebiological effects to marine life at a concentration of a few nanograms per liter havebeen recorded for triorganotins, while mono- and diorganotins have little or no biocidalactivities, and are therefore comparatively safer for laboratory and industrial appli-cations.122 Also, first-generation Stille couplings need to be carried out under inertatmospheres, using degassed and dehydrated solvents, to prevent catalyst decomposi-tion and/or homocoupling. Recent experiments, however, suggest that hydrophobic ILs,supercritical carbon dioxide, or highly polar sugar/urea/salt melts may also serve as goodreaction media for Stille coupling.123–125 While Pd with or without ligands has tradition-ally been used as a catalyst, contemporary literature is also rich in examples where CuI,ZnCl2, LiCl, MnBr2, and so on, have been used as catalysts and/or cocatalysts/additivesto enhance the yields and improve product selectivities.23 Other modifications includethe use of N,N-diisopropylethylamine, or Hunig’s base and silica-bound cysteine, thelatter a tin scavenger.23 Stille reactions have also been carried out with polymer-bound or ionic liquid-tagged organotin compounds and/or organic halides.23 Finally,a novel application of Stille coupling is related to the synthesis of 14C-labeled medicaltracers, which are used in positron emission tomography.126

Speculations on the role of Pd(0) clusters in Stille coupling began as early asthe 1990s. In a communication, Louie and Hartwig reported tri-o-tolylphosphanepalladacycle-catalyzed Stille coupling between 4-bromoacetophenone and Me3SnPh;a 31P NMR study indicated the presence of free as well as metal-bound P ligands,and it was assumed that unligated Pd(0) might play a definitive role in the mechanisticscenario.127 Synthesis of novel nanoparticle-protecting groups has also led to develop-ments in the field of Stille coupling. In 2006, Tatumi et al. designed and manufactureda new bisphosphine ligand with a long-chain alkyl “handle,” Me(CH2)7SCH2-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (C8-BINAP). This ligand was seen to stabilizehighly monodisperse 1.2 nm Pd-NPs.128 The resultant catalyst was isolated, seen to behighly efficient in promoting Suzuki as well as Stille couplings, and was unaffected bythe presence of thiols, which are known to passivate catalytic Pd surfaces. High yields(∼90%) were obtained even in subsequent catalytic cycles, leading to the conjecture thatthese BINAP-protected Pd-NPs are robust systems, capable of being used repeatedlywithout loss of activity.

Choudhary et al. used twonovel supports to immobilize catalytic Pd clusters: layereddouble hydroxides having a general formula Mg(1-x)Alx(OH)2Clx·zH2O, and Merrifieldresins.80 Both these supports were impregnated with PdCl42−, and its subsequent reduc-tion with hydrazine hydrate generated Pd-NPs. Deactivated chloroarenes were reactedwith organotin reagents using these catalysts to generate the coupled products in highyields. These catalysts were reused five times without significant changes in yield and/orselectivity. Quantitative recovery of the catalyst from the reactionmedium using a simplefiltration technique was also a remarkable achievement of this study. A similar study bythe same group evaluated Pt(0)-LDH (layered double hydroxides) as catalytic systemsfor Stille coupling, as shown in Figure 5.13. Here, too, the catalyst could be recoveredquantitatively without any diminution of catalytic activity. No evidence of leached Ptcould be found in the reaction medium.129


Ar

HydrazinePdCl4

2−Cl−

Mg Mg Al+

O O

OO

Mg Mg Al+

O O

OOO=OH

Cl

Mg1-xAlx(OH)2Cl·zH2O

Bu3Sn–Ar

Bu3SnH

PdPd

Pd PdPd Pd

PdPd

Figure 5.13. Stille coupling by Pd-NPs trapped in layerd double hydroxide (LDH) matrix.

(Adapted with permission from Ref. 80, Copyright 2002, American Chemical Society.)

PAMAM dendrimers, already known as efficient nanoparticle stabilizers, were usedby Garcia-Martinez et al. in 2005 to synthesize protected Pd-NPs via borohydride reduc-tion of PdCl42−.130 The resultant particles were highly monodisperse (∼40 Pd(II) ionswere bound by each dendrimer on average), and the resulting Pd-NPs had an averagediameter of 1.7 nm. This system served as a highly active catalyst for Stille couplingin water at room temperatures, using less toxic monoorganotin water-soluble precursorssuch as phenyltin trichloride (Figure 5.14). High yields andmoderate catalyst recyclabil-ity were observed, although at higher temperatures, there were evidences of dendrimerdecomposition and Pd black formation. Although a slight increase in Pd-NPs diameterswas observed after repeated use, probably owing to a certain degree of aggregation evenat room temperature, this did not affect the product yield significantly. Another interest-ing aspect of this study was the apparent indifference of this catalyst toward substratestructures: even large reactants threaded their way through the dendrimer shells, encoun-tered the catalyst, and reacted to produce the coupled molecule. Further investigationinto the mechanistic details of Pd dendrimer-catalyzed Stille coupling by Bernechea andcoworkers showed that for the initial catalytic cycle, Pd(OAc)2 performed better than thePd dendrimer system, but recyclability tests showed that Pd(OAc)2 became completelyinactive after the first cycle, while Pd dendrimer systems retained their activity for sev-eral catalytic cycles, although the yields decreased after each cycle.19 It is suggested thatPd leaching does occur in dendritic systems, but the leached Pd still remains bound byamide groups within the dendrimer. The presence of the dendrimer also seems to preventhomocoupling reactions in this system and thus enhances the selectivity of the reaction.

Figure 5.14. Stille coupling reaction catalyzed by dendrimer-encapsulated Pd-NPs.(Reprinted


STILLE COUPLING 161

+Im-CN

+Im-CN

+Im-CN

Im+-CN

Im+-CN

NC-Im+-CN

Im+

NC-Im+-CN

NC-Im+

Im+

Cl

CN

CN CN

CN

Substrate,

R-X

or

or or

PdR

R

X

Im+ CN Cl

ClCNPd

Carbene, e.g., 11,

weakly active precatalyst

Substrate

Active homogeneous

species

X

Dominant

active species

that enter

catalytic cycle

Cl

PdCl2

Pd

Pd

Figure 5.15. Nitrile-functionalized ILs as nanoparticle stabilizers in Stille coupling. (Adapted

with permission from Ref. 62, Copyright 2007, American Chemical Society.) (See color insert.)

ILs possess the wherewithal to serve as C C cross-coupling reaction media aswell as nanoparticle stabilizers.131 This concept was utilized by Dyson’s group, whodesigned a series of cyano-functionalized pyridinium ILs that could catalyze Stillecouplings in the presence of PdCl2 through the mediation of IL-stabilized Pd-NPs.132

FTIR showed anchoring of the –CN functionality onto the Pd-NPs. These systemsproved to be highly efficient catalysts for Stille C C coupling reactions, with highyields and extremely low Pd leaching (�5 ppm). Yields also remained unaffected afternine catalytic cycles.131 It was concluded by the investigators that the –CN moiety ofthe task-specific IL had an inherent capacity to latch onto the metal nanoparticle surfaceand inhibit agglomeration.133 The nature of the actual catalyst was examined by thesame group in 2007. They synthesized bis(nitrile)-functionalized ILs with nonhalideanions, and showed that PdCl2 reacted with these ILs to generate systems in which thePd center was coordinated to the –CN groups present in the cation of the IL.62 Thesewere found to be effective catalysts for a variety of C C coupling reactions, includingStille coupling. It was surmised that Pd-NPs served as reservoirs for mononuclear Pd(II)species, which might be the true active catalyst. The nitrile-functionalized ILs helpto stabilize such intermediates via transient coordination of the nitrile group, apartfrom forming a protecting mantle around the Pd-NPs, as shown in Figure 5.15. It wasconcluded that synergetic behavior led to the superior properties of the bis(nitrile)-functionalized ILs in Stille coupling.

Poly(vinylpyridine)s have often been used for Pd-NP stabilization. Pathak et al.synthesized high surface area poly(4- and poly(2-vinylpyridine) submicrometer beads


via emulsifier-free dispersion polymerization, and deposited prefabricated Pd-NPs ontotheir surfaces by centrifugation.134 The Pd–pyridine nitrogen interaction was invokedto explain uniform and irreversible deposition of Pd-NPs on the PVP beads. Thesewere seen to behave as model catalytic systems owing to their stability in air and inorganic solvents, their ease of separation, and their high catalytic activities. However, norecyclability studies were conducted to test if such Pd-coated PVP beads could be usedrepeatedly. Another polymeric matrix to entrap Pd-NPs was designed by Dell’Annaet al., who used copolymerized Pd(AAEMA)2 (AAEMA− is the deprotonated formof 2-(acetoacetoxy)ethyl methacrylate) with ethyl methacrylate and ethylene glycoldimethacrylate, and the palladated form of this polymer proved to be an efficient catalystfor Stille coupling.135 The recyclability of the catalytic species was satisfactory whentrimethyltin or tributylphenyltin was used with iodoarenes or activated bromoarenes;reactions of bromobenzenewith tributylphenyltin gave fair yields of the coupling productonly in the presence of additives such as TBABr or Ph4PCl, but the catalyst could notbe recycled. The reactions could be performed under air.

A heterogeneous catalytic system was fabricated by Kim et al., who mixedPd(PPh3)4, tetra(ethylene glycol), and Si(OMe)4 or Ti(OPri)4 in the ratio 1 : 10 : 170,and formed a gel-like precursor that upon drying gave a powdery material containingPd-NPs of less than 5 nm diameter.136 These systems were able to catalyze Stille cross-couplings of aryl halides with tributylvinyltin; moderate yields were noted, along withsome degree of recyclability, although this was more remarkable for the hydrogenationreactions that were carried out with the same catalysts.

Pd-NPs have also been anchored onto CNTs and carbon nanohorns via the autoregu-lated reduction of Pd(OAc)2 in the presence of SDS.137 The Pd-NP-MWCNT compositesthus formed were dispersible in polar solvents, and could catalyze Stille cross-couplings.TEM imaging showed 2–4 nm Pd-NPs attached to the surface of the MWCNTs. Ramanspectroscopy revealed that the formation of Pd-NPs onto the skeleton of CNTs wasachieved without disrupting the unique and novel�-electronic network of CNTs. Postre-action filtration through a poly(tetrafluoroethylene) (PTFE)membrane led to quantitativerecovery of these Pd-decorated CNTs, and catalytic efficiencies remained unaltered aftercatalyst isolation.

Pd-NPs supported on inorganic matrices have also been evaluated as potentialcatalysts for Stille C C coupling. Coelho et al. postulated that Pd/CaCO3 and Pd/BaSO4served as reservoirs for Pd(0) species, which were likely the actual catalysts for Stillecoupling.138,139 The catalytic system could be regenerated three timeswithout significantloss of activity; however, the reaction medium showed catalytic activity after removal ofthe catalyst and the product, thereby indicating that a molecular mechanism, rather thana nanocatalytic one, operates under the given circumstances. Conversely, catalysis byleached Pd species was not seen Kantam et al., who prepared a nanocrystalline MgO-stabilized Pd-NP system, which catalyzed Stille coupling of iodo- and bromoareneswith tributylphenyltin to produce unsymmetrical biaryls in good yields. The filtrate testshowed no catalytic activity, nor was leached Pd detected in the reactionmixture after theremoval of the catalyst.140 It was hypothesized that Pd bound to nanocrystalline MgOwas the only catalytic species. Excellent catalyst recyclability after five consecutivereactions seemed to corroborate this theory.

STILLE COUPLING 163

Zeolites have been traditionally used for immobilizing catalysts to improve theirstability and recyclability. In a study by Jana et al., mesoporous silica materials such asMCM-41 served as anchors to immobilize Pd-NPs.141 These catalysts showed notableactivity toward a wide variety of substrates with a high turnover frequency. TheRichardson–Jones solid-phase poisoning test, where 3-mercaptopropyl-functionalizedsilica is used to selectively poison soluble Pd species (poisoning due to overcoordina-tion of soluble monomeric or dimeric palladium, which rules out catalysis by Pd-NPsurfaces),142 suggested a true heterocatalytic process rather than catalysis by leachedPd; and the catalyst was fairly inexpensive and easily recycled. In a similar study, Zhaoet al. reported that Stille cross-coupling of a variety of organostannanes with aryl halideswas achieved in the presence of a catalytic amount of an MCM-41-supported mercaptoPd(0) complex in aqueous DMF (9 : 1) under aerobic conditions in good to high yields.This MCM-41-supported Pd catalyst was reused at least ten times without any decreasein activity, albeit with low TONs.143

Yang et al. noted that the preparation of Pd supported on inorganic materi-als could seldom be prepared by a green synthetic process, and hence suggested anovel IL–ionic polymer hybrid that could stabilize nanoparticles for years withoutdiminishing their catalytic activities.144 Poly(3-(4-vinylbenzyl)-1-methylimidazoliumbis(trifluoromethylsulfonyl)imide) coupled with cyano-functionalized imidazoliumbis(trifluoromethylsulfonyl)imide ILs served as efficient catalyst stabilizers in this study.This IL–ionic polymer-Pd-NP system was seen to be effective for Stille coupling of aryliodides and activated aryl bromide substrates. ICP-MS carried out on the organic frac-tions after catalysis revealed Pd concentrations of the order of 1 ppm. Notably, thesehybrid catalysts gave higher yields than the corresponding reaction using the pyridinium-based ILN-butyronitrile pyridinium bis(trifluoromethylsulfonyl)imide, bearing the samenitrile functionality with PdCl2 as catalyst precursors at 80 ◦C for 12 h. Recycling wasalso possible for Suzuki reactions, although a slight decrease in yield was observed aftereach cycle.

A multicore catalyst was synthesized by Jin and Lee, who used commercially avail-able Fe3O4 nanoparticles, with an average diameter of 20 nm, coated with a thin layer ofsilica using a sol–gel process to give silica-coated Fe3O4 (Figure 5.16). The silica shellpossessed residual hydroxyl groups for potential derivatization with different functionalgroups, and also protected the magnetite core from abrasion.145 A silylated Pd com-plex was then successfully immobilized on the surface of the SiO2/Fe3O4 beads. Thesecatalysts were able to promote Stille coupling of unactivated and sterically hindered sub-strates. A long catalyst lifetime and the ability to easily recycle the catalyst via magneticextraction, which is highly desirable for industrial applications, were observed for thesesystems. Less than 0.06% of the stating Pd catalyst was estimated to have leached outfrom the catalyst surface. Furthermore, the filtered solution did not exhibit any furtherreactivity. No obvious agglomeration of Pd(0) to form visible Pd black was observed onthe support surface even after the tenth catalytic cycle. The facile recycling of the cata-lyst in these coupling reactions was attributed to the high durability of the silica-coatedFe3O4 support. Silica gel-supported �-ketoiminatophosphane-Pd complexes (Pd/SiO2)were also seen to be powerful heterogeneous catalysts for diverse heteroaryl chloridecouplings.146


O O O

N O

N OO

OOEt

Si

Pd

Pd

Ph3P

Ph3P

CH3

CH3

(a)

(EtO)3Si

Fe3O4

SiO2 SiO2

Fe3O4 Fe3O4

(EtO)3Si

NH

1

3 4

2

(c)

(a) (b)

(d)

(b)

Figure 5.16. Pd anchored on SiO2/Fe3O4: synthesis, grafting, and magnetic separation after

ten catalytic cycles. (Adapted with permission from Ref. 145.)

Li et al. attempted to replace Pd with a cheaper alternative, copper(I) oxide nanopar-ticles. Their report, published in 2007, demonstrated that copper(I) oxide nanoparticles,alongwith P(o-tol)3 andTBAB, could catalyze the Stille coupling of different aryl halides(including aryl chlorides) with organotin reagents such as tri(butyl)phenylstannane andtri(butyl)vinylstannane. The yields were high, and the nature of substituents on the aro-matic ring did not affect the catalytic activities. The system could be recycled at leastthrice without noticeable drops in product yields.147

Wu et al. reduced Pd(acac)2 by molecular hydrogen in the presence of dendriticphosphine ligands that were supposed to serve three purposes: trap the Pd-NPs gen-erated, function as ligands, and facilitate catalyst recovery. 31P NMR and 31P magicangle spinning NMR results suggested that the phosphine ligands were oxidized togenerate phosphine oxide species, but this did not affect their nanoparticle-stabilizingproperties.148 This system could efficiently catalyze the Stille coupling reaction in aDMF/water medium, in the presence of cesium fluoride as an additive. Yields werehigh, and it was noted that these catalytic systems were much more efficient than thePd(PPh3)4 complexes commonly used in Stille couplings. The catalyst was found to berecyclable for nine runs in a Suzuki coupling experiment, although slight nanoparticlegrowth could be seen from the TEM images.

PEG-functionalized silica gel was the stabilizer of choice for Dutta and Sarkar, whoimpregnated the gel with palladate salts, and generated gel-tethered Pd-NPs by using a

STILLE COUPLING 165

Figure 5.17. Pdx-([PW11O39]7−)y nanoparticles for the Stille coupling reaction. (Reprinted


metal salt of a Fischer carbene complex as the reductant.86 Elemental analysis confirmedcomplete incorporation of the Pd in the gel matrix. TEM and AFM techniques wereapplied to study the dispersed nanoparticles. In AFM, employing the tip-deconvolutionmethod, the true diameter of each particle was determined to be 14.34 nm on average,close to the size obtained from the TEM image. Biaryls were obtained in good yieldfrom activated, neutral, and deactivated aryl bromides and phenyl tributyltin in DMFwith potassium carbonate as base. Catalyst recovery experiments showed retention ofhigh activities for about five runs, after which nanoparticle agglomeration and catalyticdeactivation set in. A hot-filtration test and a solid-phase poisoning test indicated thatthe catalyst was truly heterogeneous in nature.

Pd-substituted Keggin-type polyoxometalates (POMs) were used by Kogan et al.as Pd(0) precursors for C C coupling reactions (Figure 5.17). K5[PdPW11O39]·12H2Owas reduced by hydrogen under high pressure, and the blue-black solid thus generated


NaBH4

SnlCl3

SnCl3

HO O

OH

O

OH

OH

I

O

O


Transmetalation

Oxidativeaddition

Pd4 peptide

Pd0 Pd2+

Figure 5.18. Bioinspired Pd nanocatalysts for Stille coupling: mechanistic events. (Reprinted


was seen to turn orange-red upon aerial oxidation, indicating the formation ofPd-NPs stabilized by the highly charged POM (formulated as Pdx-([PW11O39]7−)y.Stille-type coupling reactions of both 4-bromotoluene and 1-chloro-4-nitrobenzenewith tetraphenyltin were catalyzed efficiently by this system, with products formed inalmost quantitative yields.149

Prechtl et al. reviewed C C cross-coupling reactions in ILs and commented onthe superiority of tetraalkylammonium salts as reaction media for Pd-NP-catalyzedprocesses.150 In a study by Calo et al., Pd(OAc)2 was dissolved in an excess of tetra-butylammonium acetate, and heated at 90 ◦C to form approximately 3.3 nm Pd-NPssuspended in the IL, and stabilized through an electrosteric mechanism. Using tetra-heptylammonium bromide as the solvent, the Stille coupling reaction between both arylbromides and chlorides with tributylphenyltin in the presence of the IL/Pd-NPs catalystproduced the desired coupled products in high yields.63 Recycling experiments showedvery little catalyst deactivation even after five cycles of use.

Finally, bioinspired routes for Pd-NP stabilization were studied extensivelyby Pacardo et al., who identified peptide sequences with special affinities for Pd(Figure 5.18). These peptides were used to generate 1.9 nm Pd-NPs that were capableof catalyzing Stille-type cross-couplings of aryl halides and PhSnCl3 in water underambient conditions.57

The peptide nanoparticle composites have a “kinked” structure owing to selectiveligation of residues on nanoparticle surfaces, which led to partial exposure of the metal

KUMADA–CORRIU COUPLING 167

active sites to the substrates.151 A simple borohydride reduction of K2PdCl4 in thepresence of the peptides generated the Pd-NPs. Subtle changes in the peptide sequenceby substitution of one amino acid residue by another influenced structure and reac-tivity of the Pd-NPs enormously. While these nanoparticles were active catalysts forStille couplings, the reaction most likely proceeded via a leached Pd route. This wasfurther investigated by the same group, and evidence was produced to support thisconclusion.152

KUMADA–CORRIU COUPLING

Ever since their discovery by Grignard, organomagnesium reagents have been consid-ered of paramount importance in the field of synthetic organic chemistry. Therefore,it is not surprising that the first documented example of catalytic C C cross-couplinginvolved these very reagents. The groups ofMakoto Kumada and Robert Corriu indepen-dently reported transition metal-catalyzed cross-coupling of an organic halide with anorganomagnesium reagent in 1972, and this reaction, along with its modifications, cameto be known as the Kumada–Corriu cross-coupling reaction.153,154 Usually, Ni or Pdcatalysts are used for this C C bond formation process. This elegant synthetic protocolcontinues to enjoy widespread application even to this day, including the industrial-scale productions of aliskiren (a hypertension medication),155 polythiophenes (used inorganic electronic devices),156 and styrene derivatives (Scheme 5.6). While the initialexamples used Ni for catalysis, the scope of the reaction was further broadened withthe introduction of Pd catalysts in 1975 by the Murahashi group.157 Other modificationsthat have been subsequently introduced to enhance the generality of the reaction includevariations where tosylates and triflates could be used in the place of organic halides,addition of 1,3-butadienes to facilitate Ni-catalyzed alkyl–alkyl couplings that wouldotherwise be unreactive, the use of functionalized organomagnesiums, and involvementof iron (Fe) as a catalytic species.158,159 The limitations of this synthesis are typicallyrelated to the sensitivity of the Grignard reagents toward proton sources (such as alcoholand water), the necessity for “nongreen” organic solvents (e.g., THF and ether), andthe need for an anaerobic atmosphere for the success of the reaction. The advantage ofthis reaction is the direct coupling of Grignard reagents, which avoids additional reac-tion steps such as the conversion of Grignard reagents to zinc compounds for Negishicoupling. Attempts to make this reaction more environmentally friendly via the use ofrecyclable catalysts and “green” solvents have been explored in the past decade, andsignificant achievements have been enumerated here. However, it must be noted thatthere are not a lot of examples of nanocatalyzed Kumada–Corriu coupling, possiblyowing to the air and moisture-sensitive nature of the organomagnesium reagents, whichautomatically enforces anaerobic reaction conditions. It is entirely possible, however,that some of the supported catalytic species actually serve as precursors for catalyticallyactive nanoparticles that remain trapped inside the supports.

There have been several accounts of Ni(II) complexes grafted on to heteroge-neous supports serving as catalysts for the Kumada–Corriu cross-coupling reaction.In 2001, Styring et al. designed an asymmetric salen-type Ni(II) catalyst grafted onto


R-X

X

R

R-R′


Oxidative addition

R′-MgX

R

R′

X-MgX

LnPd(II)

LnPd(II)

LnPd(0)

Transmetallation

Scheme 5.6. Mechanistic representation of Kumada–Corriu coupling.

a Merrifield resin, which functioned as an efficient catalyst for Kumada–Corriu cou-pling (Figure 5.19). Cross-coupled products were obtained in moderate yields by thismethod, but the catalyst itself was fully recyclable, with no evidence of Ni leaching evenafter multiple uses.160 An ICP-MS study revealed that the Ni was definitively retainedon the resin even after numerous reactions. The same group also published differentstudies for Kumada–Corriu reactions in minicontinuous flow and batch reactors, all of

New reactor

design

Solid phase

-assisted

catalysis

Me

MeO MeO

Me

Me

MeO O

O

M

N N13: M=Pd (Merrifield-type resin)

14: M=Ni (Merrifield-type resin)

15: M=Ni (SiO2)

tether= –(CH2)11OSi(CH3)2–O–

Br

MgBr

Conversion 65%

B(OH)2

B(OH)2

[PdEnCat] as a

stationary phase

in HPLC column

Bu4NOMe,

toluene/methanol

13, iPr2NEt, DMF/H2O,

flow rate 6μL min–1,

100 °C, 5 h

I+

+17

14, THF

16

18

+

Figure 5.19. Transition metal-catalyzed Suzuki–Miyaura and Kumada–Corriu cross-coupling

reactions under continuous flow conditions with possible involvement of metal nanoparticles.

(Reprinted with permission from Ref. 161, Copyright 2006.)

KUMADA–CORRIU COUPLING 169

them involving a salen-type Ni(II) complex immobilized on different supports (e.g.,polystyrene beads and functionalized silica), and presumably proceeding through thestabilization of Ni(0). Leaching of the metal into solution from the supported catalystproved almost negligible in most of the cases.161 However, the role of leached Ni wasstudied by Richardson and Jones, who concluded that it did play a role in the mechanis-tic scheme.162 Related salen-type Ni(II) complex immobilized on Merrifield resin wasused to perform, among other reactions, Kumada–Corriu coupling in continuous flowmode (Figure 5.19). A microreactor was constructed by placing a plug of catalysts intothe polypropylene tube, and standard high-performance liquid chromatography (HPLC)connectors and syringe pumps were used to drive a premixed solution of equivalentquantities of the aryl halide and Grignard reagent through the reactor. An enhanced rateof 4-methoxybiphenyl formation was observed in the microreactor compared with thebatch reaction.163 The Kumada–Corriu coupling reaction was also carried out at roomtemperature in a pressure-driven microflow reactor (length 25 mm and inner diameter3 mm) containing Ni(II) complex-functionalized silica (∼0.15 mmol Ni g−1 > silica gelloading) to yield the coupling product. There was negligible leaching of the metal intothe solution, and swelling issues prevalent in polymeric supports were largely absent.164

Lipshutz and coworkers extended their Ni/C work to Kumada–Corriu cou-pling.165,166 They were able to show that 5% Ni(II)/C precursors dispersed in THF in thepresence of 20 mol% Ph3P at room temperature formed the catalytically active Ni(0)/Cin situ in a few minutes upon the addition of the organomagnesium species. The reportincluded several examples of these Ni/C-catalyzed Kumada cross-couplings carriedout in refluxing THF. To establish that the heterogeneous nature of these reactions,elemental analysis of a filtered reaction mixture via ICP atomic emission spectra showedthat of the 5% Ni impregnated onto charcoal employed in these couplings, at most only2.68% (of the 5%, or a total of 0.001% Ni in solution) was found to be present. Priorcontrol experiments in THF with even greater quantities of preformed Ni(0) in solutiondemonstrate that couplings do not occur at such low Ni levels. Another class of supports,namely, mixed metal oxides, was explored by Kiss et al., who also tried combiningdifferent transition metals (such as Fe, Co, Ni, and Pd) with difference types of supports(such as hydrotalcite, mixed MgLaO, and 4 A molecular sieves) only to conclude thatthe Ni(II) precatalyst on MgLaO gave the best yields.82 The catalyst itself was not asimple “Ni-on-oxide” species; the Ni exchanged, probably with magnesium, and wasincorporated into the surface structure of the mixed oxide support. This is supportedby the ICP optical emission spectroscopy results, which showed a slight decrease in theMg : La ratio upon comparing the pure support and the catalyst. Additionally, the pres-ence of chlorine and magnesium was shown in the filtrate obtained during the workupin the preparation process of the catalyst. The hot-filtration test was applied to confirmthat leached Ni was not the actual catalytic species. X-ray fluorescence analysis of thefiltrate showed the presence of approximately 1–2 ppm Ni in the solution, which might,at best, suggest a capture-release mechanism. The X-ray fluorescence investigation ofthe isolated products showed the absence of Ni. The recyclability of the catalyst wasinvestigated, and about 16% difference in yields was noticed between two consecutiveruns. This big decrease in the yield was explained by hypothesizing precipitation ofmagnesium bromide onto the surface of the catalyst, which led to catalyst deactivation.


Figure 5.20. Pd precatalysts tethered to nanosized mesoporous silica structures. (Reprinted

with permission from Ref. 77, Copyright 2007, Elsevier.)

Its separation from the catalyst was difficult owing to its low solubility in organicsolvents.

A grafting approach was also adopted by Tsai et al., who tethered a Pd–bipyridylcomplex onto nanosized mesoporous silica (NS-MCM–41-Pd), and used it as a catalystfor Kumada–Corriu couplings.77 It was pointed out that the major advantage of this NS-MCM–41-Pd with interconnected channels was that the reactants, salts, and productscould be easily exchanged through the nanopores to avoid the saturation of activity(Figure 5.20). Various aryl halides were coupled with arylmagnesium bromides to yieldthe corresponding biaryls in good to high yields using this catalyst, and the catalyst wasrecovered and reused several times without loss of activity. Hot-filtration studies wereconducted to evaluate the role of Pd leaching, and the clear filtrate analyzed by atomicabsorption showed less than 3 ppm of Pd in the reaction media.

Microwave technology was used by Dankwardt in the Kumada–Corriu coupling ofaryl Grignard reagents with fluroarenes, and it was seen that under these conditions,the C–F bond was activated by phosphine-free Pd(dba)2.164 It was also determinedthat the presence of both Buchwald’s biarylphosphine ligand and imidazolium saltsshowed no improvement in the Pd-mediated C C bond forming reaction.167 WhilePd-NPs were not isolated, their active involvement in the catalytic cycle remained adistinct possibility, since “ligandless” Pd(OAc)2 was used as a precatalyst. The use ofhomeopathic Pd was not as successful for Kumada–Corriu coupling as it was for Negishiand Suzuki couplings.111 A ligandless, ambient temperature protocol for Pd-catalyzedKumada–Corriu coupling of unactivated alkenyl phosphates with ArMgX used PdCl2as a precatalyst, which formed Pd(0) upon reduction by the Grignard reagent.

Recently, Fe has also been used as a cheap alternative for Pd in Kumada–Corriucoupling.168 The mechanism of Fe-catalyzed C C cross-coupling is still under investi-gation, but it has been suggested that iron-catalyzed C C bond formations fall into morethan one distinct mechanistic category, with an “organoferrate regime” and “low-valent”redox chemistry being limiting cases.23 Some of these scenarios may involve catalysis

MECHANISMS 171

by Fe(0) clusters. It is to be expected that different transition metal nanoparticles willbe explored for a facile, environmentally friendly Kumada–Corriu coupling protocolin the immediate future. An investigation into nanoparticle–support interactions andmetal-leaching processes would also serve to improve the design of nanoparticulate andsupported catalysts, for both batch reactors and continuous flow reactors, for industrialpreparations as well as research purposes.

MECHANISMS

A comprehensive scheme showing the different metal species can be involved in thecatalytic reaction cycles of Hiyama, Kumada–Corriu, Stille, and Negishi couplings, andtheir interconversion is nearly impossible to depict. It is to be noted that based on presentstudies, it is very difficult to arbitrarily dismiss any Pd species (except possibly for bulkmetal) as entirely unrelated to the catalytic cycles. Pd colloids, for instance, have oftenbeen disregarded as active species; however, these can serve as a source for active Pdsubnanoclusters and/or leached Pd atoms.19 In the presence of efficient protecting agentssuch as dendrimers and peptides, even the leached Pdmay remain entrapped in thematrixduring the reaction, and may even be redeposited onto the “source” (a larger Pd particle,say a few tens of nanometers in dimension) after the completion of the catalytic cycle.152

Experiments indicate that the oxidative addition of organic halides or pseudohalides toa Pd atom on a nanoparticle surface may be the actual initiation step for C C couplingwith some organic precursors; on the other hand, presence of foreign molecules suchas surfactants may actually enhance leaching of Pd via the formation of salts such asPdBr4, and change the order of steps involved in the catalytic cycle.169

First of all, let us comment briefly on the classification of catalysts; traditionally, thishas been done on the basis of their mechanisms.While terms such as quasi-homogeneousand operationally heterogeneous have been used in the literature extensively, a moreconvenient system of catalyst classification has been introduced recently in severalreviews, where the nature of the active sites rather than the physical state of the catalyst isused as a basis for classification.18,45 Traditional homogeneous catalysts have active sitesthat are identical in nature; hence, they are monosite catalysts; heterogeneous catalystspresent a wide variety of catalytic-active sites, all different from one another. Hence,they are polysite catalysts.170 In between these two extremes lies the field of nanoparticlecatalysts. Monodisperse nanoparticles having a very narrow size distribution will haveonly a few types of active catalytic sites (say, some kinks, adatoms, faults, and so on), andthese catalyst site motifs will be replicated over and over again in several metal clustersof the same size.171 They are, thus, classified as “oligosite” (a few sites) catalysts.Another significant mechanistic aspect concerns the precursors that are used in theseC C coupling reactions. It is well-known that aryl iodides can be easily activated evenby trace amounts of Pd, and aryl bromides with electron-withdrawing substituents inthe para position react smoothly too. The challenging aspect of these reactions is to startwith aryl chlorides, which can be notoriously unreactive owing to the partial doublecharacter of the C Cl bond, or “unactivated” aryl bromides, which react slowly andtentatively with most catalysts.23 Some of the studies mentioned here have developed


catalysts that can solve this issue, possibly owing to the unique catalytic properties ofnanomaterials that are not present in conventional monosite catalysts; others have usedpseudohalides as starting materials. It must be noted that from a commercial point ofview, using chlorides as a substrate is the most realistic option, so emphasis must be puton research that focuses on C C couplings of organic chlorides using catalysts capableof fragmenting the C Cl bond. Nanocatalysts can be of immense help in this regardowing to their novel reactivity patterns. Also, the fact that these nanocatalysts do notneed exotic ligands, can be used at high temperatures, under aerobic conditions, andin solvents that are either cheaply available (like water) or recyclable (like ILs) are allpoints that favor their commercial application in the synthesis of organic molecules.

Let us now briefly examine the various tests that have been applied in some of thestudies mentioned throughout this chapter to examine the true nature of the catalyticspecies involved in the relevant coupling reaction. Although the reviewmentioned beforediscusses these tests in great detail, it is still useful to reevaluate the applicability of thesetests in determining the true nature of the catalytic species in Negishi, Stille, and Hiyamacouplings that are classified as being nanocatalytic. The easiest of these tests is a kineticstudy of the progress of the reaction. It has been noted that an “induction period” (i.e., alength of time necessary to activate the catalyst before the reaction begins) is an indica-tion of nanocatalysis: the nanoparticles are formed in that time period.172 A sigmoidalkinetic curve is also a strong indication that nanoparticle catalysts are being formed inthe reactionmedium. Kinetic reproducibility, often hailed as a sure-fire proof of homoge-neous/monosite catalysis, is no longer prima facie evidence for a molecular mechanism,since nanocluster/oligosite catalysis with approximately 15% kinetic reproducibility isnow known.173 TEM imaging of nanoparticles is another powerful weapon, and has beenused in almost all these reactions for catalytic classification, but as a test it is less useful.Mere formation of nanoparticles does not guarantee their involvement in the catalyticcycle, and the TEM electron beammay reduce metal complexes and generate nanoparti-cles in situ.174, 175 In addition, nanoclusters below 1 nm in size are very difficult to detectusing TEM, unless very sophisticated methods such as Z-contrast microscopy are used.X-ray techniques, such as small angle x-ray scattering (SAXS), EXAFS, and single-crystal X-ray studies, may also provide information about the catalyst.176 In operandomethods are currently being investigated for the study of nanoparticle-mediated redoxreactions; these may subsequently be extended to C C cross-couplings as well.177 Thenaked eye can sometimes be a better detector than sophisticated electron microscopes:appearance of an unusual coloration (due to the surface plasmon band of nanoparti-cles) and/or darkening of the reaction mixture often indicate nanoparticle formation.178

Needless to say, this is an indication as opposed to a confirmatory test for nanocatalysis.Similarly, the appearance of a metal deposit or a precipitate also hints that nanoparticleintermediates may be formed during the course of the reaction; however, the catalyticactivity of such intermediates still remains suspect unless confirmed by other tests. Sincemonosite catalysis is strongly dependent on ligands, identical reaction parameters in thepresence of different ligands and/or unchanged reactivity patterns under harsh condi-tions that can presumably lead to ligand dissociation (e.g., high reaction temperatures,presence of strong acids, and bases) usually indicate nanoparticle catalysis.179 Similarly,since nanoparticles need a stabilizer for protection against agglomeration, unaffected

MECHANISMS 173

reaction rates in ultrapure (no stabilizer) media would indicate a monosite mechanism;however, this is not conclusive evidence, since extremely small amounts of potentialstabilizers can work to protect nanoparticles against agglomeration; and even agglom-erated nanoparticles can sometimes show catalytic activity.180 The “hot-filtration” testis less reliable than it is given credit for; nanoparticles may form even after filtration orremain in the filtrate, leading to residual activity in the filtrate, and filtration often leadsto the decomposition of a monosite catalyst, generating nanoparticles and a catalyticallyinactive filtrate.181 Separation by centrifugation suffers from similar issues, along withthe fact that some very small nanoclusters will not form sediments easily. Similarly,light-scattering experiments are notorious for providing “false-positive” results due tothe presence of dust or other catalytically inactive contaminants in the sample beingmea-sured.Most of the studies discussed here use TEM to detect the presence of nanoparticlesin their reaction media, although this by itself does not ensure nanocatalysis. Richardsonand Jones, for example, used an anchored 3-iodopropyl groups for “three-phase test-ing” of heterogeneity in Kumada–Corriu reactions, along with polymer-bound triphenylphosphines for selective poisoning of soluble nickel in Kumada–Corriu coupling, prov-ing that leached Ni played a definite role in the mechanistic scenario.162 In the studyby Ranu and coworkers, TEM and EDS (EDX spectroscopy) confirmed the presenceof Pd-NPs (3–6 nm).103 While testing their Stille-active Pd/MgO catalyst, Choudharyand coworkers failed to detect any Pd via ICP-AES in the filtrate obtained after 55%and 82% completion of the coupling reaction; nor was the yield affected by repeatedcatalytic cycles, thus proving that Pd bound to nanocrystalline MgO was possibly theactive catalytic species.140

Perhaps some of the most accurate tests that can be performed to detect the pres-ence of catalytically active nanoparticles are poisoning tests, such as that where Hg(0)is introduced into the reaction system in huge excess along with vigorous stirring, sothat nanoparticle surfaces get inactivated owing to amalgam formation. Although somemetals are less susceptible to Hg poisoning than others, and Hg(0) can sometimes alterthe catalytic pathway altogether, a successful suppression of a catalytic reaction by theintroduction of Hg(0) is generally accepted as evidence for an oligosite or a polysite cat-alytic process.182 Of course, control experiments are necessary to study the interactionof the precatalyst with Hg(0). Complementary to this test is the “Crabtree toxin test,”where dibenzo[a,e]cyclooctatetraene (DCT) is introduced into the reaction medium.This is capable of poisoning metal complex monosite catalysts when present in equal toor more than 1 equivalent per metal center, but has no effect on nanoparticle catalyticactivity.183 However, DCT is difficult to synthesize and its poisoning abilities are notuniversal. Silica-bound thiols have also been used for the removal of soluble Pd fromreaction mixtures, but are seen to be benign toward Pd clusters as small as 1 nm.184 Theso-called fractional poisoning experiments, where the number of equivalents of a strong“toxic” ligand (such as CS2 and thiophene) per metal centre necessary for completeshutdown of the reaction is determined, is another poisoning test used for identificationof a catalytic mechanism; for nanoparticle catalysts, where only a fraction of the metalatoms (the “surface-active sites”) contribute to the actual catalysis, this number is muchless than 1, while for monosite catalysts that operate via a molecular mechanism need1 or more equivalent of the “toxic ligand” per metal site for deactivation. This test must,


however, be carried out under conditions where the toxic ligand does not decompose.185

It must be noted that just one positive result using one of these tests is not sufficient indi-cation for nanoparticle catalysis—several of these must be applied in conjugation (thepresence of a sigmoidal kinetic profile, nanoparticles detected visually or via TEM, poi-soning by Hg(0), ligand independence, and so on) before we can conclude that a polysiteor an oligosite catalytic process indeed operates in the C C cross-coupling reactionunder investigation. Jana et al., for instance, performed solid-phase poisoning tests ontheir MCM–Pd catalyst using commercially available 3-mercaptopropyl-functionalizedsilica (SH-SiO2), an effective palladium scavenger, which selectively coordinates anddeactivates the leached out palladium with no diminution of catalytic activity, therebyindicating that they had manufactured a true “polysite” catalyst.141 On the other hand,when Lipshutz et al. added polymer-bound PPh3 (selective inhibitors for molecular cat-alysts) to a Kumada coupling with a Ni/C catalyst, the conversion went down to 42%as compared to 100% without polymer-bound PPh3. In combination with results fromother tests, they concluded that “monosite” catalysis by dissolved Ni was operating inthe reaction medium.181

Finally, another important aspect of nanocatalyzed C C cross-couplings is the“homeopathic effect,” where extremely low metal loadings have been seen to catalyzethese reactions efficiently and generate products with high TONs.186,187 However, impu-rity artifacts are very important in such “homeopathic” catalytic reactions; even traceamounts of a catalytically active impurity in the reaction medium (including substrate,glassware, and so on) can lead to misassignment of the actual catalytic species.188,189

Often, ppb quantities of Pd present in a base metal such as Fe or Ni can serve as theactual catalytic species; hence, it is essential to identify the actual catalyst before kineticstudies, rate determination, and mechanism assignment are performed.190,191

OUTLOOK

Much progress has been made toward the use of nanocatalysts for a wide variety ofcoupling reactions, including the Hiyama, Stille, Negishi, and Kumada–Corriu C Ccoupling reactions. At this point in time, a large amount of research has been devotedto nanocatalysts for organoboron (Suzuki), organosilicon (Hiyama), and organotin cou-pling (Stille) to aryl and allyl halides, likely due to the stability of these precursorsto air and water.23 Nevertheless, there remain tremendous opportunities to explore theanalogous chemistry of organozinc and organomagnesium species in the presence ofnanoparticle catalysts. In many cases, such nanocatalysts offer the ability to dramat-ically lower the temperatures needed for coupling reactions, as there is no need forprecatalyst decomposition/activation at high temperatures. There is still contradictoryinformation on many reactions whether nanocatalytic systems are simply sources ofcatalytic species (via leaching of homogeneous species) or the initial reactions takeplace on the nanoparticle surface itself, and the leaching is an aftereffect of oxidativeadditions of aryl halides and similar species to the nanoparticle surface.19,152 Thus, thereis still much work to be done in determining the exact mechanisms of many of thesecoupling reactions, as many are by nature ex situ characterization methods and may not

REFERENCES 175

see active catalytic species, which only form under actual catalytic conditions. In thissense, in operando or in situ catalysis characterization for many coupling systems underthe exact catalytic conditions is desperately needed.192 While we have documented qual-itative poisoning and filtration/centrifugation studies that may give insight into actualcatalyst species, it again needs to be pointed out that there are always exceptions tosuch poisoning schemes, and it is extremely difficult to absolutely separate nanocatalystmaterials from the reaction mixture in many cases. Such studies will open up furtherimprovements in the use of nanoparticle catalysts; if it is determined that the activecatalyst is leached species from the nanoparticle, then improvement of the nanoparticleoxidation/leaching rate by adding oxidative promoters such as halides and other speciesmay be beneficial.

Long-term recycling of C C coupling catalysts is another direction that needsmore active exploration; many studies document recyclability up to five or ten cycles,but few if any document long-term stability and activity of catalysts.145 This is especiallyimportant given the need to development of industrial processes involving such catalysts.In this sense, many nanoparticle systems may be desirable over homogeneous catalystsystems in which it is known that the initial metal catalyst is actually a precatalyst forthe reaction. Development of materials that actually consist of the active catalysts fora given reaction should yield systems that are amenable to many catalytic turnoversand recyclability. Another common problem for coupling reactions is the use of Pd andother transition metal catalysts and impurities in the final product mixture, which resultfrom these metals; particularly in the pharmaceutical industry, purification of productsis an important consideration. Catalytic systems, which can limit metal contaminationproblems, for example, IL solvent systems inwhich the products are removed by vacuum,are particularly attractive.

CONCLUSIONS

This chapter reviewed the use of nanocatalysts for a variety of C C coupling reactionsusing organosilicon (Hiyama), organozinc (Negishi), organotin (Stille), and organo-magnesium (Kumada–Corriu) precursors. Nanocatalyzed coupling reactions represent arapidly growing field, particularly for the use of air and water-stable precursors, but thereis still much to be done in order to understand the actual mechanisms in play for eachreaction. In addition, much work has to be done to generate industrially viable catalystsfor many reactions that can operate under hundreds if not thousands of catalytic cycles.

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