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Nanocluster catalysed C-C coupling reactions

Thathagar, M.B.

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Citation for published version (APA):Thathagar, M. B. (2006). Nanocluster catalysed C-C coupling reactions.

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Download date: 25 Apr 2020

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NANOCLUSTER CATALYSED C CCOUPLING REACTIONS

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus

prof. mr. P. F. Van der Heijden ten overstaan van een door het college voor promoties ingestelde

commissie, in het openbaar te verdedigen in de Aula der Universiteit op dinsdag 21 Februari 2006, te 12.00 uur

door

Mehul Bhupendra Thathagar

geboren te Bhavnagar, India

Promotiecommisie:

Promotor: prof. dr. C. J. Elsevier

Copromotor: dr. G. Rothenberg

Overige leden: prof. dr. H. Bönnemann

prof. dr. J. G. de Vries

prof. dr. P. C. J. Kamer

prof. dr. P. J. Schoenmakers

dr. E. Eiser

Faculteit der Natuurwetenschappen, Wiskunde en Informatica

ISBN number: 90-9020275-7

© 2006, Mehul B. Thathagar

All Rights Reserved

The research reported in this thesis was carried out at the van 't Hoff Institute for

Molecular Sciences, University of Amsterdam (Nieuwe Achtergracht 166, 1018 WV

Amsterdam, The Netherlands).

Dedicated to

my brother, Niraj Thathagar,

who would have been pleased and proud

to see the results of this undertaking

&

my family

Contents

Chapter 1 Introduction 1

Chapter 2 Copper-based mixed nanoclusters: New catalysts 37

for Suzuki cross-coupling

Chapter 3 Palladium-free and ligand-free Sonogashira 57

Cross-coupling

Chapter 4 Nanocluster-based cross-coupling catalysts: A 69

high-throughput approach

Chapter 5 Pd clusters in C C coupling reactions: A 79

true catalytic species?

Chapter 6 One pot Pd/C catalyzed consecutive HALEX 105

Sonogashira reactions: A Ligand-free and Cu-free

alternative

Chapter 7 Trapping metal nanoclusters in ‘soap and water’ 121

soft crystals

Summary 143

Samenvatting (Summary in Dutch) 147

Acknowledgement 151

CV 155

List of publications 157

‘Nano mania’ started sweeping through essentially all fields of science and

engineering, when back in December 1959, future Nobel laureate Richard

Feynman gave a visionary and now often quoted talk entitled “There’s Plenty

of Room at the Bottom.” The occasion was an American Physical Society

meeting at the California Institute of Technology, Feynman’s intellectual

home. Although he didn’t intend it, Feynman’s 7,000 words were a defining

moment in nanotechnology, long before anything “nano” appeared on the

horizon.

“What I want to talk about,” he said, “is the problem of manipulating and

controlling things on a small scale. . . . What I have demonstrated is that there

is room—that you can decrease the size of things in a practical way. I now want

to show that there is plenty of room. I will not now discuss how we are going to

do it, but only what is possible in principle....We are not doing it simply

because we haven’t yet gotten around to it.”

-Richard P. Feynman, (1959)

Chapter 1 General Introduction

1

CCChhhaaapppttteeerrr 111

General Introduction

This chapter provides the motivation and objective for the research presented in this

thesis. Also, general aspects and recent advances in cross-coupling chemistry,

nanoclusters and its synthetic methods and application of these clusters in catalysis

are discussed. The interest in very small particles, or nanoclusters, originates from

their physical properties, which can be vastly different from those of bulk and

molecular counterparts. They are not only of fundamental importance, but also of

interest for many potential applications such as catalysis. I hope that for people

stepping in the nano-field, especially new PhD and Masters Students, this

introduction will be helpful.


2

1.1 Catalysis

Although nowadays we know that catalytic processes have already been

applied for a long period of time, it was not until 1836 that Berzelius

introduced the term ‘catalysis’. He derived it from the Greek words kata,

which stands for down, and loosen, which means to split or break. Later, in

1895, William Ostwald was the first to write down a definition of a catalyst: ‘A

catalyst is a substance that changes the rate of a chemical reaction without

itself appearing in the products’. It is important to note that a catalyst does

not influence the thermodynamic equilibrium of the reactants and products.

Therefore, the current definition is slightly better, though close to Ostwald’s

description: ‘A catalyst is a substance that increases the rate of approach to

thermodynamic equilibrium of a chemical reaction without being substantially

consumed’. Today, the growing environmental concern due to the increase in

chemical products demand necessitates the development of the ‘green’

production methods. In this context, ‘green’ processes can be described as

chemical conversions that consume a minimal amount of energy and

resources, and produce the least waste. Catalysis is a key solution to this

problem. Therefore, nowadays, almost 70% of all chemicals that are produced

have been in contact with a catalyst somewhere in their synthesis process.1

This number stresses the importance of the role of catalysis in the chemical

industry. Without a catalyst, processes are less selective, and sometimes

impossible to perform.

1.2 Carbon–Carbon bond formation reactions

Ever since the first laboratory construction of a carbon–carbon bond by Kolbe

in his historic synthesis of acetic acid in 1845,2 carbon–carbon bond-forming

reactions have played an enormously decisive and important role in shaping

chemical synthesis. Aldol- and Grignard-type reactions, the Diels–Alder and

related pericyclic processes, and the Wittig and related reactions are processes

that have advanced our ability to construct increasingly complex carbon


3

frameworks and, thus, enabled the syntheses of a multitude of organic

compounds.3 In the last quarter of the 20th century, a new paradigm for

carbon–carbon bond formation has emerged that has considerably enhanced

the prowess of synthetic organic chemists to assemble complex molecular

frameworks and has changed the way we think about synthesis. Based on

transition-metal catalysis, this newly acquired ability to forge carbon–carbon

bonds between or within functionalized and sensitive substrates provided new

opportunities, particularly in total synthesis but also in medicinal and process

chemistry as well as in chemical biology and nanotechnology. Few examples of

the reactions that are transition metal-catalysed include the carbonylation of

alkenes, the allylic alkylation, the co-polymerisation of alkenes and CO, the

hydroarylation, cross-coupling reactions, the Heck reaction, Sonogashira

reaction, the 1,4-addition to dienes, etc. The work described in this thesis will

mainly focus on metal-catalysed coupling reactions of aryl halides with

various nucleophiles that are highly effective and practical methods for the

formation of C–C bonds. Since excellent reviews4-7 and books8 exist on these

topics, this introduction will cover the main aspects and recent advances of the

reactions of interest, together with several important highlights.

1.2.1 Cross-coupling reactions

Cross-coupling reactions have been developed as a versatile tool for the

formation of carbon–carbon bonds.9 The importance of these reactions is

steadily growing due to their mild reaction conditions, making them

compatible with a wide variety of functional groups.8 Thus, these coupling

reactions are used at an advanced stage in a total synthesis of complex

chemicals such as drugs, vitamins, flavours and fragrances, agro-chemicals

and performance materials.10 Cross-coupling reactions are usually classified

according to the nature of the organometallic substrate applied and often

named after their discoverers (scheme 1). The most important examples

include the Grignard cross-coupling (or Kumada coupling, M = Mg),11 the


4

Suzuki-(M = B),4,7 Stille-(M = Sn),6 and the Negishi reaction (M = Zn).5 The

Heck reaction,12 which does not involve organometals as substrates, may not

be considered as a cross-coupling reaction, but its alkyne version, especially

the Sonogashira reaction13 which involves the use of catalytic amounts of CuI

salts is usually deemed as cross-coupling reaction. In most cases, the various

cross-coupling reactions are catalysed by Ni(0) and Pd(0) complexes and

proceed through a similar general mechanistic pathway (scheme 2).

R-X + R'-M R-R' + M-X

R, R ' = Aryl, vinyl, benzyl, allyl, alkyl

M = B, Mg, Zn, Sn, etc.

X = Cl, Br, I, sulfonate

Pd catalyst

Scheme 1. Definition of cross-coupling reactions.

Pdo R X

PdR

X

R' MXM

PdR

R'

R R'

Scheme 2. The generally accepted catalytic cycle of cross-coupling reactions.

The catalytic cycle involves three main elementary processes,8 which are:


5

1) Oxidative addition of an electrophile, typically an organic halide (mostly

iodides and bromides, rarely chlorides) or triflate to a Pd(0) species to

form the corresponding Pd(II)(organyl) complex.

2) Transmetallation of an (organometallic) nucleophilic coupling partner

to this complex.

3) Reductive elimination to yield the cross-coupling product together with

the starting Pd(0) complex that can re-enter the catalytic cycle.

The work described in this thesis is mainly focussed on developing new

catalysts or methods for the Suzuki, Heck and Sonogashira coupling reactions.

Electrophiles in Cross-coupling reactions

A wide range of organic electrophiles can be applied in these reactions.

Usually, aryl and vinyl iodides and bromides are employed,8 but other leaving

groups, e.g. triflates, can also be used. Often, the order of reactivity found for

aryl substrates PhX is I > OTf > Br > Cl, which roughly reflects the ease of

cleavage of the C-X bond. Unfortunately, the more reactive aryl iodides and

triflates are less widely available and more expensive than the corresponding

bromides and especially chlorides. Moreover, on a weight basis, chlorides are

most attractive in the perspective of ‘green’ industrial chemistry. Therefore,

much effort has been devoted to the development of the catalysts that enable

the conversion of chloride substrates under mild conditions (vide infra).14

1.2.1.1 Suzuki cross-coupling

The coupling of aryl halides with arylboronic acids (scheme 3), the Suzuki

reaction,15 has become increasingly popular because 1) it is compatible with

the presence of electrophilic functional groups, 2) many boron compounds are

stable and have lower toxicity compared to other organometallic reagents, 3)

many arylboronic acids are commercially available, 4) the inorganic product of

the reaction can be easily eliminated in water, and 5) the reaction conditions


6

tolerate aqueous media, which renders elimination of the boron containing

reaction products easier. In 1981, Suzuki and co-workers reported the first

[Pd(PPh3)4]-catalysed cross-coupling of aryl halides with aryl boranes and

thereby paved the way for the development of this general method.16 Advances

have been made in the way of reaction scope, including the use of aryl

chlorides17 as substrates and the ability to conduct couplings at very low

catalyst loadings18 and at room temperature.19 Moreover, it is now possible to

couple hindered substrates,20 and even asymmetric variations have been

reported.21

B(OH)2 X

RR

+

X = Cl, Br, IR = H, perfluoro, Me, NO 2, I, CF3, OMe, CN, etc.

Pd catalyst

Scheme 3. Suzuki cross-coupling reaction.

Nevertheless, improvements in Suzuki-Miyaura coupling reactions have relied

a great deal on the increased reactivity and stability of the Pd catalysts by use

of increasing efficacious supporting ligands. The most common ligands used

today are phosphine-based, although a variety of others, including N-

heterocyclic carbenes (NHC), have been employed.22 During past few years the

research attention have shifted more towards the procedures that utilize so-

called “ligand-free” conditions.23,24 The ability of other metals or combination

of Pd with other metals to catalyse this reaction, however, remains elusive.

1.2.1.2 Heck coupling

The Heck reaction can be broadly defined as the palladium-catalysed coupling

of alkenyl or aryl (sp2) halides or triflates with alkenes (Scheme 4) to yield

products which formally result from the substitution of a hydrogen atom in


7

the alkene coupling partner. Unlike other C C coupling reactions that involve

a polar addition, the Heck reaction tolerates almost any sensitive functionality

such as unprotected amino, hydroxyl, aldehyde, ketone, carboxy, ester, cyano,

and nitro groups. The first examples of this reaction were reported

independently by Mizoroki25 in 1971 and, in an improved form, by Heck12 in

1972. Since then, a number of approaches have been introduced, permitting a

great extension of the synthetic applicability of this reaction.

R

X

R

Pd catalyst+

RR


Scheme 4. Heck coupling reaction.

The Heck reaction is typically performed with 1-5 mol% of a palladium

catalyst along with a phosphine ligand in the presence of a suitable base.26

Under these conditions, both the phosphines and their palladium complexes

are prone to decomposition and an excess of phosphine is required. This

reduces reaction rate, requires higher Pd loading and increases the cost of

large-scale processes. A new generation of catalysts such as palladacycles27

and Pd-carbene complexes28 have proved highly efficient in Heck reactions.

However, all of these catalyst systems suffer from drawbacks of one kind or

another, such as the high ligand sensitivity toward air and moisture, the

tedious multistep synthesis, hence the high cost of the ligands, and the use of

various additives. Therefore, recently there has been increasing interest in the

use of “ligand-free” palladium catalysis of the Heck reaction, either using

simple palladium salts, metallic palladium, or palladium nanoclusters

immobilized on inorganic supports. The work of Jeffery29 on use of Pd(OAc)2

along with tetraalkylammonium salts in Heck reaction shifted the focus on

developing the ligand-free Pd catalysts. Reetz et al. and also De Vries and co-


8

workers have shown that the reaction between aryl iodides or bromides and

alkenes can be run with the addition of what they term “homeopathic”

quantities of Pd(OAc)2.24,30-32

Several other developments on the Heck reaction include reactions in

alternative media such as supercritical solvents,33 ionic liquids,34 water35 and

biphasic reaction systems.36 Being energy efficient, microwave heating have

been used to enhance the rate of reactions and in many cases improve product

yields in Heck reaction.37 To overcome the catalysts separation problem,

polymer-supported Pd complexes38 and Pd on various supports39 were also

used as catalysts for this reaction. However, in most cases the catalysis occurs

through the leached Pd species and thus that the catalysis is in effect

homogeneous with palladium dissolution.40 This will be discussed in more

detail later in this chapter. Finally, papers have appeared recently in which

ruthenium41,42 and rhodium43 catalysts have also been applied in the Heck

type coupling reactions.

1.2.1.3 Sonogashira coupling

The palladium-catalysed coupling of terminal alkynes with vinyl or aryl

halides (Scheme 5) was first reported independently and simultaneously by

the groups of Cassar44 and Heck45 in 1975. A few months later, Sonogashira

and co-workers13 demonstrated that, in many cases, this cross-coupling

reaction could be accelerated by the addition of co-catalytic CuI salts to the

reaction mixture. Today the Sonogashira reaction is most straightforward and

widely applied methods to synthesize arylalkynes and conjugated enynes.

Generally, the Sonogashira coupling is carried out in the presence of a

catalytic amount of a palladium complex as well as copper iodide in an amine

based solvent to obtain a good yield.46,47 This protocol suffers from the fact

that CuI co-catalyst can result in the formation of some Cu(I) acetylides in situ

that can readily undergo oxidative homocoupling reaction of alkynes (Hay


9

coupling or Glaser coupling).48 To overcome these drawbacks, many ligand-

free and copper-free palladium catalysed Sonogashira cross-coupling protocols

have been developed.49,50 An impressive variety of modifications have so far

been developed for this reaction including the phase transfer,51 aqueous,52

solventless methods,53 the use of a variety of promoters54 and ionic liquids.55

X

R

+Pd catalyst

RCuI


Scheme 5. Sonogashira cross-coupling reaction.

Whereas the above systems contributed to the improvement of the

Sonogashira reaction, they remained based on homogeneous Pd complexes.

Recently, there has been significant interest in Pd-free systems or supported

Pd catalysts to avoid the unacceptable contamination of the products by

palladium. Nickel-catalysed Sonogashira reactions have been described by

Beletskaya et al. using homogeneous Ni(II) species56 and by Wang et al. using

Ni(0) particles.57 However, these catalysts require the use of CuI co-catalyst

and PPh3 in order to achieve high activities. Only few reports describe the

Sonogashira reaction heterogeneously catalysed by supported palladium

catalysts, but the presence of a co-catalyst was important to obtain good

yields.58 There is only one report of a transition-metal free Sonogashira

coupling, developed by Leadbeater et al., using PEG–NaOH (aqueous) under

microwave irradiation conditions,59 but this approach was limited by the

narrow choice of the reactants (only to aryl iodides and aromatic terminal

alkynes). Therefore there is still room for improvement in the Sonogashira

protocol. A particularly interesting system would be one that is Pd-free,

ligand-free and co-catalysts-free.


10

Future developments will most likely involve further improvements on some

of the themes mentioned briefly here together with many others. For example,

development of new methods or ligand-free catalysts is aimed at activating

unreactive aryl chlorides, which are cheaper and widely available starting

materials for the cross-coupling reactions. The design of new, active, stable

and selective catalysts will lead to efficient catalysis that is generally

applicable and eventually to more processes that are economically and

ecologically feasible.

1.3 Introduction to the Nanoworld

"Nano-," once a seldom-used prefix found in the back of scientific textbooks,

has moved into the industrial mainstream. Within the past two decades, a

variety of terms sharing the prefix "nano-," such as nanoparticle,

nanomaterial, nanophase and nanostructure have emerged to describe certain

materials, technologies, and even businesses. They are defined as materials or

particles having at least one dimension between 1 to 100 nm. A nanometer is

one billionth of a meter. For perspective, a row of 10 hydrogen atoms would

span about 1 nanometer, a bacterial cell measures a few hundred nanometers

across, and the width of a human hair is about 50,000 to 150,000 nanometers.

It is not clear when humans first began to take advantage of nanosized

materials. It is known that in fourth-century A.D. Roman glassmakers were

fabricating glasses containing nanosized metals. An artifact from this period

called the Lycurgus cup resides in the British museum in London (figure 1).

The cup, which depicts the death of King Lycurgus, is made from soda lime

glass containing silver and gold nanoparticles. The colour of the cup changes

from green to a deep red when a light source is placed inside it. The great

varieties of beautiful colours of the windows of medieval cathedrals are due to

the presence of metal nanoparticles in the glass.


11

Figure 1. Lycurgus cup, 4th century AD (now at the British Museum,

London). The colors originate from metal nanoparticles embedded in the glass.

The foundation of modern colloid science was laid by Michael Faraday as early

as 1857.60 He established that several dyes were indeed made of metal

particles. After a thorough study of gold sols, Faraday concluded “. . . the gold

is reduced in exceedingly fine particles which becoming diffuse, produce a

beautiful fluid. . . the various preparations of gold, whether ruby, green, violet

or blue. . . consist of that substance in a metallic divided state”. Thus, colloidal

metal particles in sols came to be known as divided metals. At its inception,

the science of colloids did not quite catch popular fancy. It remained the

domain of a few individuals. For example, Ostwald’s 1915 book on colloids is

titled “The world of neglected dimensions”.61 Thus, the theoretical works of

Mie,62 Gans,63 and Kubo64 which were successful in predicting the optical

properties and electronic structure of metal particles and Einstien’s success in

relating Brownian motion to diffusion coefficient65 were largely ignored.

Heralded by the visionaries such as Feynman,66,67 the science of colloids

staged a gradual revival in the 1980s. Since then, significant advances in both

experimental and theoretical aspects have led to an explosion of interest in the

areas of nanoscience and nanotechnology and are attracting rapidly increasing

investments from governments and from businesses in many parts of the

world. This is reflected by the number of books and review articles68-74 that

have been published in recent years on the nanoscale materials, and also by


12

the fact that now an entire ten volume encyclopedia exists, dedicated to this

research area.75

In this nanoscale regime neither quantum chemistry nor classical laws of

physics hold.72 In materials where strong chemical bonding is present,

delocalization of valence electrons can be extensive, and the extent of

delocalization can vary with the size of the system. This effect, coupled with

structural changes with size variation of the nanoscale materials, can lead to

unique properties (electronic, optical, electrical, magnetic, chemical and

mechanical) that are entirely different from their corresponding bulk and

molecular ones. Some examples of these properties are lower melting point76,

an increased solid-solid phase transition pressure,77 a decreased ferroelectric

phase transition temperature,78 higher self-diffusion coefficient,79 changed

thermophysical properties80 and of course a unique catalytic activity.81,82

Besides these strange properties there is another important difference

between nanoscale particles and bulk solids, namely the ratio between the

numbers of surface and bulk atoms.73 A major fraction of the atoms in a

nanometer-size particle is located at the surface, i.e. surface area, whereas

this fraction is extremely small for macroscopic solids. For example, 90%

surface atoms for 1 nm particle, 10% for a 10 nm particle and in bulk

materials the surface effects can usually be neglected. This property can be

exploited in processes where surfaces are important, such as catalysis.83,84

This thesis will explore the catalytic properties of nanoclusters in various

industrially important reactions.

1.4 Mechanism of nanoclusters formation

Before discussing the synthetic methods, it is important to understand the

mechanism of the nanocluster formation. The synthesis of particles in solution

occurs by chemical reactions that result in the formation of stable nuclei and


13

subsequent particle growth. The term precipitation is often used to describe

this series of events.85 For nucleation to occur, the solution must be

supersaturated either by directly dissolving the solute at higher temperature

and then cooling to low temperatures or by adding the necessary reactants to

produce a supersaturated solution during the reaction86 for e.g. reduction of

metal salts to make metal nanoparticles. After the nuclei are formed from the

solution they grow via atomic addition, which relieves the supersaturated

step. When the concentration drops below the critical level, nucleation stops

and the particles continue to grow until the equilibrium concentration of the

precipitated species is reached.

Uniformity of the size distribution is achieved through a short nucleation

period that generates all of the particles obtained at the end of the reaction

followed by a self-sharpening growth process. At this stage, the smaller

particles grow more rapidly than the larger ones because the free energy

driving force is larger for smaller particles than for larger ones if the particles

are slightly larger than the critical size. At this stage, focusing in size occurs.86

Nearly monodisperse size distribution can be obtained at this stage by either

stopping the reaction (nucleation and growth) quickly or by supplying reactant

source to keep a saturated condition during the course of the reaction. On the

other hand, when the reactants are depleted due to particle growth, Ostwald

ripening or defocusing will occur, where the larger particles continue to grow,

and the smaller ones get smaller and finally dissolve. If the reaction is quickly

stopped at this stage, the particles will have a broad size distribution, which is

featured by a distribution centering two size regimes, a bigger one and a

smaller one, with the critical size now somewhere in between.

Nanoclusters are small and are not thermodynamically stable. For our

purpose stable suspension of nanoclusters is required for catalysis in liquid

phase. To produce stable nanoclusters, these nanoclusters must be arrested

during the reaction by adding a suitable stabilising agent to prevent the


14

agglomeration to the bulk.a The nanoclusters dispersions are stable if the

interaction between the stabilising groups (figure 2) and the solvent is

favorable, providing an energetic barrier to counteract the van der Waals and

magnetic (for magnetic materials) attractions between nanoclusters.

Microparticles(Inactive)

Reduction

Stable Nanoclustersuspension

Metal cationsin solution

Metal atoms in solution

Stabilise

r

Aggregation

++

++

+

++

Reducing agent (H2, NaBH4, etc)

Microparticles(Inactive)

Reduction




Stabilise

r

Aggregation

++

++

+

++


Reduction




Stabilise

r

Aggregation

++

++

+

++


Figure 2. Cartoon of nanocluster formation via reduction of metal salts.

Stabilisation can be achieved by two methods: electrostatic stabilisation and

steric stabilisation.73

1.4.1 Electrostatic stabilisation

Anions and cations from the starting materials remain in solution, and

associate with the metal particles. The metal particles are surrounded by an

electrical double layer, due to adsorbed negatively charged ions and cations

which are attracted to them. This results in a Coulombic repulsion between

particles that varies approximately exponentially with the interparticle

distance, as shown schematically in figure 3. The weak minimum in potential

energy at moderate interparticle distance defines a stable arrangement of

metal particles that is easily disrupted by medium effect and, at normal

a At short interparticle distances two particles would attracted to each other by van der Waals forces and, in the absence of repulsive forces to counteract this attraction, unprotected clusters would coalesce.


15

temperature, by the thermal motion of the particles. Thus if the electric

potential associated with the double layer is sufficiently high, electrostatic

repulsion will prevent particle agglomeration.

r

van der waalsattraction

E

Electrostatic repulsion

+-

++

++

++

+

--

-

-

--

-

+-

++

++

++

+

--

-

-

--

-

r


E


r


E


+-

++

++

++

+

--

-

-

--

-

+-

++

++

++

+

--

-

-

--

-

Figure 3. Electrostatic stabilisation of metal nanoclusters. The attractive van

der waals forces are outweighed by the repulsive electrostatic forces between

the electrical double layers.

A dispersion of electrostatically stabilised metal clusters can coagulate if the

ionic strength of the dispersing medium is increased sufficiently, since this

compresses the double layer and shortens the range of the repulsion. The

stabilising effect of the surface ions depends on their concentration, and if the

surface charge is reduced by the displacement of adsorbed anions by a more

strongly binding neutral adsorbate, the cluster particles can now collide and

agglomerate under the influence of the van der Waals forces. Even in less

polar organic media, in which electrostatic effects would not normally be

considered important, a charge will develop on a metal surface in contact with

organic phases such as solvent and polymers. For example the acquisition of

charge by gold particles was measured, and the sign and magnitude of the

charge was found to vary as a function of the donor properties of the liquid.


16

Thus, even for the particles in suspension in relatively non-polar liquids

electrostatic stabilisation may be present.

High local concentrationof stabiliser

High local concentrationof stabiliser

Figure 4. Steric stabilisation of the metal nanoclusters. The adsorbed large

molecules on the nanocluster’s surface provide a protective layer and prevent

them from aggregation.

1.4.2 Steric stabilisation

A second means by which metal particles can be prevented from aggregating

is by the adsorption of large molecules such as polymers or surfactants at the

surface of the particles, providing a protective layer. The way in which

adsorbed large molecules prevent aggregation can be seen in a simplified

manner by visualising the close approach of two particles, each with long

chain molecules adsorbed at their surfaces as shown in Figure 4. In the inter-

particle space the adsorbed molecules would be restricted in motion, fewer

conformations will be accessible, causing a decrease in entropy and thus an

increase in free energy. A second effect is caused by the local increase in

concentration of adsorbed molecules as the protective sheaths on each particle

begin to interpenetrate. This causes an osmotic repulsion as the solvent re-

establishes equilibrium diluting the stabiliser molecules, separating the

particles. The stabiliser molecule, in order to function effectively, must not

only coordinate to the particle surface, but also be adequately solvated by the


17

dispersing fluid. It is effective in both aqueous and nonaqueous media and is

less sensitive to impurities or trace additives than electrostatic stabilisation

and is particularly effective in dispersing high concentrations of particles. In

this work we use tetraoctylammonium salts as a stabiliser. Thus we expect

that the metal clusters are mainly stabilised by steric stabilisation. However,

in our case the metal clusters were synthesized in polar solvents and a charge

can develop on the metal nanoparticle surface. Therefore, electrostatic

stabilisation can not be excluded.

1.5 Common nanocluster synthesis methods

A variety of synthetic methods for nanoclusters have been developed.

Recently, the emphasis of synthesis has been on the preparation of

monodisperse particles, with well-defined size, shape and surface properties.

Control over these parameters is crucial for a successful utilization of the size-

dependent properties that are unique to nanoclusters. Generally, lipophilic

stabilizing agents give metal clusters that are soluble in organic media

(organosols), while hydrophilic agents yield water-soluble clusters (hydrosols

or aquasols). Many different stabilisers have been used as capping agents for

the synthesis of metal nanoclusters such as polymers,87 dendrimers,88 block

copolymer micelles,89 surfactants,83,90-93 and solvents such as THF,94 propylene

carbonate95 and long-chain alcohols.96

Chemical reduction of the precursor metal salt is the most widely used method

of synthesizing metal nanoclusters. There are other synthetic methods to

prepare metal nanoclusters that are not as commonly used. These methods

are photochemical,97 sonochemical98-100, ligand reduction and displacement

from organometallic precursors,101 metal vapor condensation,102 and

electrochemical reduction.103

Here, only the chemical reduction method using commonly used reducing

agents to prepare transition metal nanoclusters are discussed briefly.


18

xMn+ + nxe- M0n(clusters) (1)

1.5.1 Chemical reduction methods

In 1857, Faraday60 was first to publish the chemical reduction of transition

metal salts in the presence of stabilizing agents to generate metal colloids in

aqueous or organic media and this approach has become one of the most

common and powerful synthetic methods in this field (eqn 1).70,71,73,83,104,105 The

next major contribution was made by Turkevich, who reported the first

reproducible method for preparing metal colloids (e.g., for 20 nm gold by

reduction of [AuCl4]2 with sodium citrate).106 The most famous ligand-

stabilized metal cluster is probably Au55(PPh3)12Cl6 (1.4 nm), a full shell

(‘‘magic number’’) prepared by Schmid et al.107 Careful addition of diborane to

an AuIII ion solution in the presence of PPh3, gives small and quite uniform Au

nanoclusters, most of them having a Au55 structure.

1.5.1.1 Alcohol as reducing agent

Hirai and Toshima108 developed the ‘‘alcohol reduction method’’, using mainly

ethanol and methanol, in the presence of organic polymers such as

poly(vinylpyrrolidone) (PVP), poly(vinyl alcohol) (PVA), and poly(methylvinyl

ether).109 In this reduction method, the alcohol acts both as a solvent and

reducing agent and the reduction of the metal salt takes place under reflux.

The use of alcohols results in a fast reduction of the precursor metal salt, with

fast cluster formation. In this reduction process, the metal salts are reduced to

form the metal nanoclusters, while the alcohols are oxidized to form the

corresponding carbonyl compounds. There have been many studies conducted

on how the size of the metal clusters is dependent on the structure and the

quantity of alcohol.110 It has also been shown that in the case of the formation

of platinum, palladium, and rhodium nanoclusters, the higher the boiling

point of the alcohol used as the reducing agent, the smaller the size of the


19

nanoparticles formed. This method is also useful for preparing bimetallic

nanoparticles by the co-reduction of mixed ions.105

1.5.1.2 H2 as reducing agent

Hydrogen gas111,112 has also been employed as a common reducing agent for

the preparation of the metal nanoclusters. The hydrogen reduction method

involves bubbling hydrogen gas into a solution containing the metal salt and

through a slow reduction process, metal nanoclusters are formed. Various

shapes of platinum nanoclusters have all been formed by the hydrogen

reduction method.112 Tetrahedral clusters, which are composed of (111) facets,

are especially attractive to use as catalysts due to the large fraction of surface

atoms that are present in the edges and corners. Hydrogen reduction has also

been used to reduce precursor iridium and rhodium organometallic complexes,

generating electrosterically stabilized nanoclusters with a well-defined

formation stoichiometry.113

1.5.1.3 Sodium borohydride as reducing agent

Sodium borohydride88,114 is one of the strongest reducing agents and is used

frequently for synthesizing the metal nanoclusters. This method is generally

very fast with clusters forming shortly after the addition of sodium

borohydride. Sodium borohydride reduction has been used to synthesize

platinum, palladium, copper, gold, and silver nanoparticles in the presence of

dendrimers.88 Many transition metal nanoclusters have also been synthesized

using the sodium borohydride reduction method in the presence of polymer

protecting agents.115 However, this reducing agent has the disadvantage that

transition metal borides are often found alongside the nanoclusters.116

1.5.1.4 Hydrotriorganoborates as reducing agent

Bönnemann et al.74,93 have developed general routes for the multigram

syntheses of 1–10 nm transition metal nanoclusters via the reduction of metal


20

salts in THF by tetraalkylammonium hydrotriorganoborates (scheme 6). In

this case, the reductant [BEt3H] is combined with the stabilizing agent (e.g.

NR4+). The surface-active NR4+ salts are formed immediately at the reduction

center in high local concentration and prevent the particle aggregation.

R4N+(BEt3H)-+ Mcolloids + +nBEt3 n/2H2MXn

M = metals of groups 4-11; X = Cl, Br, n = 1-3; R = alkyl, C6-C20

Scheme 6. Cluster synthesis using hydrotriorganoborates as reducing agents.

Trialkylboron is recovered unchanged from the reaction mixture and no

borides contaminate the products. Moreover, this method has several

advantages; it yields very stable metal clusters that are easy to isolate as dry

powders, it is applicable to metal salts of Groups 4 11 in the Periodic table,

the particle size distribution is nearly monodisperse, bimetallic clusters are

easily accessible by co-reduction of two different metal salts and the synthesis

is easy to scale up.83 However, one of the drawbacks of this method is that the

particle size of the resulting sols cannot be varied by altering the reaction

conditions. Bönnemann and co-workers74b have also reported the synthesis of

metal colloids that are putatively only solvent stabilized. Reducing

TiBr4.2THF with KBEt3H in THF yields very small (<0.8 nm), extremely

oxophilic, ether soluble clusters formulated as ‘(Ti0.0.5THF)’. These are

claimed to be stabilized against agglomeration by coordinated ether molecules.

1.5.1.5 Tetraoctylammonium carboxylates as reducing agents

Reetz et al.92 have developed a new and simple size- and morphology-selective

procedure to prepare metal nanoclusters, using tetraalkylammonium

carboxylates of the type NR4+R`CO2 (R = octyl; R` = alkyl, aryl, H) as both the

reducing agent and the stabiliser (scheme 7).


21

M+ + R4N+R'CO2- (R4NR'CO2)x + CO2 + R-R'

50-90 oCMo

M+ = metal ion; R = Octyl; R' = alkyl, aryl, H

Scheme 7. Cluster synthesis using tetraoctylammonium carboxylates as

reducing agents.

The resulting particle sizes were found to correlate with the electronic nature

of the R` group in the carboxylate. For example, depending on the type of R`

group (electron withdrawing or donating substituents), Pd clusters of varying

size (2.2-5.4 nm) were formed when Pd(NO3)2 was reduced using an excess of

NR4+R`CO2 . Carboxylates with electron donating substituents (as in the case

of pivalate, (CH3)3CCO2 ) afford small nanoparticles in a relatively fast

reaction, whereas those having electron withdrawing substituents (e.g.

dichloroacetate, Cl2CHCO2 ) induce the opposite, namely the slow formation of

large particles. Thus, the choice of the reducing agent allows for the control of

particle size within the range of 2.2-5.4 nm. Bimetallic clusters of the

following were obtained with tetra(n-octyl)ammonium formate as the

reductant: Pd/Pt (2.2 nm), Pd/Sn (4.4 nm), Pd/Au (3.3 nm), Pd/Rh (1.8 nm),

Pt/Ru (1.7 nm), and Pd/Cu (2.2 nm).92

The shape of the particles was also found to depend on the reductant: With

tetra(n-octyl)ammonium glycolate and Pd(NO3)2, a significant amount of

trigonal particles was detected in the resulting Pd clusters.117 The presence of

the -hydroxy group in carboxylate that can interact with the surface of the

metal clusters was proposed as the morphology-determining factor in this

case. Above all, the advantages of this redox controlled method is that it

requires no complicated separation or purification procedures and the clusters

can be redispersed in polar solvents.


22

We used this method, because of the ease of synthesis of metal clusters of

varying size and shape in polar solvents that can then be used directly for

catalysis in solution.

1.6 Catalysis by metal nanoclusters

Most catalysts have been described as either homogeneous or heterogeneous,

each with its own methods and applications. Homogeneous catalysts are

molecularly dispersed with the reactants in the same phase, which provides

easy access to the catalytic site but can make the separation of the catalyst

and products difficult. Heterogeneous catalysts (usually solids) are in a

different phase from the reactants, which reduces separation problems but

provides more limited access to the catalytic site due to diffusion resistance.

The question is what will happen in an intermediate case, i.e. nanocatalysts,

which have a much higher mobility with respect to the heterogeneous case,

but a lower mobility with respect to the homogeneous case? Metal

nanoclusters are attractive as catalysts because:

1) They display unique catalytic properties118-120 and can catalyse new types

of reactions not accessible to traditional homogeneous and heterogeneous

catalysts.

2) They have a large number of co-ordinatively unsaturated surface atoms,

which can lead to high catalytic activity either via leached species or

surface reaction.121

3) Their size,92 shape122 and composition (alloy bimetallic or core-shell

clusters)105 can easily be adjusted by varying parameters like type and

concentration of metal salts, reducing/stabilising agents, temperature

and clustering time. Thus, it is possible to easily manipulate and

optimize the catalyst design.

4) Their synthesis is simple and straightforward as opposed to that of metal

complexes.


23

5) They can be isolated and re-dispersed in various solvents and are

stable95,123 up to 150 C compared the metal complexes; consequently they

retain their catalytic activity.

Since 1995, the field of nanocatalysis (in which nanoclusters are used to

catalyze reactions) has undergone an exponential growth. Two types of studies

have been carried out; catalysis in solution32,95,119,124-126 and by nanoclusters

supported on a substrate.83,127,128 The use of supported nanoclusters in

heterogeneous catalysis accounts for the majority of the publications, while

the catalysis by cluster suspension accounts for only about 15-20% of the

work. There have been several reviews that discuss the use of metal

nanoclusters as catalysts for homogeneous catalysis, and also some of the

major reactions that this type of nanoparticles has catalysed. One review has

focused on whether transition metal colloidal nanoparticles are potential

recyclable catalysts.126 The use of various polymer stabilised clusters as

catalysts in liquid phase has been reviewed.129 The use of monometallic and

bimetallic clusters stabilised by solvent and surfactants as catalysts has been

surveyed.93 Bimetallic catalysts in colloidal dispersions that are stabilised

with PVP as potential catalysts are also discussed in great detail.105 Here we

will mainly focus on the catalysis by the cluster suspension in cross-coupling

reactions.

1.6.1 Nanoclusters in cross-coupling reactions

Three main types of cross-coupling reactions that have been catalysed using

metal nanoclusters are the Suzuki, Sonogashira and the Heck cross-coupling

reactions. In 1996 Beller et al.130 were the first to try Heck coupling reaction

with preformed palladium clusters as catalysts. However, these clusters were

found to be unstable under the reaction conditions and had to be added slowly

to the reaction mixture in order to hamper metal aggregation, leading

eventually to the precipitation of inactive palladium black. In the same year


24

Reetz and coworkers32,95 reported twice on the application of palladium

clusters for the catalysis of C–C coupling reactions. In one case, they used sols

of Pd clusters prepared electrochemically as well as by thermal decomposition

of simple palladium salts in propylene carbonate. Both methods yielded 8–10

nm clusters, which were stable for days even at 140–155 oC in solution. In

another paper, they briefly described the use of a different kind of palladium

as well as palladium/nickel clusters (2–3 nm in size) as catalysts for the

Suzuki reaction. A mechanistic study has shed some light on the role of

clusters in many phosphane-free Pd-catalysed processes.31 It was observed

that using Pd/PPh3 traditional catalysts showed no formation of clusters at

any stage, but simple Pd(OAc)2 led, as expected, to small, unstable clusters

(1.2 nm). This seminal paper points to the important role of Pd nanoclusters in

many catalytic reactions where strongly coordinating Pd ligands are not

employed.

Since then the interest continues unabated and cases using Pd nanoclusters in

cross-coupling reactions have been reported. The Suzuki reaction has been

conducted using Pd clusters in 3:1 acetonitrile:water as solvent,131 and under

microwave heating.132 The Heck and Suzuki reaction were also carried out

using Pd clusters in ionic liquids,133-135 where there is a possibility of

recovering the catalysts easily. El-Sayed et. al.136,137 have also studied the

effect of size, shape and stabilisers on the catalytic activity of Pd clusters in

the Suzuki reaction. Another variant uses palladium nanoparticles

encapsulated in a dendrimer as catalysts in biphasic organic fluorous solvent

systems have been reported.138 In 2004 2005, the Sonogashira reaction has

also been studied using Pd nanoclusters as catalysts.139-141 The most

remarkable ligand-free and co-catalysts-free Sonogashira reaction reported is

using Cu119 and Pd/Ni143 nanoclusters as catalysts. Most of the cluster

catalysts reported till date for these reactions are based on Pd, whereas Ru,142

Ni,143 Cu,119,120,144 and bimetallic32,119,145 or trimetallic nanoclusters146 are used

to a much smaller extent. Therefore, there remains ample opportunity to


25

develop new cluster catalysts that can serve as alternative to the expensive Pd

catalysts.

1.6.2 The nature of cluster catalysis

There are several reports on the use of Pd clusters and Pd dispersed on

various supporting materials in cross-coupling reactions, especially the Heck

and Suzuki reactions. A detailed knowledge of the nature of the catalysis is

essential for process optimization. Several reports discuss the mechanistic

aspects of the supported Pd catalysts in these reactions,147-150 and it is clear

that in most cases the catalysis takes place via the leaching of Pd species into

the solvent. Conversely, little is known about how cluster catalysts work in

the cross-coupling reactions.31,134,147,151,152 For Pd on a solid support, the

Maitlis’ filtration test153 and ICP analysis of the filtrate can tell us whether Pd

is leaching or not. With nanoclusters, however, testing is difficult due to the

small cluster size.

In this connection, Bradley and co-workers151 were the first to study catalysis

by PVP-stabilized Pd clusters in the Heck reaction. They concluded that the

catalysis occurs at the defect sites on the metal surface, since the initial

reaction rates were directly proportional to their number on the particle

surface, rather than to the total metal surface area or to the total amount of

palladium introduced. However, these findings may be linked to soluble

palladium species too. In fact, the palladium atoms located at the defect sites

are most reactive (co-ordinatively unsaturated) and it is likely that they are

quickly brought in solution. This process would give soluble palladium species,

in concentration proportional to the initial number of the defective sites. Reetz

and Westermann,31 observed that Pd clusters react with stoichiometric

amounts of aryl iodide to give quantitatively Pd(II) species. This implies that

the palladium clusters are destroyed by stoichiometric amounts of the aryl


26

halide and survival or the accumulation of colloidal metal is possible only if

the attack of the aryl halide to the metal surface is relatively slow.

Also, De Vries and co-workers154 in their report on the ‘homeopathic ligand-

free’ Pd catalyst suggested that the reaction proceeds via the formation of

soluble palladium clusters and that there is an equilibrium between these and

a lower-order species such as a monomeric or dimeric moiety that is the

actual catalytically active species. Recently, Dupont et. al.134 showed the TEM

analysis of Pd clusters dispersed in ionic liquid, before and after the Heck

reaction, and also measured the Pd leaching from ionic liquid phase to the

organic phase at different substrate concentrations. Their results point to the

homogeneously catalysed mechanism where the Pd clusters only acts as

reservoir of active Pd species.

Therefore, the question of ‘Does cluster catalysis occur on the cluster surface,

or via leaching of Pd species into the solution?’ is not clearly answered. This

requires more studies, especially in-situ investigation of cluster catalysts

using TEM, XPS and EXAFS in liquid phase reactions.

1.7 Self assembly

Nowadays, researchers are trying to build devices and novel nanostructured

materials by pushing molecules, atoms or nano-objects around by various

sophisticated techniques, e.g. using scanning tunneling microscope (STM) tips,

lithography, or chemical vapour deposition (CVD).155,156 In every case, we try

to impose our wills on these very small objects and manipulate and tweak

them to be just how we want them. However, to really shape our future and

become part of everyday life nanostructures will have to be manufactured in

bulk using simple methods.


27

Wouldn't it be glorious if we could just mix chemicals together and get

nanostructures by letting the molecules sort themselves out? One approach to

nanofabrication attempts to do exactly this is called self-assembly.157,158 The

idea behind self-assembly is that molecules will always seek the lowest energy

level available to them. If bonding to an adjacent molecule accomplishes this,

they will bond. One way to imagine self-assembly is to imagine holding a box

containing a jigsaw puzzle, giving the box a shake, and peeking inside to find

that the puzzle had assembled itself! While such behaviour would be shocking

in a jigsaw puzzle, a little reflection reveals that it's not so surprising to find

self assembling systems in the natural world. After all, no one put you

together did they? Self-assembly techniques are based on the idea of making

components that naturally organize themselves the way we want them to.

Self-assembly is almost certainly going to be the preferred method for making

large nanostructure arrays for electronic applications.69,159 The chemistry part

of self-assembly is discussed in chapter 7.

1.8 Motivation & objective of my research

As mentioned before, the catalysts for C–C coupling reactions such as Heck,

Suzuki and Sonogashira reactions are usually homogeneous palladium-ligand

complexes that are often laborious to synthesize and/or air sensitive. For a

reaction to be attractive for application in the fine chemical or pharmaceutical

industries, the palladium contamination of the product must be in the low

ppm region, often necessitating expensive product clean-up. This, coupled with

the high price of not only the palladium but often the ligands, can make the

whole process prohibitively expensive. A solution for this problem could be the

use of ligand-free cheaper metals or combination of different metals as

catalysts.

It is known that during the reaction, and especially at high conversions, the

palladium complexes deactivate and ultimately precipitate as micrometric


28

aggregates (palladium black) or coat the vessel with a mirror. However,

between the active Pd(0) atoms and the inactive bulk aggregates, the catalyst

passes through an intermediate phase, forming small clusters. Such

nanoclusters are themselves capable of catalysing Suzuki, Heck, and

Sonogashira-type coupling reactions. If aggregation is prevented, catalytic

activity comparable with homogeneous systems can be achieved. Therefore, we

decided to use nanoclusters of various metals also in combination with Pd to

catalyse these reactions, a ligand-free option that may be attractive also for

large-scale production. The main objective of this research has been to

synthesize, characterise and develop alternative metal nanocluster catalysts

for C–C coupling reactions. Furthermore, the much debated mechanism of

cluster catalysis in cross-coupling reactions is also investigated. Mechanistic

understanding of the reaction forms an important tool in research, since a

better insight into the catalytic reaction mechanism can help us design better

catalysts.

1.8.1 Outline

In chapter 2, the synthesis of mixed metal nanoclusters using a size and

shape-selective method is described. The results obtained from the screening

of library of nanocluster catalysts for activity in Suzuki cross-coupling reaction

are presented, and the mechanism of cluster deactivation and the sensitivity

of the cluster-catalysed reaction to substituent effects are also discussed.

In chapter 3, the application of the ligand-free and Pd-free Cu nanoclusters

catalyst system is extended to another important C C bond formation

reaction: the Sonogashira reaction. It summarizes the results obtained for the

catalytic activity of pre-prepared Cu nanoclusters in Sonogashira coupling of

phenylacetylene with various aryl iodides and activated bromides. No co-

catalyst, Pd or ligand was used during the reaction. The comparison of activity


29

of Cu clusters with various catalysts and co-catalysts combination is also

described.

Microwave heating has emerged as a versatile method to speed up many

chemical reactions, delivering high yields in a few minutes. In chapter 4, the

pros and cons of high throughput testing of nanocluster catalysts using 8×12

parallel screening system in the microwave oven are discussed. The spatial

reproducibility of this system is also examined and the catalytic activity is

compared with a conventional oven.

Chapter 5 addresses the important and long debated question of the actual

participating catalytic species responsible for catalysis in Pd cluster catalysed

cross-coupling reactions. It consists of two sections:

Section A describes the mechanistic study on cluster catalysis using kinetic

analysis and transmission electron microscopy (TEM). It also includes the

study of the effect of counter anions on the catalytic activity of Pd clusters,

effect of premixing reactants and reusability of the clusters. A two pathway

mechanism is proposed for the Pd clusters catalysed Sonogashira coupling

reaction. In Section B, the results from well planned membrane experiments

are described to reveal the true nature of catalytic species in the Pd cluster

catalysed Heck reaction. A new approach using two compartment membrane

reactor is presented, which was designed to physically separate Pd clusters

(size, 15 nm) from the reaction mixture by a nano-porous membrane acting as

a partition.

Chapter 6 explores the use of a heterogeneous ligand-free and cocatalyst-free

Pd/C catalyst system for activating aryl bromides and chlorides via a one-pot

consecutive Halogen exchange (HALEX)-Sonogashira reaction. The influence

of the solvent, base, iodide source and catalyst is studied. The reusability of

the Pd/C catalyst is highlighted. Also, a variation on this one-pot reaction

using catalytic amounts of KI is proposed.


30

In Chapter 7, a simple and general method to trap or confine the stable metal

nanoclusters (~2 nm in diameter) coated with hydrophobic coronas in self-

assembled hexagonal micellar rods is described. The system’s crystal structure

and phase behaviour are studied in detail. The possibilities of using these

nano-structures in catalysis and for making nanowires are discussed.

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32

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Chapter 2 Copper-based mixed nanoclusters: New catalysts

37

Chapter 2

Copper-based mixed nanoclusters: New catalysts for Suzuki

cross-coupling*

Abstract

Quantum dots (2–5 nm) of copper and copper/palladium mixtures are found to be

good catalysts for Suzuki cross-coupling. The catalysts are applicable to a wide range

of iodo- and bromoaryl substrates, and give moderate yields using chloroaryl

substrates. Cluster activity and stability is found to depend strongly on the

preparation method and the reaction conditions. The mechanism of cluster

deactivation and the sensitivity of the cluster-catalysed reaction to substituent effects

are studied and discussed.

* Part of this work has been published: M. B. Thathagar, J. Beckers and G. Rothenberg, J. Am.

Chem. Soc., 2002, 124, 11858. Featured in Science as Editor’s Choice, see Science, 2002, 297, 2171. Adv. Synth. Catal., 2003, 345, 979.

B(OH)2 X

+ 2 mol% nanoclustersDMF, K2CO3, 110 oC

N+

N+

+N

+N

+N

R

R

2

1

3

4

6

8

75

10

9

11

12

13

14

15

PtPd RuCu

B(OH)2 X

+ 2 mol% nanoclustersDMF, K2CO3, 110 oC

N+

N+

+N

+N

+N

R

R

2

1

3

4

6

8

75

10

9

11

12

13

14

15

PtPd RuCu2

1

3

4

6

8

75

10

9

11

12

13

14

15

PtPtPdPd RuRuCuCu


38

Introduction

Catalysis is traditionally divided into ‘heterogeneous’, ‘homogeneous’ and

‘enzymatic’ subsections, each with its own methods and applications. Metal

nanoclusters in the 2–5 nm range (also called ‘quantum dots’) are too big to be

‘homogeneous catalysts’, and too small to be considered ‘bulk metals’.1 These

nanoclusters can display unique catalytic properties that differ from their

homogeneous and/or heterogeneous analogues. A second important aspect of

metal nanoclusters is their huge surface area. In small clusters most atoms

are at the surface, which can lead to very high catalytic activity.2,3 Transition

metal nanoclusters, especially those of noble metals, have been reported as

catalysts in olefin hydrogenation,4-8 hydrosilation,9 and C–C coupling

reactions.10-12

Formation of carbon–carbon bonds via cross-coupling of aryl halides with

arylboronic acids (the Suzuki-Miyaura reaction) is a key synthetic step in the

production of agrochemicals, polymers, and pharmaceuticals.13 This reaction

benefits from low reagent toxicity and easy separation of by-products.

Traditionally, C–C coupling is carried out using palladium(0), in the presence

of ligands,14,15 that are often laborious to synthesise.16 During the reaction,

and especially at high conversions, the palladium complexes deactivate and

ultimately precipitate as micrometric aggregates (palladium black) or coat the

vessel with a mirror. However, between the active Pd(0) atoms and the

inactive bulk aggregates, the catalyst passes through an intermediate phase,

forming small clusters. Such nanoclusters are themselves capable of

catalysing Suzuki,12,17 Heck,12 and Ullmann-type coupling reactions18 (see

Figure 1). If aggregation is prevented, catalytic activity comparable with

homogeneous systems can be achieved.

Sinfelt and co-workers19,20 have vigorously studied inorganic oxide-supported

bimetallic nanoclusters for catalysis the hydrogenation of olefins and carbon-


39

skeleton rearrangement of hydrocarbons. In contrast, supported or suspended

multimetallic nanoclusters are rarely used for catalysis. Multimetallic cluster

systems are important as incorporation of different metals can induce large

changes in the structure and enhance the catalytic properties of the active

component.21-24

Pdo clusters (2–5 nm)

homogeneous Pd o

Pdo aggregates (inactive)

clustering

B(OH)2 X

R

R

+

aggregation

X = Cl, Br, IR = H, perfluoro, Me, NO2, I, CF3, OMe, CN

Figure 1. Cross-coupling of phenylboronic acid and halobenzene to give a

biaryl derivative, showing clustering of the homogeneous palladium(0)

catalysts followed by catalyst deactivation through aggregation.

The high activity reported for monometallic25-29 and bimetallic12 nanoclusters

encouraged us to investigate further cluster catalysts for the Suzuki reaction.

Copper-based alternatives are attractive because they are both cheaper and

“greener” than any noble metals. Moreover, Cu(I) salts and Cu2O have

recently been reported as co-reagents30-32 and co-catalysts33 in C–C and C–N34

coupling reactions. In this chapter, we report the first application of copper-

based mixed nanoclusters as Suzuki cross-coupling catalysts and present a

detailed investigation of the reaction scope and try to gain some insight into

its mechanism.


40

Results and Discussion

Nanocluster catalysts via NaBH4 reduction

We first synthesised nanoclusters by using sodium borohydride as reducing

agent in presence of tetraalkylammonium bromide (TAAB) as stabiliser. In a

typical synthesis, 0.26 equivalents of aqueous borohydride were added

dropwise to a toluene solution of palladium chloride containing 1.5 equivalents

of tetra-n-octylammonium bromide (TOAB). A black colloidal suspension

formed. This suspension, containing the Pd (or, Ru or Pd/Ru) clusters was

tested as is in the cross-coupling of phenylboronic acid and iodobenzene to give

biphenyl (eq 1).

B(OH)2 I

+ (1) colloid 1–15, 2 mol%DMF, K2CO3, 110 oC

A mixture of iodobenzene, 1.5 equivalents of phenylboronic acid, 3 equivalents

of K2CO3 and 1 mol% of metal clusters was stirred in toluene at 110 C under

N2 for 3 h. Reaction progress was monitored by GC. The palladium clusters

were most active, Ru gave 7% conversion after 3 h and no synergistic effect

was observed for the bimetallic Pd/Ru clusters. The palladium clusters

aggregated and precipitated after 90 min. We thought that the high initial

concentration of Pd clusters led to more collisions between the particles and

faster aggregation. To study the deactivation of Pd clusters, the same reaction

was carried out using 1 mol% Pd in three portions (3 0.33 mol% Pd), added

at intervals of 30 min. The initial activity of the clusters in the first two

portions is high, but they also deactivate quickly (cf. data for and in Figure

2). The third portion deactivates even faster than the first two and this may be

due to aggregates already present in reaction mixture. Thus, it is not the high

initial concentration that causes catalyst deactivation. Rather, the


41

deactivation is more likely due to thermal instability and/or contamination by

borides.

0

5

10

15

20

25

0 60 120Time/ min.

PhI

Con

vers

ion

/ %

1st portion2nd portion

3rd portion

0

5

10

15

20

25

0 60 120Time/ min.

PhI

Con

vers

ion

/ %

1st portion2nd portion

3rd portion

Figure 2. Suzuki coupling of PhB(OH)2 with PhI catalysed by palladium

nanoclusters (prepared via NaBH4 reduction). Reaction conditions: 3.00 mmol

PhI, 6.00 mmol PhB(OH)2, 6.00 mmol K2CO3, 50 mL toluene, 110 ºC. ( ) 1

mol% catalyst, added in one portion at t = 0; ( ) 1 mol% catalyst in total,

added in three equal portions at intervals of 30 min.

The preparation of TOAB-protected Pd and Ru nanoclusters by borohydride

reduction was straightforward, but our attempts to prepare Cu, Co, and Ni

clusters by this method were unsuccessful. In all three cases metal aggregates

formed in the aqueous phase, indicating that the interaction of these metals

with the TOAB was insufficient. To avoid this biphasic system we switched to

dimethylformamide (DMF), but here all clusters aggregated (including Pd and

Ru) and precipitated out of the solution. The reason for this may be the strong

reducing power of borohydride in the monophasic system.


42

2

1

3

4

6

8

75

10

9

11

12

13

14

15

PtPd RuCu

N+

N+

+N

+N

+N

2

1

3

4

6

8

75

10

9

11

12

13

14

15

PtPd RuCu2

1

3

4

6

8

75

10

9

11

12

13

14

15

PtPtPdPd RuRuCuCu

N+

N+

+N

+N

+N

N+

N+

+N

+N

+N

Figure 3. Cartoon of a metal cluster stabilised by tetraoctylammonium ions

and experimental design for preparing cluster catalyst mixtures of copper,

palladium, platinum and ruthenium.

Nanocluster catalysts via formate reduction

To control the reduction rate we adopted the approach reported by Reetz and

Maase, who used tetraalkylammonium carboxylates both as reducing and as

stabilising agents.35 The Pd clusters prepared in DMF were more active than

those prepared in toluene, perhaps because the polar solvent itself acts as a

stabiliser.36 The results below all pertain to clusters prepared in DMF. A

mixture design37 assuming no prior knowledge was applied to test the singular

and the combined catalytic effects of copper with three noble metals

(palladium, platinum and ruthenium, see Figure 3). A library of 15 colloidal

mixtures was prepared, by mixing the appropriate homogeneous stock

solutions of the metal chloride precursors, followed by reduction with

tetraoctylammonium formate (TOAF) in DMF at 65 C. All syntheses,

reactions, and catalyst storage were performed under nitrogen. Cluster size

was measured using Transmission electron microscopy (TEM) (Figure 4, left).


43

In all cases, the average particle size of the metal clusters, for eg. Average size

of Cu/Pd clusters was 5.0 nm, with a narrow particle size distribution (Figure

4, right).

0

10

20

30

40

50

60

70

4 5 6 7

Particle size/ nm

Freq

uenc

y/ %

0

10

20

30

40

50

60

70

4 5 6 7

Particle size/ nm

Freq

uenc

y/ %

Figure 4. Transmission electron micrograph (left) and corresponding size

distribution (right, based on 130 particles counted) of the Cu/Pd clusters.

Screening of nanocluster catalysts for activity

This library was then screened for activity in the cross-coupling of

phenylboronic acid with iodobenzene. The reactions were carried out using 2

mol% metal relative to PhI. The main results are shown in Figure 5 (also see

supporting information at the end of this chapter). As expected, among the

homometallic catalysts palladium 2 was most efficient, giving 100% yield after

4 h at 110 C. No reaction was observed with the platinum clusters, but

ruthenium and, surprisingly, copper clusters were found to be active and

stable.

Cu/Pd 5 was the most active of the bimetallic combinations, comparable to

pure Pd 2 (cf. Table 1, entries 4 and 2). Note that the amount of Pd in 5 is half

of that in 2. The physical mixture of Cu and Pd clusters gave only 64%


44

conversion. This result further indicates that there is a synergistic effect

between Cu and Pd bimetallic clusters. However, the lower activity of the

Pd/Pt catalyst 9 shows that no simple extrapolation can be made from one

combination to another.

0102030405060708090

100

0 1 2 3 4Time/ h

PhI

con

vers

ion/

%

Cu

Cu + Pd

Cu/Pd/Ru

PdCu/Pd

0102030405060708090

100

0 1 2 3 4Time/ h

PhI

con

vers

ion/

%

Cu

Cu + Pd

Cu/Pd/Ru

PdCu/Pd

Figure 5. Time-resolved reaction profiles observed for Suzuki coupling of

PhB(OH)2 and PhI using various nanocluster catalysts (left). Standard

reaction conditions: 0.50 mmol iodobenzene, 0.75 mmol phenylboronic acid, 1.5

mmol K2CO3, 0.01 mmol catalyst (2 mol% total metal relative to PhI), 12.5 mL

DMF, under N2, 110 ºC.

No reaction was observed with catalysts 6, 7 and 10. Activity trends continued

with 12 > 11 > 14 for the trimetallic clusters. 15 was less active but stable,

reaching 100% conversion after 24 h. Duplicate experiments carried out after

4 weeks using same stock solution of nanoclusters, confirmed that the results

were reproducible, and that the catalysts retain their activity.


45

Table 1. Biphenyl yields and rate constants using various nanoclusters

catalysts.a

Entry CatalystbYieldc

[%]

kobs

[L/mol min–1]

r2

[5 obs.]

1 1 (Cu) 62 3.2 10–3 0.985

2 2 (Pd) 100 5.9 10–2 d 0.990

3 4 (Ru) 40 2.0 10–3 0.938

4 5 (Cu/Pd) 100 6.1 10–2 d 0.992

5 8 (Pd/Pt) 94 9.7 10–3 0.934

6 9 (Pd/Ru) 100 2.9 10–2 0.985

7 11 (Cu/Pd/Pt) 92 2.5 10–2 0.991

8 12 (Cu/Pd/Ru) 100 3.8 10–2 d 0.996

9 14 (Pd/Pt/Ru) 81 7.3 10–3 0.923

10 15 (Cu/Pd/Pt/Ru) 62e 2.8 10–3 0.992

a Reaction conditions were as in figure 4. b No conversion was observed with

catalysts 3, 6, 7, 10, and 13. c GC yield after 6 h, corrected for the presence of

internal standard. d Value is the average of two repeated experiments. e 100%

yield obtained after 24 h.

Cu/Pd clusters catalysed Suzuki coupling of various aryl halides

The bimetallic Cu/Pd clusters were active over a wide range of substrates

(Table 2). In general, aryl iodides reacted faster then the corresponding

bromides (entries 2–4). Aryl bromides containing electron-withdrawing groups

(entries 8 11) gave quantitative yields after 1–6 h. 4-Bromoanisole, on the

other hand, took 24 h to reach full conversion. The catalyst was also active

towards arylchlorides with electron withdrawing groups, indicating that it is

active enough to initiate the oxidative addition step of the strong C Cl bond.


46

Table 2. Nanocluster-catalysed Suzuki cross-coupling with various

substrates.a

Entry Substrate Catalyst/

composition Time/h Conversion /%b

1 Me I 1 (Cu) 8 100

2 Me I 5 (Cu/Pd) 2 100

3 F I

FF

F F

5 (Cu/Pd) 2 100c

4 F3C I 5 (Cu/Pd) 2.5 100

5 I I 5 (Cu/Pd) 24 100d

6 Br 12 (Cu/Pd/Ru) 24 62

7 Br 5 (Cu/Pd) 24 100

8 BrH3CO 5 (Cu/Pd) 24 100 c

9 BrF 5 (Cu/Pd) 24 100 c

10 BrF3C 5 (Cu/Pd) 4 100

11 BrNC 5 (Cu/Pd) 1 100

12 BrO2N 5 (Cu/Pd) 0.5 100 c

13O2N

CH3

Br 5 (Cu/Pd) 6 100 c

14NO2 CH3

Br 5 (Cu/Pd) 4 100

15 BrO2N

CF3

5 (Cu/Pd) 4 100

16NO2

BrH3CO5 (Cu/Pd) 6 100 c

17 NC Cl 5 (Cu/Pd) 48 43

18ClO2N 5 (Cu/Pd) 48 54


47

19 Cl

Cl12 (Cu/Pd/Ru) 24

25 c

a Standard reaction conditions same as figure 5. b GC conversion, corrected for

the presence of an internal standard. Only the cross-coupling product was

observed, unless otherwise noted. c 8–10% biphenyl as by-product. d 75%

conversion to 1,4-diphenylbenzene (terphenyl).

In several experiments ca. 10% biphenyl was also observed. The amount of

copper in these experiments is not enough to form biphenyl via the

stoichiometric Ullmann reaction,38 and in any case no 4,4'-dimethylbiphenyl

was observed when p-iodotoluene was used as the substrate. It is more likely

that some homocoupling of phenylboronic acid occurs in these cases when the

cross-coupling is slow.39,40 With hindsight, we see that the choice of model

reaction was not ideal, as it is difficult to distinguish between the cross-

coupling of iodobenzene and boronic acid and the homocoupling of the latter.

Mechanistic study

The accepted catalytic cycle for the homogeneous complex-catalysed Suzuki

cross-coupling begins with oxidative addition of the aryl halide, followed by

transmetallation and reductive elimination of the product.41 Does this

mechanism also apply to nanocluster catalysis? A partial answer to this

question can be obtained by examining the influence of substituents on the

reaction rate. For the substrates we studied, the reaction profile fit well to a

second-order rate equation (see, e.g., the data for p-bromobenzotrifluoride in

Figure 6). One may assume that the rate-determining step with nanocluster

catalysts is, similar to the homogeneous reaction, the oxidative addition of

ArX to the catalytic site. Indeed, a Hammett plot of the relative reactivity of

various substituted bromobenzenes vs. P gave = 1.48 (Figure 7), in close

comparison with the value obtained by Weissman et al. using homogeneous


48

palladium complexes.42 The positive value indicates that the reaction is

more sensitive to the electronic effects of electron-withdrawing substituents,

which are expected to accelerate the oxidative addition step. It is likely that

the two reactions involve similar transition states.

0

1020

3040

50

6070

8090

100

0 60 120 180 240 300

Time/ min

Con

vers

ion/

%

y = 0.0419xR2 = 0.9885

0

1

2

3

0 20 40 60 80Time/ min

XA/(1

-XA

)

0

1020

3040

50

6070

8090

100

0 60 120 180 240 300

Time/ min

Con

vers

ion/

%

y = 0.0419xR2 = 0.9885

0

1

2

3

0 20 40 60 80Time/ min

XA/(1

-XA

)

Figure 6. Suzuki coupling of PhB(OH)2 with 4-bromobenzotriflouride using a

mixed Cu/Pd nanocluster catalyst. Inset shows the fit of the initial reaction

rate to a second-order rate equation. Reaction conditions are as in figure 4.

In principle, this similarity can also result from partial dissolution of the

clusters in the reaction medium.43,44 Metal atoms could ‘leach out’ from the

cluster and initiate a homogeneous catalytic cycle. We cannot disprove this

hypothesis, but it seems to us less likely, especially considering the catalysis

by copper nanoclusters. If atom leaching was the cause of the activity, we

would expect Cu(0) complexes to be good cross-coupling catalysts.


49

p

y = 1.48x + 1.04R2 = 0.95

0

0.5

1

1.5

2

2.5

3

-0.4 -0.2 0 0.2 0.4 0.6 0.8 1

1 +

Log(

K X/K

H)

OCH3

F

CF3

CN

NO2

Ac

Me

CF3

H

p

y = 1.48x + 1.04R2 = 0.95

0

0.5

1

1.5

2

2.5

3

-0.4 -0.2 0 0.2 0.4 0.6 0.8 1

1 +

Log(

K X/K

H)

OCH3

F

CF3

CN

NO2

Ac

Me

CF3

H

Figure 7. Plot of the relative rate constants vs p (Hammett plot); ( ) results

for cluster catalysts; ( ) results reported for Palladacycle catalyst in ref. 42.

Conclusion

In the case of the Suzuki reaction, Cu nanoclusters are good catalysts, unlike

Cu complexes or micrometric Cu particles. Furthermore, mixing two or more

metal precursors can lead in this case to synergistic effects. The activity and

stability of such clusters is strongly dependent on the reaction conditions and

particularly on the stabilising shell. We anticipate that metal(0) nanclusters

could have a high impact in catalysis of carbon-carbon coupling reactions, and

may provide new possibilities that are normally inaccessible using

conventional homogeneous and heterogeneous catalysts.

Experimental Section

Materials and instrumentation

1H and 13C NMR spectra were recorded in deuterated DMF on a Varian Inova

instrument generating at 500 MHz for 1H and 125 MHz for 13C NMR. GC


50

analysis was performed using an Interscience Trace GC-8000 gas

chromatograph with a 100% dimethylpolysiloxane capillary column (DB-1, 30

m 0.325 mm). GC/MS analysis was performed using a Hewlett-Packard

5890/5971 GC/MS equipped with a ZB-5 (zebron) column (15 m 0.25 mm).

All products are known compounds and were identified by comparison of their

spectral properties to those of authentic samples. Samples for GC were diluted

with 1 mL DMF and filtered through an alumina plug prior to injection. GC

conditions: isotherm at 105 ºC (1 min); ramp at 20 ºC min 1 to 260 ºC; isotherm

at 260 ºC (5 min). All reactions were carried out under N2 atmosphere in

Schlenk-type glassware that was oven dried prior to reaction. Solutions were

dispensed using a micropipette. Unless noted otherwise, chemicals were

purchased from commercial firms and were used as received. TEM images

were obtained with a JEOL-100 CXII instrument, operated at an accelerating

voltage of 80 kV. At least two images were taken for each sample.

Synthesis of colloids by reduction with NaBH4

Example: Pd colloids. A Schlenk-type vessel equipped with a rubber septum

and a magnetic stirrer was evacuated and refilled with N2. An aqueous

solution of NaBH4 (2.0 mL, 26.0 mM) was added dropwise over 1 h to the

reaction mixture in the vessel containing PdCl2 (0.20 mmol, 34.0 mg), TOAB

(0.30 mmol, 164.0 mg) and toluene (50 mL) at 20 ºC. The mixture was stirred

further for 2 h after which the toluene layer was separated and used directly

in the reaction.

Preparation of terta-n-octylammonium formate (TOAF)

This is a modification of procedure reported by Maase.45 40 g of ion exchange

resin suspended in a 1.5 M NaOH solution were charged to a column that was

subsequently flushed with 3 L of 1.5 M NaOH. A slight N2 overpressure was

applied. The elute was tested for Cl– using AgNO3. The colour of the resin

changed from yellow (Cl– form) to orange (OH– form). The column was then


51

flushed with 3 L of distilled water followed by 500 mL of 0.2 M formic acid

solution (without using N2 overpressure), 3 L distilled water and finally 1 L

MeOH to switch to an organic medium. The resin was left to swell for 1 h and

the column was subsequently flushed with an 18 mM solution of tetra-n-

octylammonium bromide (TOAB) in MeOH, until the elute tested positive for

Br– using AgNO3. The MeOH was evaporated on a rotavapor and the crude

TOAF (light oil) was dried for 24 h under vacuum.

Synthesis of colloid catalysts 1–15 using TOAF

Example: Cu/Pd 5. A Schlenk-type vessel equipped with a rubber septum and

a magnetic stirrer was evacuated and refilled with N2. The vessel was charged

with CuCl and PdCl2 solutions in DMF (3 mL of each, 3.33 mM) using a

syringe. 0.5 mL of a 0.2 M TOAF solution in DMF was added in one portion to

the solution at 65 ºC, and the mixture was stirred for 24 h under a slight

overpressure of N2. The color of the mixture changed from reddish brown to

black. The resulting colloidal suspension (particle size ~ 2.5 nm) was then

stored under N2 and was used as a stock solution in the cross-coupling

reactions. The other catalysts were prepared in a similar manner using stock

solutions of the corresponding metal chlorides as starting materials.

Transmission electron microscopy (TEM) analysis

TEM was used to determine the particle size and the morphology after the

synthesis. Samples were prepared by placing 150 µL of 1 mM Pd cluster

suspension or the reaction mixture on carbon-coated copper grids. These were

then placed in vaccum oven at 50 ºC at 250 mm of Hg to evaporate the solvent.

The clusters size distribution was determined by counting the size of

approximately 130 Cu/Pd clusters from TEM images obtained from different

places on the TEM grids.


52

Cross-coupling of aryl halides with phenylboronic acid

Sets of five reactions were performed in parallel, and in order to minimise

errors and to test the reproducibility of the results, one reaction from each set

was duplicated in the next set.

Example (1): 4-Nitrobiphenyl. A Schlenk-type glass vessel equipped with a

rubber septum and a magnetic stirrer was evacuated and refilled with N2. The

vessel was then charged with a Cu/Pd 5 colloidal suspension prepared in DMF

(10.0 mL, 10.0 mM, 2.0 mol%), phenylboronic acid (0.914 g, 7.5 mmol), and

K2CO3 (2.07 g, 15.0 mmol). 4-bromonitrobenzene (1.01 g, 5.0 mmol) was added

and the mixture was stirred at 110 ºC for 4 h under a slight overpressure of

N2. Reaction progress was monitored by GC and GC/MS. After 4 h the

reaction mixture was poured into a separatory funnel, diluted with water (20

mL) and extracted with dichloromethane (2 20 mL). The organic layers were

washed with 1M aqueous NaOH (20 mL), dried over anhydrous MgSO4 and

concentrated under vaccum at 40 ºC to yield a yellow solid (1.0 g, >99% yield

based on 4-bromonitrobenzene). The crude product was recrystallised from hot

ethanol to give light-yellow needles (0.955 g, 95.5% based on 4-

bromonitrobenzene), mp 106 ºC (lit., 103–104 ºC 15). H 8.371 (d, 2H, J = 8.7

Hz), 8.034 (d, 2H, J = 5.5 Hz), 7.854 (d, 2H, J = 7.5 Hz), 7.549 (t, 3H, J = 7.2

and 7.5 Hz); C 147.48, 147.43, 138.69, 129.57, 129.37, 128.30, 127.72, 124.417.

Good agreement was found with literature values.15

Example (2): 4-Phenyl toluene. Reaction and work-up were performed as

above, but using 4-bromotoluene (1.026 g, 6 mmol), to give 0.865 g (84.3%) of

product. The crude material was recrystallised from hot ethanol to give a

white solid, mp = 46 ºC (lit., 49-50 ºC46). H 7.688 (d, 2H, J = 8.4 Hz), 7.602 (d,

2H, J = 8.1 Hz), 7.478 (t, 2H, J = 7.8 Hz), 7.365 (t, 1H, J = 7.248 Hz), 7.309 (d,

2H, J = 8.1 Hz), 2.376 (s, 3H); C 141.0, 138.1, 137.3, 129.8, 129.1, 127.4, 126.9,

126.7, 20.5. Good agreement was found with literature values.46


53

Experimental Procedure for kinetic Studies

Conditions and apparatus were similar to the cross-coupling procedure given

above. The typical second-order rate constants observed for coupling of

unsubstituted and various substituted bromobenzene with phenyl boronic acid

were i) bromobenzene ( kobs= 9.70 10 3 M–1min 1, r2 = 0.980 for 5

observations), ii) 4-bromoanisole (kobs= 7.50 10 3 M–1min 1, r2 = 0.991 for 5

observations), iii) 4-bromo fluorobenzene (kobs= 1.18 10 2 M–1min 1, r2 =

0.992 for 5 observations), iv) 4-bromo nitrobenzene (kobs= 2.60 10 1 M–

1min 1, r2 = 0.981 for 5 observations), v) 4-bromobenzonitrile (kobs= 1.04 10 1

M–1min 1, r2 = 0.966 for 5 observations), vi) 4-bromobenzotrifluoride (kobs= 4.19

10 2 M–1min 1, r2 = 0.988 for 5 observations).

Supporting information

Reaction profiles and kinetic analysis. The reaction profiles obtained for the

monometallic, bimetallic, trimetallic and tetrametallic are shown in figures S1

– S2.

0

10

20

30

40

50

60

70

80

90

100

0 60 120 180 240 300 360 420

Time/ min

PhI

con

vers

ion/

%

22repeat

1

4

30

10

20

30

40

50

60

70

80

90

100

0 60 120 180 240 300

Time/ min

PhI

con

vers

ion/

%

12

11

14

13

0

10

20

30

40

50

60

70

80

90

100

0 60 120 180 240 300 360 420

Time/ min

PhI

con

vers

ion/

%

22repeat

1

4

30

10

20

30

40

50

60

70

80

90

100

0 60 120 180 240 300

Time/ min

PhI

con

vers

ion/

%

12

11

14

13

0

10

20

30

40

50

60

70

80

90

100

0 60 120 180 240 300

Time/ min

PhI

con

vers

ion/

%

12

11

14

13

Figure S1. Suzuki coupling of phenylboronic acid with iodobenzene (PhI)

using monometallic (left) and bimetallic clusters (right) as catalysts. Reaction

conditions are same as figure 5.


54

0

10

20

30

40

50

60

70

80

90

100

0 60 120 180 240 300 360 420

Time/ min

PhI

con

vers

ion

0

10

20

30

40

50

60

70

80

90

100

0 60 120 180 240 300 360 420

Time/ min

PhI c

onve

rsio

n/ %

5

8

9

6 7 10

15

0

10

20

30

40

50

60

70

80

90

100

0 60 120 180 240 300 360 420

Time/ min

PhI

con

vers

ion

0

10

20

30

40

50

60

70

80

90

100

0 60 120 180 240 300 360 420

Time/ min

PhI c

onve

rsio

n/ %

5

8

9

6 7 10

15

0

10

20

30

40

50

60

70

80

90

100

0 60 120 180 240 300 360 420

Time/ min

PhI c

onve

rsio

n/ %

5

8

9

6 7 100

10

20

30

40

50

60

70

80

90

100

0 60 120 180 240 300 360 420

Time/ min

PhI c

onve

rsio

n/ %

5

8

9

6 7 10

15

Figure S2. Suzuki coupling of phenylboronic acid with iodobenzene (PhI)

using trimetallic (left) and tetrametallic clusters (right) as catalysts. Reaction

conditions are same as figure 5.

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(15) Wolfe, J. P.; Buchwald, S. L. Angew. Chem. Int. Ed. 1999, 38, 2413.

(16) Zim, D.; Lando, V. R.; Dupont, J.; Monteiro, A. L. Org. Lett. 2001, 3, 3049.


(18) Mukhopadhyay, S.; Rothenberg, G.; Gitis, D.; Sasson, Y. J. Org. Chem. 2000, 65, 3107.


55

(19) Meitzner, G.; Via, G. H.; Lytle, F. W.; Sinfelt, J. H. J. Chem. Phys. 1983, 78, 882.

(20) Sinfelt, J. H. Acc. Chem. Res. 1987, 20, 134.

(21) Toshima, N.; Lu, P. Chem. Lett. 1996, 729.

(22) Toshima, N.; Shiraishi, Y.; Shiotsuki, A.; Ikenaga, D.; Wang, Y. Eur. Phys. J. D 2001,16, 209.

(23) Wang, Y.; Liu, H. F.; Toshima, N. J. Phys. Chem. 1996, 100, 19533.

(24) Schmid, G.; Lehnert, A.; Malm, J. O.; Bovin, J. O. Angew. Chem. Int. Ed. 1991, 30,874.

(25) Bradley, J. S.; Hill, E.; Leonowicz, M. E.; Witzke, H. J. Mol. Catal. 1987, 41, 59.

(26) Bönnemann, H.; Brijoux, W.; Brinkmann, R.; Dinjus, E.; Joussen, T.; Korall, B. Angew. Chem. 1991, 103, 1344.

(27) Bönnemann, H.; Brijoux, W. Nanostruct. Mater. 1995, 5, 135.

(28) Moiseev, I. I.; Stromnova, T. A.; Vargaftik, M. N. J. Mol. Catal. 1994, 86, 71.

(29) Schmid, G.; Maihack, V.; Lantermann, F.; Peschel, S. J. Chem. Soc., Dalton Trans.1996, 589.

(30) Alphonse, F. A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Synlett 2002,447.

(31) Boland, G. M.; Donnelly, D. M. X.; Finet, J.-P.; Rea, M. D. J. Chem. Soc., Perkin Trans. 1 1996, 2591.

(32) Savarin, C.; Liebeskind, L. S. Org. Lett. 2001, 3, 2149.

(33) Liu, X. X.; Deng, M. Z. Chem. Commun. 2002, 622.

(34) Kiyomori, A.; Marcoux, J. F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657.



(37) Godbert, S. In Design and Analysis in Chemical Research; Tranter, R. L., Ed.; Sheffield Academic Press: Sheffield, 2000, p 188

(38) Ullmann, F. Ber. dtch. chem. Ges. 1903, 36, 2389.

(39) Lehmler, H. J.; Robertson, L. W. Chemosphere 2001, 45, 1119.

(40) Lehmler, H.-J.; Brock, C. P.; Patrick, B.; Robertson, L. W. PCBs; The University Press of Kentucky, 2001.

(41) MorenoManas, M.; Perez, M.; Pleixats, R. J. Org. Chem. 1996, 61, 2346.

(42) Weissman, H.; Milstein, D. Chem. Commun. 1999, 1901.


(44) de Vries, A. H. M.; Parlevliet, F. J.; Schmieder-van de Vondervoort, L.; Mommers, J. H. M.; Henderickx, H. J. W.; Walet, M. A. M.; de Vries, J. G. Adv. Synth. Catal. 2002,344, 996.

(45) M.Maase Ph.D. Thesis, verlag Mainz, Aachen, 1999.

(46) Leadbeater, N. E.; Resouly, S. M. Tetrahedron 1999, 55, 11889.


56

Chapter 3 Palladium-free and ligand-free Sonogashira cross-coupling

57


Palladium-free and ligand-free Sonogashira cross-coupling ***

Abstract

Copper nanoclusters catalyse the cross-coupling of alkynes and aryl halides to give

the corresponding disubstituted alkynes. No palladium, ligand, or co-catalyst is

needed, and products are isolated in good isolated yields (80–85%) and high

selectivity. The clusters are simple to prepare, stable and can be applied to a variety

of iodo- and bromoaryls. Mechanistic pathways for homocoupling and cross-coupling

of alkynes are examined by comparing the activity of different catalyst and co-

catalyst combinations. The copper clusters show different catalytic properties than

their homogeneous analogues.

* Part of this work has been published: M. B. Thathagar, J. Beckers and G. Rothenberg, Green

Chem., 2004, 6, 215.

RX

N++N

N+

R Ph PhPh

Ph + 5 mol% Cu clustersDMF, Bu4NOAc, 110 oC

+

X = I, Br

R = H, Me, Perflouro, CF3, NO2, OMe, CN


58

Introduction

The ever-growing search for new drugs and polymers is bringing alkyne

chemistry forward. In the fine-chemical industry, C–C triple bonds are sought

because they can be easily functionalised using multiple addition reactions. In

materials science, polyalkyne derivatives are used to make organic LEDs,1

new carbon allotropes and carbon-rich materials.2

The key reaction here is the formation of an alkyne-carbon bond, i.e. the

attachment of an alkyl or aryl group onto the triple bond without destroying

it. In 1963, Stephens and Castro3 demonstrated the coupling of aryl halides

with alkynylcopper(I) species to obtain arylacetylenes (eq 1). Since then, much

effort was directed to elucidate the mechanism of the Stephens-Castro

reaction, and to develop synthetic protocols that would not require

stoichiometric copper.4 Sonogashira and co-workers found that combining

catalytic amounts of Pd(PPh3)4 and CuI enabled the same coupling without

the need for stoichiometric copper or for isolating the alkynylcopper(I)

intermediate.5 Many variations of this reaction have since been reported6-10

including palladium-catalysed copper-free versions11-16 and, notably,

palladium-free versions.17-22 This seems already like an optimal solution, but

for large-scale synthesis the phosphine ligands themselves are a problem.

They are usually unrecoverable and can complicate further synthetic steps. In

fact, the ligand problem is one reason why homogeneous catalysis, so popular

in the lab, is often shunned by the fine-chemical industry.23

However, while ligands are ubiquitous in homogeneous catalysis, ligand-metal

complexes are not always the only active catalytic species. This is especially

true in the case of C–C coupling reactions, where catalysis by metal

nanoclusters (2–10 nm in diameter) is often observed.24-28 These clusters often

exhibit unique catalytic properties due to their high surface area and the

ArX + CuC C R C RArCpyridine, reflux (1)


59

possibility of charge distribution in electron transfer reactions.29 In chapter 2,

we showed that Cu nanoclusters can catalysed Suzuki cross-coupling

reaction,30,31 this prompted us to explore these clusters in Sonogashira

reaction. In this chapter, we present the first palladium-free and ligand-free

Sonogashira cross-coupling, using stable copper nanoclusters as catalysts.


The metal clusters (Cu, Cu/Pd and Pd) were prepared by reducing solutions of

the chloride salt precursors with tetraoctylammonium formate (TOAF) in

DMF at 65 ºC.31,32 TOAF also acts simultaneously as a stabiliser, forming an

organic corona around the clusters that prevents their aggregation. The

clusters were used as is in the coupling of phenylacetylene 1 with various aryl

halides (eq 2). In a typical reaction, 1.5 equiv of 1 and one equiv of aryl halide

2 were mixed in the presence of 1.5 equiv base and 0.05 equiv of metal clusters

at 110 ºC. Reaction progress was monitored by GC. After 24 h, the clusters

were separated and the substituted diphenylalkyne 3 was isolated and

analysed by GC/MS and 1H NMR.

RX

N++N

N+

R Ph PhPh

Ph + 5 mol% Cu clustersDMF, Bu4NOAc, 110 oC

1 2+

3 4

(2)

X = I, Br

R = H, Me, Perflouro, CF3, NO2, OMe, CN

Cu-catalysed Sonogashira coupling of various aryl halides

Table 1 shows the conversion and yield obtained for various aryl iodides and

bromides in the presence of 5 mol% Cu clusters. Iodoarenes gave quantitative

yields, while bromoarenes gave good to moderate yields. Control experiments

confirmed that no conversion occurs without Cu clusters. The cross-coupling


60

product accounted for 100% of the haloarene (the limiting reagent). In some

cases, the excess phenylacetylene reacted to give 10–15% of the homocoupling

(Hay coupling33) product 4, as well as small amounts (2–4%) of a heavy (not

identified) product.

Table 1. Cross-coupling of aryl halides with 1 using Cu nanoclusters.a

Entry Substrate Conversion /%b Yield /%b

1 H I 100 82c

2 H3C I 100 84c

3 F I

FF

F F

100 >99

4 F3C I 100 >99

5 O2N I 100 94c

6 IH3CO 100 >99

7 IHO 100 >99

8 IH3COC 100 88c

9 BrF3C 55 53

10 BrO2N 100 >99

11 BrNC 92 91

12 H3C Br 20d 20

13 BrH3CO 16d 16

a Reaction conditions: 0.25 mmol substrate, 0.38 mmol 1, 0.40 mmol TBAA,

0.012 mmol copper nanoclusters, 2.5 mL DMF, N2 atmosphere, 110 ºC, 24 h

(time was not optimised). b Conversion of 2 and yield of 3, respectively, based

on GC, corrected for the presence of an internal standard. c Isolated yield. d 10

mol% of Cu clusters was used.


61

Copper clusters performed better than their homogeneous analogues, not only

with iodoarenes but also with the activated bromoarene substrates p-Br-C6H4-

CN and p-Br-C6H4-CF3 (92% and 55% conversion with Cu clusters, cf. with

<25% reported18 for CuI/PPh3 and no reaction observed using Cu 1,10-

Phenanthroline complexes19). However, attempts to perform the cross-coupling

of phenylacetylene with electron rich bromoarenes using 10 mol% Cu clusters

gave only modest yields (15–20%), and no conversion was observed also for

triisopropylsilyl acetylene with iodoarenes (in the latter case, large aggregates

formed within 15 min). To check whether triisopropylsilyl acetylene interacts

with the clusters and destabilises them, we stirred triisopropylsilyl acetylene,

tetra-n-butylammonium acetate (TBAA) and Cu clusters at 110 ºC. No

aggregation was observed even after 24 h.

Sonogashira coupling under various conditions

The facile cross-coupling and the product specificity in the presence of copper

clusters raise some interesting questions regarding similarities and

differences between the coupling mechanisms using copper and palladium,

and regarding the role of cuprous iodide. To try and answer these questions,

we performed a series of cross-coupling experiments between phenylacetylene

and iodotoluene, using various nanocluster/co-catalyst combinations (Table 2).

Palladium clusters were active in the Sonogashira cross-coupling (Table 2,

entry 10), but they aggregated as Pd black at the end of the reaction. The

copper clusters, on the other hand, remained stable – no aggregation was

observed – and could be re-used. Adding CuI did not improve the performance

of either cluster catalyst (entries 6, 11). Moreover, CuI as sole catalyst gave

only 18% conversion after 24 h (entry 3). Bimetallic Cu/Pd and mixed 34

clusters gave nearly the same conversions and were both less active than pure


62

Pd clusters.† The presence and type of base proved crucial to the reaction. No

reaction occurred in absence of base, and only ~25% conversion was observed

when TBAA was substituted with Et3N or with Na(OAc)2 (entries 8,9). Tetra-

n-butylammonium fluoride gave good conversion but was not as effective as

TBAA.

Table 2. Cross-coupling of 1 with 4-iodotoluene.a

Entry Catalyst /mol% Base Time /h Conversion /%b

1 none TBAA 24 0

2 Cu /5 none 24 0

3 CuI /5 TBAA 24 18

4 CuI + TOAB /5+5 TBAA 24 20

5 Cu /5 TBAA 8 90

6 Cu+CuI /5+5 TBAA 8 72

7 Cu /5 TBAF 24 75

8 Cu /5 Et3N 24 25

9 Cu /5 Na(OAc)2 24 22

10 Pd /2 TBAA 2 100

11 Pd+CuI /2+5 TBAA 2 100

12 Pd+Cu /2+5c TBAA 2 86

13 {CuPd} /2d TBAA 2 92

a Reaction conditions: 0.25 mmol 4-Iodotoluene, 0.38 mmol 1, 0.40 mmol tetra-

n-butylammonium acetate (TBAA), 2.5 mL DMF, N2 atmosphere, 110 ºC. b GC

conversion of the 4-Iodotoluene, corrected for the presence of an internal

standard. c A mixture of Cu clusters (5 mol%) + Pd clusters (2 mol%). d Pre-

prepared bimetallic {Cu/Pd} clusters (2 mol%).

One important question is: Do the tetraoctylammonium cations ligate to Cu(I)

that could possibly leach out from the clusters, pairing with iodide that

originates in the iodoarene? If this is so, the clusters would be merely ‘copper † Cf. the synergistic effect observed in the case of Suzuki cross-coupling (ref. 24).


63

reservoirs’ rather than catalysts. This possibility, however, was ruled out by

control experiments using CuI and CuI + tetraoctylammonium bromide

(TOAB) (Table 2, entries 3 and 4). Both experiments gave only ~20%

conversion, showing that the tetraoctylammonium cations are not good

ligands for cuprous ions as far as Sonogashira cross-coupling is concerned. We

used TOAB in these tests instead of TOAF, because TOAF can reduce cuprous

ions to form clusters, which would void the results.

The Hay coupling of phenylacetylene 2 to diphenyldiacetylene 4 requires the

presence of oxygen.33,35 10–15% homocoupling was observed under a dry N2

atmosphere, indicating that oxygen was still present in the system. We

managed to prevent the homocoupling entirely by degassing the solvent and

the stock suspension of the copper nanoclusters with dry N2 for 1 h prior to

reaction. In theory copper can oxidise to form copper oxide clusters, but in our

case it is highly unlikely as all syntheses and reactions were performed under

nitrogen. Moreover, Okuro et al.18 showed that copper oxide catalysts are

ineffective in Sonogashira coupling.

We also tested the reusability of the Cu clusters in the coupling of 1 with p-I-

C6H4-CF3. In each re-run, we added another equivalent of reactants and base.

The clusters could be used three times without deactivation, giving a final

TON of 73.

Proposed mechanism

The above experiments shed some light on the cross-coupling mechanism with

copper nanoclusters. Although we do not have a detailed mechanistic picture

yet, the mechanism is certainly different from that proposed by Okuro et al.

for CuI + phosphine ligands18 and also from that involving both copper and

palladium.34 We suggest that phenylacetylene co-ordinates to the copper

cluster, forming an {alkenyl–Cu cluster} species. This then reacts with the aryl

halide, after which the product is removed and HX eliminates from the cluster


64

in the presence of a base (Scheme 1). One important difference between

clusters and monoatomic complexes is that the positive charge created in the

oxidative addition can be shared among the copper atoms in the cluster. This

may facilitate the product formation and the reductive elimination steps.

Further studies on this mechanism and on the catalyst deactivation process

will be done in our laboratory.

Ph

Ph

R

X

PhR

X

R

PhX H

Base

BHX

H

H

Scheme 1. Suggested cycle for cluster-catalysed Sonogashira cross-coupling

(the stabilising tetraoctylammonium ions are omitted for clarity).

Conclusion

In summary, we have developed a protocol for the cross-coupling of aryl

iodides and activated bromides with phenylacetylene using 5 mol% Cu

nanoclusters as the catalyst, 1.5 equivalents of TBAA as the base in DMF.

This method tolerates a wide-variety of functional groups including electron-

withdrawing and electron-donating groups. The lower price of copper

compared to palladium, plus the fact that no phosphine ligands are needed,

make this an interesting catalytic alternative for the synthesis of substituted

carbon-carbon triple bonds.


65

Experimental


1H NMR spectra were recorded in CD2Cl2 on a 300 MHz Varian Inova

instrument. Chemical shift values are in ppm relative to Me4Si. Melting points

were measured on a Gallenkamp melting point apparatus and are

uncorrected. GC analysis was performed using an Interscience GC-8000 gas





spectral properties to those of authentic samples. Samples for GC were added

in equivalent amount of water, extracted with hexanes and filtered through an

alumina plug prior to injection. GC conditions: isotherm at 105 ºC (2 min);

ramp at 30 ºC min 1 to 280 ºC; isotherm at 280 ºC (5 min). All reactions were

carried out under N2 atmosphere. Unless noted otherwise, chemicals were

purchased from commercial firms and were used as received. The nanoclusters

were synthesised according to a procedure described in previous chapter.31 In

all cases, the metal core diameter was between 1.6 and 2.5 nm, with a

distribution of ±0.1 nm.

Parallel screening of catalysts and substrates

Sets of 16 reactions were performed using a Chemspeed Smartstart 16-reactor

block, modified in-house for efficient reflux and shaking/stirring. The reactors

were charged with a cluster suspension prepared in DMF (1.25 mL, 10.0 mM,

5.0 mol%), phenylacetylene 2 (0.50 ml, 745 mM, 0.38 mmol), tetra-n-

butylammonium acetate (TBAA) (1.0 mL, 400 mM, 0.40 mmol) and aryl halide

2 (0.50 mL, 495 mM, 0.25 mmol). Glass beads were added in each reactor and

the reactors were placed on an electronic shaker. The reactors were evacuated

and refilled with N2 three times and the mixture was shaken at 110 ºC for 24


66

h under a slight N2 overpressure. Reaction progress was monitored by GC

(pentadecane internal standard).

Copper-catalysed Sonogashira cross-coupling

Example (1): 4-Nitrodiphenylethyne. The Cu cluster suspension and DMF

were degassed before use. A Schlenk-type glass vessel equipped with a rubber

septum and a magnetic stirrer was evacuated and refilled with N2. The vessel

was then charged with a Cu cluster suspension prepared in DMF (12.0 mL,

10.0 mM, 5.0 mol%), phenylacetylene (0.35 g, 3.40 mmol), TBAA (1.02 g, 3.40

mmol) and 12 mL of DMF. 4-Iodonitrobenzene (0.56 g, 2.25 mmol) was added

and the mixture was stirred at 110 ºC for 6 h under a slight overpressure of

N2. Reaction progress was monitored by GC and GC/MS. After 6 h the reaction

mixture was poured into a separatory funnel, diluted with water (20 mL) and

extracted with hexanes (3 15 mL). The organic layers were combined and

dried over anhydrous MgSO4 and concentrated under vacuum at 25 ºC to yield

0.53 g of yellow product (94 % yield based on 4-iodonitrobenzene). The crude

material was recrystallised from hot ethanol to give a light yellow solid, mp =

112–114 ºC (lit.35 114–116 ºC). 1H NMR H 7.416 (d, 3H J = 8.7 Hz), 7.592 (m,

2H), 7.717 (d, 2H, J = 8.7 Hz), 8.22 (d, 2H, J = 8.7 Hz). Good agreement was

found with literature values.35

Example (2): 4-Acetyldiphenylethyne. Reaction and work-up were

performed as above, but using 4-iodoacetophenone (0.55 g, 2.25 mmol) to give

0.48 g of product (88 % yield based on 4-iodoacetophenone). The crude

material was recrystallised from hot ethanol to give a cream coloured needles,

mp = 95–97 ºC (lit.35 96–98 ºC). 1H NMR H 7.406 (m, 3H), 7.593 (m, 4H), 7.956

(d, 2H, J = 8.6 Hz), 2.604 (s, 3H). Good agreement was found with literature

values.35

Example (3): Diphenylethyne. Reaction and work-up were performed as

above, but using 4-iodobezene (0.45 g, 2.25 mmol) to give 0.37 g of product (82

% yield based on 4-iodobenzene). The crude material was recrystallised from


67

hot ethanol to give a white needles, mp = 57–58 ºC (lit.19 59 ºC). 1H NMR H

7.34 (m, 6H), 7.52 (m, 4H). Good agreement was found with literature

values.19

Example (4): 4-methyldiphenylethyne. Reaction and work-up were

performed as above, but using 4-iodotoluene (0.49 g, 2.25 mmol) to give 0.41 g

of product (84 % yield based on 4-iodotoluene). The crude material was

recrystallised from hot ethanol to give a cream coloured solid, mp = 72–73 ºC

(lit.19 71 ºC). 1H NMR H 7.15 (m, 2H), 7.35 (m, 3H), 7.42 (d, 2H, J = 8.3 Hz),

7.55 (m, 2H), 2.38 (s, 3H). Good agreement was found with literature values.19

Catalyst reusability

The reaction set-up and the pre-reaction procedure were similar to that used

in Sonogashira cross-coupling on preparative scale. The vessel was then

charged with a Cu cluster suspension prepared in DMF (2.5 mL, 10.0 mM, 5.0

mol%), phenylacetylene (0.07 g, 0.75 mmol), TBAA (0.22 g, 0.75 mmol) and 5

mL of DMF. 4-iodobenzotriflouride (0.13 g, 0.5 mmol) was added and the

mixture was stirred at 110 ºC for 24 h under a slight overpressure of N2. After

complete conversion of 4-iodobenzotriflouride the same amount of fresh

reactants were added to the reaction mixture and sample was analysed every

24 h. The procedure was repeated until conversion lower then 100% was

observed. Reaction samples were analysed by GC and GC/MS.

References

(1) Martin, R. E.; Diederich, F. Angew. Chem.Int. Ed. 1999, 38, 1350.

(2) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem. Int. Ed. 2000, 39, 2633.

(3) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 2163.


(5) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.

(6) Mori, Y.; Seki, M. J. Org. Chem. 2003, 68, 1571.

(7) Köllhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem. Int. Ed. 2003, 42, 1056.

(8) Köllhofer, A.; Plenio, H. Chem. Eur. J. 2003, 9, 1416.


68

(9) Erdélyi, M.; Gogoll, A. J. Org. Chem. 2001, 66, 4165.

(10) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729.

(11) Méry, D.; Héuze, K.; Astruc, D. Chem. Commun. 2003, 1934.

(12) Fu, X.; Zhang, S.; Yin, J.; Schumacher, D. P. Tetrahedron Lett. 2002, 43, 6673.

(13) Alonso, D. A.; Nájera, C.; Pacheco, M. C. Tetrahedron Lett. 2002, 43, 9365.

(14) Choudary, B. M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc. 2002, 124, 14127.

(15) Böhm, V. P. W.; Herrmann, W. A. Eur. J. Org. Chem. 2000, 3679.

(16) Leadbeater, N. E.; Tominack, B. J. Tetrahedron Lett. 2003, 44, 8653.

(17) Okuro, K.; Furuune, M.; Miura, M.; Nomura, M. Tetrahedron Lett. 1992, 33, 5363.

(18) Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org. Chem. 1993, 58,4716.

(19) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315.

(20) Kang, S. K.; Yoon, S. K.; Kim, Y. M. Org. Lett. 2001, 3, 2697.

(21) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843.



(24) Moreno-Mañas, M.; Pleixats, R. Acc. Chem. Res. 2003, 36, 638.

(25) Narayanan, R.; El-Sayed, M. A. J. Am. Chem. Soc. 2003, 125, 8340.



(28) Beller, M.; Fischer, H.; Kühlein, K.; Reisinger, C. P.; Herrmann, W. A. J. Organomet. Chem. 1996, 520, 257.

(29) Aiken, J. D.; Finke, R. G. J. Mol. Cat. A-Chem. 1999, 145, 1.




(33) Hay, A. S. J. Org. Chem. 1962, 27, 3320.

(34) Cai, C. Z.; Vasella, A. Helv. Chim. Acta 1995, 78, 2053.

(35) Elangovan, A.; Wang, Y. H.; Ho, T. I. Org. Lett. 2003, 5, 1841.

Chapter 4 Cluster catalysed microwave-assisted cross-coupling reactions

69


Nanocluster-based cross-coupling catalysts: A high-

throughput approach*

Abstract

Microwave irradiation is used to create ‘hot spots’ on metal clusters in solution,

facilitating catalytic cycles in which these clusters participate. An 8×12 parallel

screening system is built based on this concept, and tested using the Heck reaction as

a case study. The spatial reproducibility of this system is examined and the pros and

cons of using monomode and multimode setups are discussed.

* Part of this work has been published: M. B. Thathagar, J. Beckers and G. Rothenberg, Chemical Industries (CRC press), 24, Catal. Org. React., 2005, 104, 211.

A CuB Pd

F Pd in situG Pd/PVP

E TOAB

H Pd/(PPh3)3

D RuC Cu/Pd

010 20 30 40 50 60 70 80 90 100

1 2 3 4 5 6 7 8 9 121110

1 2 3 4 5 6 7 8 109 11 12

I

CH3

I

NO2

I

OCH3

I

H

Br

CF3

Br

CN

Br

NO2

Br

CH3

Br

OCH3

Br

F

Cl

CN

Cl

NO2

A CuB Pd


E TOAB

H Pd/(PPh3)3

D RuC Cu/Pd

A CuB Pd


E TOAB

H Pd/(PPh3)3

D RuC Cu/Pd

010 20 30 40 50 60 70 80 90 100

1 2 3 4 5 6 7 8 9 121110

010 20 30 40 50 60 70 80 90 100

010 20 30 40 50 60 70 80 90 100

1 2 3 4 5 6 7 8 9 1211101 2 3 4 5 6 7 8 9 121110

1 2 3 4 5 6 7 8 109 11 121 2 3 4 5 6 7 8 109 11 12

I

CH3

I

NO2

I

OCH3

I

H

Br

CF3

Br

CN

Br

NO2

Br

CH3

Br

OCH3

Br

F

Cl

CN

Cl

NO2


70

Introduction

Carbon-carbon coupling reactions are very useful in organic synthesis.1

Petrochemistry gives us simple olefins and aromatics, and these can be

coupled to construct a variety of agrochemical and pharmaceutical

intermediates. Metal clusters feature in many C–C coupling mechanisms, e.g.

in the Heck, Suzuki, and Ullmann-type reactions.2 Whether clusters are the

actual catalysts for these reactions or not remains a hot scientific debate,3 but

it is certain that clusters participate in the catalytic cycle.4 Our interest in

these clusters is two-fold: First, if the clusters are indeed the catalysts, then

ligand-free applications may be envisaged.5 Second, combining different

metals may result in synergistic effects, as we demonstrated for Suzuki cross-

coupling.6,7

The activity of metal clusters in cross-coupling reactions led us to think that

selective heating of the catalytic sites may be possible. If catalysis occurs on

the clusters’ surface, this could give higher substrate conversion and/or better

product selectivity. The clusters are small pieces of metal, so they could be

selectively heated in solution using microwave (m/w) irradiation. There have

been several reports of so-called ‘non-thermal microwave effects’ in organic

reactions.8,9 However, Strauss and co-workers showed that microwaves merely

create ‘hot spots’ in the solution.10,11 In any case, using microwaves is a

versatile and efficient heating technique,12 and we reasoned that the metal

clusters could serve as focal points for these hot spots, resulting in a ‘hot

catalyst’ and a favourable reaction environment.13 Another incentive is the

possiblity of parallel screening, which is a must if one wants to investigate

many cluster catalysts.

In this chapter, we present pros and cons of using household microwave for

rough high throughput screening and activation of nanocluster catalysts,

using the Heck reaction as a case study.


71

Theory of Microwave

Microwaves are electromagnetic radiations that fall at the lower frequency

end of the electromagnetic spectrum with wavelengths ranging from 1 cm to 1

m (0.3-300 GHz). Within this region of electromagnetic energy, only molecular

rotation is affected, not molecular structure. A frequency of 2.45 GHz is the

preferred frequency for industrial, scientific and medical applications because

it has the right penetration depth to interact with the materials.10,11

Microwave irradiation does not affect the activation energy, but provides

momentum to overcome this barrier and complete the reaction more quickly

than conventional heating methods. Chemical reactions driven by

conventional heating are more likely to perform under kinetic control. These

reactions usually require only mild conditions. Alternatively,

thermodynamically controlled reactions have higher activation energy and

require harsh conditions to complete. In microwave driven reactions, the

molecules are provided powerful instantaneous energy, which allows them

reach higher activation energy levels and leads to the thermodynamic product.

Heat transfer advantages of applying microwave power, a non contact energy

source, into the bulk of a material include: faster energy absorption, reduced

thermal gradients, selective heating, and virtually unlimited final

temperature. For chemical production, the resultant value could include: more

effective heating, fast heating of catalysts, reduced equipment size, faster

response to process heating control, faster start-up, increased production, and

less process steps.


Our first objective was to construct a simple, inexpensive experimental system

for the synthesis and rough-quality parallel screening of nanocluster catalysts.


72

For this, we adapted the 96 well plate format to a conventional m/w oven. The

setup was tested on the Heck cross-coupling of various aryl halides with n-

butylacrylate. Reactions were perfomed in 2 mL glass vials set in a PTFE

matrix and monitored by GC.

Screening of catalysts and substrates in m/w oven

We screened twelve different substrates, 1–12, and eight different catalysts,

A–H (see Figure 1). The nanocluster suspensions A–D were prepared by

reducing stock solutions of their metal chloride precursors using tetra-n-

octylammonium formate (TOAF) in DMF at 65 C. Row E was used as a

control (no metal catalyst). Row G was prepared using NaEt3BH as reducing

agent and poly(N-vinylpyrrolodinone) (PVP) as stabiliser. A homogeneous

palladium complex, Pd(PPh3)3, was placed in row H for comparison.

Substrate reactivity was as expected (ArI > ArBr >> ArCl). In contrast to the

Suzuki cross-coupling, however, Cu and Ru clusters were not active in the

Heck reactions, and the activity of Cu/Pd clusters was lower than that of pure

Pd clusters. Note the higher activity of Pd clusters prepared in situ (row F)

compared to pre-prepared clusters (rows B and G). This increased activity

tallies with our findings for Suzuki cross-coupling 7. After reaction, palladium

black was observed in all the vials in rows B and G, but not in row F.

Control experiments confirmed that DMF solutions containing small amounts

of PVP-stabilised metal clusters are heated much faster under m/w irradiation

than pure DMF or DMP/PVP solutions. Thus, pure DMF and DMF/PVP took 7

min to reach boiling (153 ºC), while a 10 mM soln of PVP-stabilised Pd clusters

in DMF boiled after 2 min (all other parameters were identical, including

reaction vessel position in the oven, vide infra). This observed effect indicates

that metal clusters do get heated faster and more selectively than the other

components present in the reaction mixture. It is possible that the


73

temperature on the surface of metal clusters might be much higher than the

bulk reaction temperature. Therefore it is possible that limited number of

reactant molecules near to the clusters can get excited and react to give

desired products, allowing greater control over the reaction and selectivity.

A CuB Pd


E TOAB

H Pd/(PPh3)3

D RuC Cu/Pd

010 20 30 40 50 60 70 80 90 100

1 2 3 4 5 6 7 8 9 12 11 10

1 2 3 4 5 6 7 8 109 11 12

I

CH3

I

NO 2

I

OCH3

I

H

Br

CF3

Br

CN

Br

NO 2

Br

CH3

Br

OCH3

Br

F

Cl

CN

Cl

NO2

Figure 1. Rectangular 8 12 PTFE matrix containing 96 2 mL glass reaction

vials (left) and the resulting conversions of aryl halides (1–12) using the

catalysts A–H (right). Conditions: 0.062 mmol aryl halide, 0.12 mmol n-

butylacrylate, 0.18 mmol KOAc, catalyst (2 mol% total metal relative to aryl

halide), 0.5 mL DMF, 240 W m/w irradiation for 15 min.

Further, we examined the Heck reaction between n-butyl acrylate and 4-

bromobenzotrifluoride 5 in the presence of 2 mol% Pd clusters in a single-

vessel monomode m/w oven fitted with an infrared thermometer. 100%

conversion with quantitative yield to the cinnamate was obtained after 5 min

irradiation at 75 W/240 ºC. We then repeated the reaction under conventional

heating at 240 ºC. After 3.5 min a black tarry gel formed. Extraction followed

by GC analysis showed only cinnamate, but the tarry material (probably

acrylate polymers/oligomers) could not be analysed. These experiments show

that when clusters are present different results are obtained depending


74

whether m/w heating or conventional heating is used. In principle, this could

be the result of ‘hot spots’ created on the metal clusters.

Spatial reproducibility

We also examined the spatial reproducibility of the parallel 96-vessel matrix.

Two groups of twenty-one reactions were performed simultaneously: the

coupling of n-butylacrylate with iodobenzene using pre-prepared Pd clusters,

and with 4-bromobenzotriflouride using Pd clusters prepared in situ. For easy

distinction, the first group was covered with red septa and the second with

white septa. The vials were arranged to study the influence of the positioning

on the reactor plate, the presence/absence of neighbours, and the type of these

neighbours. Figure 2 shows the arrangement of vials on the matrix and the

results.

0102030405060708090

100

0 5 10 15 20 25

Experiment No./ arbitrary units

Con

vers

ion/

%

0102030405060708090

100

0 5 10 15 20 25

Experiment No./ arbitrary units

Con

vers

ion/

%

Figure 2. Spatial reproducibility tests: Forty-two repeats of the Heck reaction

between iodobenzene and 4-bromobenzotrifluoride. ‘ ’ Symbols are the results

from the red-capped vessels (pre-prepared clusters) and ‘ ’ symbols indicate

white-capped vessels (in situ prepared clusters). Inset photo shows the

arrangement of vials on the matrix.


75

The reproducibility in the ‘white’ group was better than that of the ‘red’ group.

For both reaction sets, rather to our surprise, the vials placed without any

neighbours gave lower conversion, regardless of where they were placed on the

matrix, while vials with many neighbours gave better results. For each

reaction, we can divide the vials into fourteen ‘edge’ vials, four ‘middle’ vials,

and three ‘lonely’ vials. Table 1 shows the mean conversion values and the

standard deviations for the three types of positions.

The high standard deviation values reflect the inhomogeneous heating in the

multimode m/w oven. Nevertheless, the advantages of fast and inexpensive

parallel screening should not be neglected, for it can be used as a rough ‘go/no

go’ indicator. Monomode ovens offer uniform heating, but they are harder to

adapt to parallel experiments. Nevertheless, it might be possible to combine

parallel testing and homogeneous energy distribution via two approaches: one

way is to incorporate in the multimode cavity a rotating metal propeller that

breaks up the standing waves. Alternatively, a monomode cavity can be

constructed that has uniform energy distribution and sufficient space for

multiple reaction vessels. However, this study was out of the scope of thesis.

Table 1. Mean conversion values and the standard deviation for the spatial

reproducibility tests.

Pre-prepared Pd

clusters

In situ prepared Pd

clustersSr.

No.Position

% Mean

conversionStdev

% Mean

conversionStdev

1 ‘edge’ 22.1 10.8 7.1 3.2

2 ‘middle’ 78.5 20.4 23.8 9.7

3 ‘lonely’ 6.0 1.7 0 0


76

Conclusion

Metal nanoclusters in DMF interact strongly with microwaves. In reactions

catalysed by these clusters, the microwave heating may be tantamount to

preferentially heating the catalytic site, which can lead to more effective

catalysis. Such cluster-catalysed reactions can be in principle screened in

parallel in multimode m/w ovens reducing both time and operational costs.

However, the ovens must be adapted so that the parallel reactors are

uniformly heated.

Experimental


A detailed description of the analytics and procedures for the synthesis of

TOAF and catalysts A–D are given in chapter 2.6 Parallel m/w experiments

were performed using a Samsung domestic microwave oven (M1712N, 2.45

GHz source, 800W o/p). Reactions were carried out in 2 mL glass vials sealed

with PTFE septa. The reaction volume was filled not exceeding 1/4th of the

total volume of the vial, thereby allowing headspace for pressure buildup.

Holes were punched in the septa using a 15-gauge needle to prevent the caps

of the vials from blowing. Care was taken to place identical quantity of DMF

in each vial to avoid uneven heating. All reactions were performed without

stirring. In situ preparation of Pd clusters (Figure 1, row F) was performed

according to literature procedures. 2

Pd nanoclusters, sodium triethylborohydride (Na(Et)3BH) method

This is a modification of Bönnemann’s method.14 A Schlenk-type vessel was

evacuated and refilled with N2. The vessel was charged with PVP (0.22 g, 2

mmol) and a PdCl2 solution in DMF (10 mL, 10 mM). 0.3 mL of a 1 M

Na(Et)3BH solution in THF was added in one portion at 25 ºC, and the

mixture was stirred for 2 h under a slight N2 overpressure. The color changed


77

from yellow-orange to black. The suspension was taken as is for the catalysis

studies.

Heck coupling under m/w irradiation

Stock solutions of the reactants were prepared in DMF. Aryl halide (125 L,

495 mM), n-butylacrylate (125 L, 1.0 M), KOAc (base, 3 equiv) and the

nanocluster suspension (125 L, 10 mM) were placed in the reaction vials. The

96 reactor PTFE matrix was then placed in the m/w oven on the turntable

glass plate and irradiated in five-minute bursts at 240 W for 15 min,

separated by 5 min pauses for cooling. The vials were cooled to room

temperature. Pentadecane solution (external standard, 125 L, 234 mM) was

added and the suspension was filtered through a plug of Al2O3 and analysed

by GC.

Heck coupling using conventional heating

4-bromobenzotriflouride (0.5 mL, 495 mM), n-butylacrylate (0.5 mL, 1.0 M),

KOAc (approx. 3 equiv), and nanocluster suspension (0.5 mL, 10 mM) were

sealed in a 5 mL glass tube and heated (240 ºC, 3.5 min) in a water-cooled

oven. Workup and analysis was performed as above.

References

(1) Metal-catalysed cross-coupling reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1997.


(3) Biffis, A.; Zecca, M.; Basato, M. J. Mol. Catal. A: Chem. 2001, 173, 249.

(4) Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68, 5660.

(5) Wall, V. M.; Eisenstadt, A.; Ager, D. J.; Laneman, S. A. Platinum Met. Rev. 1999, 43,138.



(8) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.

(9) Kuhnert, N. Angew. Chem. Int. Ed. 2002, 41, 1863.


78

(10) Strauss, C. R. Angew. Chem. Int. Ed. 2002, 41, 3589.

(11) Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48, 1665.

(12) Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582.

(13) Thomas, J. R. Catal. Lett. 1997, 49, 137.


Chapter 5 Pd clusters in C C coupling reactions: A true catalytic species?

79


Pd clusters in C C coupling reactions: A true catalytic

species?*

Abstract

A long debated question of the actual catalytic species responsible for catalysis in Pd

cluster catalysed cross-coupling reactions is investigated. By combining a detailed

kinetic analysis with transmission electron microscopy in Pd cluster catalysed

Sonogashira reaction, we studied this problem. Based on the results, we present a

possible two-path mechanism for Sonogashira reaction in the presence of Pd

nanoclusters. Moreover, a different approach to this problem has been presented

using a nano-porous membrane as a filter for the Pd clusters catalysed Heck

coupling. The results clearly point to the catalysis by released Pd species from the

cluster surface.

-See supporting information at the end of section A for kinetic analysis, catalysts recycling

experiments and additional TEM results.

* Part of this chapter has been published: M. B. Thathagar, P. J. Kooyman, R. Boerleider, E.

Jansen, C. J. Elsevier, G. Rothenberg, Adv. Synth. Catal., 2005, 347, 1965.

CNBr+

Pd clusters

Bu4NOAc, 50 oC PhPh

or ?leached Pd

Pd catalystCN

19 nm

before reaction after reaction

19 nm

CNBr+

Pd clusters

Bu4NOAc, 50 oC PhPh

or ?leached Pd

Pd catalystCN

19 nm

before reaction

19 nm19 nm


19 nm

after reaction

19 nm19 nm


80

Section A

Introduction

Nanometric palladium clusters can exhibit catalytic activities comparable to

those of traditional Pd complexes in Heck, Suzuki and Sonogashira cross-

coupling.1,2 Several reports discuss the mechanisms for heterogeneous Pd

catalysts,3,4 but little is known about how cluster catalysts work in the liquid

phase.5-7 For palladium on a solid support, the Maitlis’ filtration test8 and ICP

analysis of the filtrate can tell us whether Pd is leaching or not.9 With

nanoclusters, however, testing is difficult due to the small cluster size. El-

Sayed and co-workers10 and Bradley et al.11 studied the cluster size effect in

the Suzuki and Heck reactions, and concluded that the reaction occurs at low

coordination sites of the Pd cluster surface. In previous chapters, we showed

that Pd, Cu, and mixed metal clusters can catalyze the Sonogashira cross-

coupling.12 In this chapter, we try to pinpoint the actual active species in the

catalytic cycle. Does catalysis occur on the cluster surface, or via leaching of

Pd atoms/ions into the solution? The answer to this question will help us in

future to design atom economical and selective cluster catalysts.

To try and answer this fundamental question, we studied the mechanism of

the Sonogashira cross-coupling reaction,13 catalysed by Pd clusters at 50

ºC.14,15 We combined kinetic studies and transmission electron microscopy

(TEM) analysis. The results indicate that a homogeneously catalysed

mechanism is likely.


Pd clusters were synthesized by reduction of Pd(NO3)2 with

tetraoctylammonium glycolate in DMF.16 In a typical reaction (Figure 1, top),

phenylacetylene 1 (1.5 equiv) was mixed with 4-bromobenzontrile 2 (1 equiv),

Pd clusters (0.01 equiv) and tetrabutylammonium acetate (TBAA, 1.5 equiv)


81

as base. Quantitative yields of 1-cyano-4-phenylethynylbenzene 3 were

obtained in 2 h. Diphenyldiacetylene (3–5%) from the homocoupling of excess

1 was also observed.

CNBr+

1 2

R Ph

3

Ph

Pd clusters

Bu4NOAc, 50 oC

or ?leached Pd

Pd catalyst

19 nm


19 nm

CNBr+

1 2

R Ph

3

Ph

Pd clusters

Bu4NOAc, 50 oC

or ?leached Pd

Pd catalyst

19 nm

before reaction

19 nm19 nm


19 nm

after reaction

19 nm19 nm

Figure 1. Sonogashira coupling of phenylacetylene with 4-bromobenzonitrile

using Pd clusters as catalyst and TEM images before (left) and after (right)

the reaction.

Cluster samples were taken for TEM analysis before, during, and after the

reaction (Figure 1, bottom). Prior to reaction one can see separate Pd particles,

of average size of 15 nm diameter. About 20% of the clusters are triangular,

and the rest show an irregular morphology. Surprisingly, the samples taken

during and after the reaction show smaller particles, compared to the sample

before the reaction. This observation is contrary to the Oswald ripening

process, where atoms detach from (thermodynamically unstable) smaller

clusters and reattach to bigger clusters.17,18 Such ripening usually leads to

growth of the bigger clusters and eventual disappearance of the smaller ones.

In our case, the decrease in the particle size during the reaction strongly

indicates that Pd atoms and/or ions are leaching out of the clusters. The

leached species may be the real catalysts, instead of the defect sites on the


82

clusters’ surface.19-21 When the substrate is consumed, these homogeneous

species can re-cluster to form new (smaller) particles with the stabilizing

influence of the TBAA. We did not observe any Pd black after the reaction, but

control experiments using K2CO3 instead of TBAA yielded larger particles as

well as Pd black (see supporting information for details). We also investigated

the catalytic activity of these smaller particles for the second cycle by adding

another equivalent of the reactants and base to the reaction mixture of first

run. We observed a drop in reaction rate and catalytic activity compared to

first run (see supporting information, figure S5). These results further

indicate that catalysis does not occur on the surface, as one would expect an

increase of with the decrease in particle size.

0102030405060708090

100

0 30 60 90 120 150 180 210Time/ min

Br-C

6H4-

CN

con

vers

ion/

%

Pd(OAc)2

PdCl2Pd(dba)2Pd(NO3)2

0102030405060708090

100

0 30 60 90 120 150 180 210Time/ min

Br-C

6H4-

CN

con

vers

ion/

%

Pd(OAc)2

PdCl2Pd(dba)2Pd(NO3)2

Figure 2. Sonogashira coupling of 1 with 2 catalysed by homogeneous

Pd(dba)2 or by the Pd clusters prepared from various precursors. Reaction

conditions: 1.5 mmol Phenylacetylene, 1.5 mmol TBAA, 1 mol% catalyst (total

Pd clusters relative to Br-C6H4-CN), 8 mL DMF, 50 ºC, N2 atmosphere.

We also studied the effect of various counteranions on the catalytic activity,

using clusters prepared from Pd(NO3)2, PdCl2 and Pd(OAc)2. Note that the size

of the particles and particle size distribution in each case was approximately

the same. The activity decreased in the order NO3 > Cl > OAc (Figure 2).


83

Finke and Özkar22,23 showed that the coordinating ability of anions to the

cluster surface affects the clusters’ stability. Acetate is a strong coordinating

ion to Pd, while nitrate is a weak one.24,25 This difference affects the stability,

rendering the clusters more (or less) susceptible to leaching. Furthermore,

clusters prepared from Pd(NO3)2 showed similar activity to that of a

homogeneous Pd0(dba)2 complex. This may reflect the weaker coordination of

NO3 that increases the Pd leaching rate.

There are very few reports on the copper-free version of the Sonogashira

reaction, and the mechanism is not clear.26-28 Using initial rate methods, we

found that the reaction follows the rate law v = k[Pd][2]. Note that [Pd]

represents the initial concentration of the Pd nanoparticles and not the

leached Pd during the reaction. This indicates that the oxidative addition is

the rate-determining step. Moreover, we observed a decelerating effect of 1 on

the oxidative addition of 2 (Figure 3). This may be due to the unreactive

complex formed by the coordination of 1 with the leached Pd species, as

observed by Amatore et al.29

0102030405060708090

100

0 10 20 30 40 50 60 70 80 90

Time/ min

Br-C

6H4-

CN

con

vers

ion/

%

Clusters mixed with 1st reagent

2nd reagentadded

0102030405060708090

100

0 10 20 30 40 50 60 70 80 90

Time/ min

Br-C

6H4-

CN

con

vers

ion/

%

Clusters mixed with 1st reagent

2nd reagentadded

Figure 3. Time-resolved profiles showing the effect of mixing either 4-

bromobenzonitrile 1 or phenylacetylene 2 with the Pd clusters prior to

reaction. The ‘ ’ and ‘ ’ symbols denote {1+Pd} with 2 added after 30 min and

vice versa, respectively.


84

Based on our results, we propose a mechanism for the Pd cluster catalysed

Sonogashira cross-coupling. This mechanism includes two pathways (Figure

4): Path A involves the leaching of Pd0 from defect sites on the cluster, that is

then stabilized by the coordinating anions and the solvent, forming a

homogeneous Pd0 complex. Subsequent oxidative addition of the aryl bromide

2 gives a PdII complex that enters the conventional catalytic cycle.

Alternatively, in path B, 2 first attacks a defect site on the Pd cluster,

releasing a PdII complex into solution, that then enters the catalytic cycle, as

observed by Biffis et al.19 The nucleophilic attack of 1 on the Aryl–PdII–

Br(solvent)X complex takes place concomitant with the deprotonation of 1.

Finally, the dissolved Pd species can recluster, to form new (smaller) particles

after the reductive elimination step.

RBr

Pd(II)

Pd(II)

Ph

R

Br

HPh

R

Br

R

R

RBr

Ph

X

X X

X

X

Pd (0) atom

base+

+

Pd cluster

Pd(0) leaching

Pd(II) leaching

reclustering after reaction

+

oxidative addition

oxidative addition

reductive elimination

base-H + Br

Solvent

Solvent

Path B

Path A

Where X = NO3, Cl and OAc

RBr

Pd(II)

Pd(II)

Ph

R

Br

HPh

R

Br

R

R

RBr

Ph

X

X X

X

X

Pd (0) atom

base+

+

Pd cluster

Pd(0) leaching

Pd(II) leaching


+

oxidative addition

oxidative addition


base-H + Br

Solvent

Solvent

Path B

Path A

RBr

Pd(II)

Pd(II)

Ph

R

Br

HPh

R

Br

R

R

RBr

Ph

X

X X

X

X

Pd (0) atom

base+

+

Pd cluster

Pd(0) leaching

Pd(II) leaching


+

oxidative addition

oxidative addition


base-H + Br

Solvent

Solvent

Path BPath B

Path APath A

Where X = NO3, Cl and OAc

Figure 4. Proposed mechanism for the Pd cluster catalysed Sonogashira

cross-coupling involving two possible pathways.


85

Conclusion

In summary, we show here that the cluster-catalysed Sonogashira reaction

probably proceeds via a soluble Pd species, and that the counteranions present

in solution influence the leaching of the Pd ions/atoms.



GC analysis was performed using a Interscience Trace GC-8000 gas

chromatograph with a 100% dimethylpolysiloxane capillary column (VB-1, 30




GC retention times to those of authentic samples and by MS analysis.

Samples for GC were added in equivalent amount of water, extracted with

hexanes and filtered through an alumina plug prior to injection. GC


at 280 ºC (3 min). All the reactions were carried out under N2 atmosphere in

Schlenk-type glassware that was oven dried prior to reaction. Solutions were

dispensed using a micropipette. Unless noted otherwise, chemicals were

purchased from commercial firms and were used as received.

Tetraoctylammonium glycolate was prepared according to the procedure

described in chapter 3, except that in the second stage of ion-exchange process

glycolic acid was used instead of formic acid. TEM images were obtained with

a JEOL-100 CXII instrument, operated at an accelerating voltage of 80 kV. At

least four images were taken for each sample.

Synthesis of Pd clusters

A Schlenk-type vessel equipped with a rubber septum and a magnetic stirrer

was evacuated and refilled with N2. The vessel was then charged with Pd


86

precursor salt solution in DMF (20 mL, 10 mM) and 2.5 mL of a 0.2 M TOAG

solution in DMF was added in one portion to the solution at 65 ºC. The

mixture was stirred for 6 h under a slight N2 overpressure. The color of the

mixture changed from dark orange to black. The resulting Pd cluster

suspension was then used as a catalyst stock solution in the Sonogashira

cross-coupling.

Cross–coupling of phenylacetylene with 4-bromobenzonitrile using

Pd clusters

A Schlenk-type glass vessel equipped with a rubber septum and a magnetic

stirrer was evacuated and refilled with N2. The vessel was then charged with

a Pd cluster suspension prepared in DMF (1.0 mL, 10.0 mM, 1.0 mol%),

phenylacetylene (2 ml, 750 mM, 1.5 mmol), TBAA (2 ml, 750 mM, 1.50 mmol)

and 3 mL of DMF. 4-bromobenzonitrile (0.182 g, 1.00 mmol) was added and

the mixture was stirred at 50 ºC for 6 h under a slight overpressure of N2.

Reaction samples were taken at regular intervals and monitored by GC

(Pentadecane internal standard).


TEM was used to determine the particle size and the morphology before,

during and after the reaction. Samples were prepared by placing 150 µL of 1

mM Pd cluster suspension or the reaction mixture on carbon-coated copper

grids. These were then placed in vaccum oven at 50 ºC at 250 mm of Hg to

evaporate the solvent. To see the effect of catalysis on the particle size the

TEM samples were taken during and after the reaction.

Testing for {Pd + reagent} pre-activation

To form the active Palladium complex 4-bromobenzonitrile (0.182 g, 1.0

mmol), DMF (7 ml) and Pd cluster suspension (1 ml, 10 mM, 1.0 mol%) were


87

first stirred at 50 ºC for 30 min. Phenylacetylene (0.152 g, 1.5 mmol), TBAA

(0.44 g, 1.5 mmol) and internal standard were then added under slight N2 over

pressure. The samples were taken at regular intervals and analysed by GC. A

similar experiment was performed wherein phenylacetylene was added before

to form an inactive palladium complex.

Pd cluster reuse in 2nd cycle

A Schlenk-type glass vessel equipped with a rubber septum and a magnetic

stirrer was evacuated and refilled with N2. The vessel was then charged with

a Pd cluster suspension prepared in DMF (1.0 mL, 10.0 mM, 1.0 mol%),

phenylacetylene (2 ml, 750 mM, 1.5 mmol), TBAA (2 ml, 750 mM, 1.50 mmol)

and 3 mL of DMF. 4-bromobenzonitrile (0.182 g, 1.00 mmol) was added and

the mixture was stirred at 50 ºC for 6 h under a slight overpressure of N2.

After complete conversion of 4-bromobenzonitrile same amount of fresh

reactants were added to the reaction mixture. Reaction samples were taken at

regular intervals and monitored by GC (Pentadecane internal standard).

Supporting information

Reaction profiles and kinetic analysis

The reaction profiles obtained by varying concentration of Pd clusters and 4-

bromobenzonitrile are shown in figures S1 and S2. Initial reaction rates (ri)

were calculated from the slope of the conversion v/s time plot. The order of

reaction was found by plotting log (ri) v/s log (concentration) as shown in

figures S3 and S4.


88

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50

Time/ min

Br-C

6 H4 -

CN

con

vers

ion/

%

0.25 mol%

0.5 mol%

0.75 mol%

1.0 mol%

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50

Time/ min

Br-C

6 H4 -

CN

con

vers

ion/

%

0.25 mol%

0.5 mol%

0.75 mol%

1.0 mol%

Figure S1. Sonogashira cross-coupling of phenylacetylene with 4-

bromobenzonitrile using various concentrations of using Pd clusters as

catalysts. The mol% of Pd clusters used is relative to 4-bromobenzonitrile

concentration. Reaction conditions: 1.0 mmol Br-C6H4-CN, 1.5 mmol

Phenylacetylene, 1.5 mmol TBAA, 8 mL DMF, 50 C, N2 atmosphere.

010

2030

4050

6070

8090

100

0 10 20 30 40 50Time/ min

Br-C

6 H4 -

CN

con

vers

ion/

%

0.062 mM

0.093 mM

0.125 mM

010

2030

4050

6070

8090

100

0 10 20 30 40 50Time/ min

Br-C

6 H4 -

CN

con

vers

ion/

%

0.062 mM

0.093 mM

0.125 mM

Figure S2. Sonogashira cross-coupling of phenylacetylene with various

concentrations of 4-bromobenzonitrile using Pd clusters as catalysts. Reaction

conditions: 1.5 mmol Phenylacetylene, 1.5 mmol TBAA, 1 mol% catalyst (total

Pd clusters relative to Br-C6H4-CN), 8 mL DMF, 50 C, N2 atmosphere.


89

1.0 mol%

0.75 mol%

0.25 mol%

0.5 mol%

y = 1.1248x + 1.9088R2 = 0.9888

-2.1

-2

-1.9

-1.8

-1.7

-1.6

-1.5

-1.4

-1.3

-1.2

-3.7 -3.5 -3.3 -3.1 -2.9 -2.7 -2.5Log [Pd cluster]

Log

r i

Figure S3. Log plot of the initial reaction rate dependence on concentration of

Pd clusters with other parameters constant. Reaction conditions are the same

as in figure S1.

0.062 mM

0.093 mM

0.125 mM

y = 0.9473x - 0.4166R2 = 0.9665

-1.6

-1.55

-1.5

-1.45

-1.4

-1.35

-1.3

-1.25

-1.2

-1.3 -1.2 -1.1 -1 -0.9 -0.8Log [CN-PhBr]

Log

r i

Figure S4. Log plot of the initial reaction rate dependence on concentration of

4-bromobenzonitrile, with other parameters constant. Reaction conditions are

same as in figure S2.


90

Recycling experiment

This experiment was carried out to check the activity of the newly formed

smaller particles after the first run. We expected if reaction occurs on the

surface of the clusters, the smaller particles with high surface area should give

higher activity and/or reaction rate. However, this was not the case and

reasons for this low activity in 2nd cycle might be either due to surface

poisoning or because the smaller particles with tighter radii are less prone to

leaching.

0102030405060708090

100

0 10 20 30 40 50

Time/ min

CN

-PhB

r con

vers

ion/

%

1st cycle

2nd cycle

0102030405060708090

100

0 10 20 30 40 50

Time/ min

CN

-PhB

r con

vers

ion/

%

1st cycle

2nd cycle

Figure S5. Activity of Pd clusters prepared using Pd(NO3)2 in the 1st and 2nd

cycle of Sonogashira reaction.

Additional TEM results

The TEM images taken during the reaction (t = 20 min) show smaller particles

(Figure S5, left) compared to that before the reaction. This is probably due to

the stabilizing influence of TBAA used as a base. To check this hypothesis, we

carried out a control experiment, with K2CO3 as base. Indeed, the TEM image

after the reaction showed very large particles (Figure S5, right) and also some

aggregates were observed at the bottom of the reactor. This clearly indicates

that TBAA plays an important role in preventing the growth of newly formed

clusters after the reaction completion.


91

19 nm19 nm 19 nm19 nm19 nm19 nm

Figure S6. TEM image of the sample taken during the reaction when TBAA

was used as a base (left) and image obtained after the reaction when K2CO3

was used as a base (right). Reaction conditions: 1 mmol 4-bromobenzonitrile,

1.5 mmol Phenylacetylene, 1.5 mmol base, 1 mol% catalyst (total Pd clusters

relative to 4-bromobenzonitrile), 8 mL DMF, 50 C, N2 atmosphere.

References

(1) (a) Moreno-Mañas, M.; Pleixats, R. Acc. Chem. Res. 2003, 36, 638-643. (b) Reetz, M. T.; Westermann, E. Angew. Chem. Int. Ed. 2000, 39, 165-168; (c) Beller, M.; Fischer, H.; Kuhlein, K. C.; Reisinger, P.; Herrmann, W. A. J. Organomet. Chem. 1996, 520, 257-259; (d) Narayanan, R. and El-Sayed, M. A. J. Am. Chem. Soc., 2003, 125, 8340-8347. (e) Thathagar, M. B.; Beckers, J.; Rothenberg, G. J. Am. Chem. Soc. 2002, 124, 11858-11859. (f) Thathagar, M. B.; Beckers, J.; Rothenberg, G. Adv. Synth. Catal. 2003, 345, 979-985.

(2) For a general overview on metal nanoclusters and their applications in catalysis see (a) Aiken, J. D III.; Finke, R. G. J. Mol. Catal. A 1999, 145, 1-44. (b) Bradley, J. S.; Hill, E.; Leonowicz, M. E.; Witzke, H. J. Mol. Catal. 1987, 41, 59-74. (c) Bönnemann, H.; Richards, R. M. Eur. J. Org. Chem. 2001, 2455-2480.

(3) (a) Biffis, A.; Zecca, M.; Basato, M. J. Mol. Catal. A 2001, 173, 249. (b) Zhao, F. Y.; Bhanage, B. M.; Shirai, M.; Arai, M. Chem. Eur. J 2000, 6, 843 (c) Augustine, R. L.; Oleary, S. T. J. Mol. Catal. A 1995, 95, 277. (d) Choudary, B. M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc. 2002, 124, 14127. (e) Köhler, K.; Heidenreich, R. G.; Krauter, J. G. E.; Pietsch, M. Chem. Eur. J. 2002, 8, 622. (f) Prockl, S. S.; Kleist, W.; Gruber, M. A.; Köhler, K. Angew. Chem. Int. Ed. 2004, 43, 1881.

(4) Conlon, D. A.; Pipik, B.; Ferdinand, S.; LeBlond, C. R.; Sowa, J. R.; Izzo, B.; Collins, P.; Ho, G. J.; Williams, J. M.; Shi, Y. J.; Sun, Y. K. Adv. Synth. Catal. 2003, 345, 931.

(5) Cassol, C. C.; Umpierre, A. P.; Machado, G.; Wolke, S. I.; Dupont, J. J. Am. Chem. Soc.2005, 127, 3298.


(7) Hu, J.; Liu, Y. B. Langmuir 2005, 21, 2121.


92

(8) Hamlin, J. A.; Hirai, K.; Millan, A.; Maitlis, P. M. J. Mol. Catal. 1980, 7, 543.

(9) Widegren, J. A.; Finke, R. G. J. Mol. Catal. A 2003, 198, 317.

(10) Li, Y.; Boone, E.; El-Sayed, M. A. Langmuir 2002, 18, 4921.

(11) Le Bars, J.; Specht, U.; Bradley, J. S.; Blackmond, D. G. Langmuir 1999, 15, 7621.



(14) The Heck reaction is often used as an example in mechanistic studies on cross-coupling, but the problem is that the high temperatures can affect the surface chemistry of the Pd clusters and influence the leaching of Pd atoms.

(15) Biffis, A.; Zecca, M.; Basato, M. J. Mol. Catal. A 2001, 173, 249.


(17) Narayanan, R.; El-Sayed, M. A. J. Am. Chem. Soc. 2003, 125, 8340.

(18) Howard, A.; Mitchell, C. E. J.; Egdell, R. G. Surf. Sci. 2002, 515, L504.



(21) Reetz, M. T.; de Vries, J. G. Chem. Commun. 2004, 1559.

(22) Finke, R. G.; Özkar, S. Coord. Chem. Rev. 2004, 248, 135.

(23) Özkar, S.; Finke, R. G. J. Am. Chem. Soc. 2002, 124, 5796.

(24) Maekawa, M.; Munakata, M.; Kuroda-Sowa, T.; Suenaga, Y. Anal. Sci. 1998, 14, 447.

(25) Amatore, C.; Carre, E.; Jutand, A.; Mbarki, M. A.; Meyer, G. Organometallics 1995,14, 5605.




(29) Amatore, C.; Bensalem, S.; Ghalem, S.; Jutand, A.; Medjour, Y. Eur. J. Org. Chem.2004, 366.


93

Section B*

Introduction

"In the Pd cluster catalysed cross-coupling reactions, does catalysis occur on

the cluster surface or via leached Pd atoms/ions into the solution?"†

Concerning this question in section A we concluded that in the Pd clusters

catalysed Sonogashira reaction the active species responsible for catalysis is

‘probably’ released Pd from the cluster surface. However, the conclusions are

based on circumstantial evidence. There is no single definitive experiment

that can reveal the true nature of cluster catalysis in the liquid phase. Here,

we present the first direct and unambiguous test proving that leached Pd

species are the true catalysts in Pd cluster-catalysed C C coupling reactions.

We used a nano-porous membrane based experiments to distinguish between

the catalysis by Pd clusters and the leached Pd species.

Concept of membrane based approach

This approach is based on physically separating the Pd clusters from the

reaction mixture and thus from the leached Pd, which is considered to be an

active species. A nano-porous membrane was used as a partition between the

Pd clusters and reaction mixture. An -alumina supported nanoporous -

alumina membrane with a pore size of 5 nm was synthesized according to

literature procedure.1 A stainless steel ‘U-tube permeation cell’2 type reactor

was built in-house consisting of two compartments divided by a membrane

(see figure 1, right). In further description those compartments will be

referred as side A and side B. The basic idea is to place a Pd cluster

suspension as catalyst reservoir on one side of the membrane reactor, and a

* Part of this work has been submitted for publication: M. B. Thathagar, J. E. ten Elshof and G. Rothenberg, 2006.

† Check the introduction and references in section A for a detailed discussion.


94

reaction mixture on the other side (see figure 1, left). Monitoring the reaction

in time on the reaction mixture side will tell us if the catalysis is occurring on

the clusters surface or via the leached Pd species.

Pd clusters (15 nm) cannot pass through the

membrane

Side A

leached Pd species diffused through the membrane

reaction mixture without catalyst

Side B

membrane with 5 nm pores

membrane

inert gas attachment


membrane

Side A



Side B



membrane

Side A



Side B


membrane


membrane


Figure 1. Cartoon of the membrane reactor showing the basic concept of

distinguishing the catalysis via the clusters and the leached Pd species that

can pass through the membrane (left). Photo of our nanoporous membrane

reactor consisting of two compartments divided by a membrane (right).


Pd clusters were synthesized by reducing Pd(NO3)2 with tetraoctylammonium

glycolate in DMF as described in section A.3 TEM analysis showed that the

average particle size of clusters was 14.5 nm and the particle size distribution

was broad (figure 2). The minimum particle size was 12 nm which is bigger

than the maximum pore size of the membrane and hence they cannot pass

through the membrane. While measuring the pore size of the membrane by

permporometry method,4 we observed that few pores were larger than 5 nm,

the maximum size being about 11.8 nm. However, a connected path through

the membrane going from one side of the membrane to the other side will


95

probably not consist only of pores of maximum size. So effectively it will also

retain particles that are somewhat smaller than this maximum value.

Secondly the pore structure is not straight but tortuous. This will also help in

retaining the nanoclusters with sizes smaller than the maximum.

0

10

20

30

40

50

12 13 14 15 16 17

Particle size/ nm

Freq

uenc

y/ %

19 nm

0

10

20

30

40

50

12 13 14 15 16 17

Particle size/ nm

Freq

uenc

y/ %

19 nm19 nm

Figure 2. Transmission electron micrograph (left) and corresponding size

distribution (right, based on 85 particles counted) of the Pd clusters.

I

Ph Ph+70 oC, TBAA

Pd clusters

Scheme 1. Sonogashira coupling of phenylacetylene with iodobenzene (PhI).

Sonogashira reaction in the membrane reactor

First, we carried out Sonogashira coupling of phenylacetylene with

iodobenzene as the test reaction (scheme 1). All the reactions were performed

using DMF is a solvent. In this experiment, we placed a Pd clusters

suspension on side A of the reactor and the reactants and

tetrabutylammonium acetate (TBAA) as base on side B. Note that the base is

soluble in this case. The reactor was then stirred at 70 ºC. As expected after 3


96

days, we observed 72% product yield on side B (where there was no catalyst).

However, since the reactants and base are not evenly distributed on both sides

of a membrane, the difference in their concentration forms a concentration

gradient. Due to the concentration gradient, the reactants and a base might

have diffused from the area of higher concentration (side B) to the area of

lower concentration (side A). Therefore, it is possible that the reaction is

occurring on the Pd clusters side and product thus formed could have diffused

from side A to B. We did observe 9% yield of 3 on side A, which could be

attributed to the product coming from side B or forming on side A.

Consequently, this experiment did not give a clear answer to our question. To

reveal the actual catalytic species, it was necessary to prevent the diffusion of

the reactants through the membrane and to use an insoluble base. We

therefore switched to the Heck reaction in the presence of NaOAc, which is

insoluble in DMF. We used the coupling of n-butyl acrylate (NBA) with

iodobenzene (PhI) to give n-butyl cinnamate (NBC) as a model reaction

(scheme 2).

COOBu

I

Pd clusters

+COOBu100 oC, NaOAc

Leached species

Scheme 2. Heck coupling of n-butyl acrylate (NBA) with iodobenzene (PhI) as

a model reaction.

Before performing the actual reaction, we examined the time-dependent

transport of NBA, PhI and pure NBC through the membrane (figure 3). In this

experiment, we placed only DMF on side A and NBA, PhI and pure NBC on

side B. The results show that indeed all three of them are transported from

side B to side A. Note that no pressure was applied to the system and


97

transport was purely due to the concentration gradient. The transport of

molecules was dependent on the molecule size; the trend of diffusion rate was

NBA > PhI > NBC. After 100 h, 10.5 mol% of NBA, 6.5 mol% of PhI and 4.5

mol% of NBC were transported to side A. This blank experiment gives a

measure of the background diffusion of these specific compounds through the

membrane. A similar transport behavior can be expected during the reaction.

0123456789

1011

0 30 60 90 120

Time/ h

mol

% t

rans

porte

d

COOBu

I

COOBu

0123456789

1011

0 30 60 90 120

Time/ h

mol

% t

rans

porte

d

COOBu

I

COOBu

Figure 3. Time-dependent transport of molecules through the membrane

from side B to A.

Heck reaction in the membrane reactor

We then ran the Heck reaction experiment using 1.5:1 molar mixtures of 4

and 2 on both the sides of the membrane. This was done to avoid reactants

concentration gradients. NaOAc (1.5 equiv) was then added to side B and the

Pd clusters (0.01 equiv) suspension was added to side A at 100 ºC. Note that

the base is necessary for closing the catalytic cycle. Since there is no base on

side A, no product can form there. Thus, any product observed on side A must

come from side B.


98

0102030405060708090

100

0 30 60 90 120 150

Time/ h

NBC

Yie

ld /

%

side B

side A(catalyst, no base)

(base, no catalyst)

0102030405060708090

100

0 30 60 90 120 150

Time/ h

NBC

Yie

ld /

%

side B

side A(catalyst, no base)

(base, no catalyst)

Figure 4. Time resolved profile for the yields obtained for n-butyl cinnamate

(NBC) on side B of membrane reactor and its transport to side A.

Figure 4 shows the time resolved profile of the product NBC formed on side B

and that diffused on side A. No reaction was observed for first 5 h. This may

be because some Pd species from side A must diffuse through the membrane

to initiate the catalytic cycle on side B. Once the catalytic cycle starts the

reaction rate slowly increases with time. However, the reaction becomes

sluggish as PhI is consumed appreciably. After 120 h, the NBC yield on side

B was 88%. Before repeating this experiment membrane was washed using

acetone and was placed in ethanol for one day. This was done to remove the

organic molecules blocking the pores of the membrane. Repeat experiment

showed results within ± 8% error and the NBC yield after 120 h was 80%,

which is less compared to the previous run. The error in the results might be

due to the blocking of the pores or the tortuous pore structure of the

membrane itself. No aggregation was observed after the reaction on both sides

of the reactor. We did not observe any diffused product during first 12 h on

side A, however, 4.9% of product was observed after 120 h probably because it

diffuses from side B.


99

XPS study on the membrane after the Heck reaction

XPS measurements on the membrane were performed after the reaction to

identify whether the Pd is entering into the pores. There were no significant

differences between the elemental compositions of the surface and sub-surface

layers. Traces of Pd were found on all spots on or below the membrane

surface, but the concentration was in all cases within the range of 0.02 0.07

at%. Since the specific surface area5 of this -alumina is ~285 m2/g, this is

equivalent to a surface concentration of roughly one Pd atom per 20 nm2.

The results obtained from the membrane based experiments prove that the

reaction indeed proceeds via the released Pd species and the Pd clusters are

just acting as the reservoirs for these species. However, we still do not

understand if these species are Pd(0) atoms released from the defect sites or

Pd(II) soluble species formed after the oxidative addition of PhI as discussed

in section A. This is clearly in agreement with the de Vries6 propositions for

ligand-free Pd catalysts in Heck reactions.

Conclusion

In summary, using a simple approach based on physical exclusion, we prove

here that the Pd cluster-catalyzed Heck reaction (and probably also the

Sonogashira reaction) proceeds via soluble Pd species released from the

clusters’ surface. Further investigations into this mechanism will be the

subject of future research in our laboratory.



GC analysis was performed using an Interscience Trace GC-8000 gas

chromatograph with a 100% dimethylpolysiloxane capillary column (VB-1, 30



100



GC retention times to those of authentic samples and by MS analysis.

Samples for GC were added in equivalent amount of water, extracted with

hexanes and filtered through an alumina plug prior to injection. GC


at 280 ºC (3 min). Solutions were dispensed using a micropipette. Unless noted

otherwise, chemicals were purchased from commercial firms and were used as

received. Pd clusters were synthesized using procedure discussed in the

previous section A. TEM images were obtained with a JEOL-100 CXII

instrument, operated at an accelerating voltage of 80 kV. At least four images

were taken for each sample. X-ray Photoelectron Spectroscopy (XPS) was

performed using a PHI Quantera Scanning ESCA Microprobe.


TEM was used to determine the particle size and the morphology. Samples

were prepared by placing 150 µL of 1 mM Pd cluster suspension or the

reaction mixture on carbon-coated copper grids. These were then placed in

vaccum oven at 50 ºC at 250 mm of Hg to evaporate the solvent. The clusters

size distribution was determined by counting the size of approximately 85 Pd

particles from TEM images obtained from different places on the TEM grids.

Membrane preparation

The -alumina membrane consists of a macroporous -alumina support and a

thin nano-porous -alumina layer. The -alumina supports were made by

colloidal filtration of well-dispersed 0.3 m -alumina particles (AKP-30,

Sumitomo). The 50 wt% dispersion was stabilized by peptizing with 0.02 M

HNO3. After drying at 25 °C for 24 h, the filter compact was sintered at 1100

°C in air for 2 h. Flat disks (Ø 39 mm, 2.0 mm thickness) were obtained by

machining and polishing. The final porosity of these supports is ~30% and the


101

average pore size is in the range of 80 120 nm. The nano-porous -alumina

membrane was prepared by dip-coating the -alumina supports in a boehmite-

based dip sol. The boehmite sol was prepared by hydrolysis of 0.5 mole of

aluminium-tri-sec-butoxide (Fluka) in 70 moles of double-distilled water at 95

°C. The dip sol was prepared by mixing 30 ml of boehmite sol with 20 ml of

PVA (polyvinyl alcohol, Fluka, 98% purity) solution, which was made from 150

g of 0.05 M HNO3 in water added to 4.5 g of PVA (MW=72000 g/mol) and

stirred for 2 h at 80 ºC. The -alumina supports were dip-coated into the -

alumina sol with a dip-coating speed of 1.1 cm s–1. The coated supports were

dried for 3 h (25 °C, relative humidity 40%), and calcined for 1 h (600 °C, air,

heating/cooling rates 0.5 °C/min). The deposition/calcination cycle was

repeated twice.

Membrane analysis by permporometry

The -alumina membrane was characterized by permporometry.4

Permporometry is based on the controlled blocking of the pores by capillary

condensation and the simultaneous measurement of the gas diffusion flux

through the remaining open pores. When a condensable vapour (cyclohexane)

is introduced at low vapour pressure, first a molecular adsorption layer (the

so-called “t-layer”) is formed on the inner surface of the pores. The pore size (d,

in nm) is defined by d = 2(rK + t), where rK is the Kelvin radius, and t is the

layer thickness of the t-layer (approx. 0.3 nm).


102

0

2

4

6

8

10

12

14

0 1 2 3 4 5 6

Kelvin radius/ nm

Num

ber o

f por

es/ a

.u.

Description of membrane reactor

A stainless steel membrane reactor consists of two compartments (referred as

side A and side B) divided by an -alumina membrane. Each compartment can

handle 75 ml of liquid. The o-ring made up of Buna-n tightens the membrane

and also make the installation free of leaks. The reactor also has the

connections for applying inert atmosphere. The reactor equipped with two

magnetic stirrers (one in each compartment) was placed in the oil bath and

the reactions were performed under N2 atmosphere.

Sonogashira coupling of phenylacetylene with iodobenzene using the

Pd clusters in the membrane reactor

The phenylacetylene (4 ml, 750 mM, 3.0 mmol), iodobenzene (0.40 g, 2.0 mmol)

and TBAA (4 ml, 750 mM, 3.0 mmol) were placed on side B of the membrane

reactor. Pd cluster suspension (3 ml, 10 mM, 1.0 mol%) prepared in DMF was

added on side A. The total volume of DMF on each side was 50 ml. The reactor

was heated at 70 ºC and the samples from both the sides were analyzed using

GC.


103

Heck coupling of n-butylacrylate with iodobenzene using the Pd

clusters in the membrane reactor

Equal amount of the n-butylacrylate (3.0 mmol, 0.38 g) and iodobenzene (2.0

mmol, 0.40 g) were placed on both the sides of the membrane reactor. NaOAc

(3.0 mmol, 0.41 g) was then added on side B and the Pd cluster suspension (3

ml, 10 mM, 1.0 mol%) on side A. The total volume of DMF in each

compartment was 50 ml. The reactor was heated at 100 ºC and the samples

from both the compartments were analyzed using GC (pentadecane internal

standard). After each reaction the membrane was washed using acetone (4 ×

10 mL) and then was kept in the ethanol for at least 24 h.

XPS study of -alumina membrane used for the Pd clusters retention

The elemental composition of the -alumina layer on and below the surface

after membrane reactor experiments was determined by XPS. After

determining the elements present in the system, the C 1s, N 1s, Na 1s, Al 2p,

O 1s, Fe 2p, Pd 3d and I 3d peaks were measured. Measurements were done

at several selected spots on the membrane surface. To obtain the elemental

composition of the -alumina membrane at a depth of about 40 nm below the

surface, the surface layer was removed by sputtering an area of 3 3 mm with

2 keV Ar+ ions (estimated sputter rate 5.1 nm/min), and spectra were

recorded. Table 1 lists the typical atomic concentrations at and below the

surface of the -alumina layer as found by XPS. Hydrogen cannot be detected

by XPS. The main elements found are Al, O, C and N. These can be attributed

to the mesoporous -Al2O3 phase, and the reactants and solvent used in the

reaction. Carbon is also a naturally present element in all samples. The trace

elements Na, Pd and I can all be attributed to the reactants, base, solvent

and/or catalyst that were used in the Heck reaction.


104

Table 1. Atomic concentration of elements found using XPS.

Element Atomic concentration (at %)

Surface Sub-surface

C 23.74 19.15

N 2.61 2.08

O 49.93 51.42

Na 0.15 0.04

A 23.29 27.10

Fe 0.18 0.00

Pd 0.02 0.05

I 0.08 0.16

References

(1) Chowdhury, S. R.; ten Elshof, J. E.; Benes, N. E.; Keizer, K. Desalination 2002, 144,41.

(2) Jirage, K. B.; Hulteen, J. C.; Martin, C. R. Science 1997, 278, 655.


(4) Benes, N.; Nijmeijer, A.; Verweij, H. In Recent Advances in Gas Separation by Microporous Ceramic Membranes; Kanellopoulos, N. K., Ed.; Elsevier: Amsterdam, 2000.

(5) Chowdhury, S. R.; Keizer, K.; ten Elshof, J. E.; Blank, D. H. A. Langmuir 2004, 20,4548.

(6) de Vries, A. H. M.; Mulders, J.; Mommers, J. H. M.; Henderickx, H. J. W.; de Vries, J. G. Org. Lett. 2003, 5, 3285.

Chapter 6 One pot Pd/C catalysed consecutive HALEX-Sonogashira reaction

105


One pot Pd/C catalysed consecutive HALEX-Sonogashira

reactions: A Ligand-free and Cu-free alternative*

Abstract

The advantages of combining heterogeneous catalysis and aryl chloride substrates for

cross-coupling are introduced. A heterogeneous Pd/C catalyst is used for activating

aryl bromides and chlorides via a one-pot HALEX-Sonogashira reaction. No ligand or

co-catalyst is required, and the cross-coupling products are obtained in moderate to

good yields. The influence of the solvent, base, iodide source and catalyst is evaluated.

The catalyst can be recycled for at least six consecutive reaction cycles. A variation on

this Domino reaction using catalytic amounts of KI is also proposed.

* Part of this work has been submitted for publication: M. B. Thathagar and G. Rothenberg, 2005, 4, 111. Featured on issue cover.

Cl

R

+130 oC

base, KIR3 mol% Pd/C

X = Br, Cl

R = H, Me, CF3, CHO, COCH3, CN


106

Introduction

The palladium and copper co-catalysed coupling of terminal alkynes with aryl

halides (the Sonogashira reaction) is one of the most widely used tools to form

C–C bonds.1 It provides an efficient route to aryl alkyne derivatives, which are

useful in diverse areas ranging from natural product chemistry2 to materials

science.3

Since its discovery, a variety of modifications has been reported for this

reaction, including microwave conditions4,5 and Pd-free6-11, Cu-free,5,12-16 and

ligand-free versions.8,17,18 However, in most studies aryl iodides are used as

coupling partners to the alkynes. For practical purposes, the less reactive

bromo- and chloro-aryls are attractive because of their lower cost and wider

availability compared to iodides.19 The few efficient protocols reported for

coupling of these substrates rely heavily on the use of electron-rich Pd

complexes with or without CuI co-catalyst.20-26 These homogeneous Pd

catalysts are laborious to synthesize, and their separation from the product

mixture is often difficult and costly. In chapter 2 and 3, we presented ligand-

free Cu and Cu/Pd nanoclusters as catalysts for Sonogashira11 and Suzuki

coupling reactions.27,28 While they are highly active, the separation and

recovery of these nanoclusters is tedious and may result in metal-

contaminated products. This problem can be overcome by using easily

separable supported catalysts that are extensively studied for Heck and

Suzuki reactions.29 Nevertheless, only a few reports describe the Sonogashira

reaction catalysed by these catalysts.15,18,30-32 Kotschy and co-workers31 have

shown that the heterogeneous system (5 mol% Pd/C + 10 mol% CuI + 10 mol%

PPh3) is active for coupling of aryl bromides and two activated chlorides with

alkynes. However, its success remained linked to the use of CuI as co-catalyst,

that also catalyzes the undesired oxidative homocoupling (Hay coupling) of

terminal alkynes to the corresponding diyne.33,34 A Cu-free Pd modified zeolite

catalyst was also recently applied to couple non-activated bromides,18 but the


107

yields were moderate (20%–45%). Therefore, an efficient ‘Pd/C only’ catalyst

system for coupling of aryl halides other than iodides would be of major

interest for both industrial and academic applications.

KI KX

X I

RR

I

R R

X

R

R

HI

(1)+ +

+130 oC base (2)

+130 oC

base, KI(3)

130 oC

3 mol% Pd/C

3 mol% Pd/C

3 mol% Pd/C

+

1 2

3 42

1 3 4

X = Br, Cl

R = H, Me, CF3, CHO, COCH3, CN

One of the possible ways of activating these halides is to use the halogen

exchange (HALEX) reaction35,36 (eqn. 1) prior to Sonogashira coupling (eqn. 2).

In this two-step system, the aryl chloride is first converted to the reactive

iodide, that can then readily couple with the alkyne. However, for economical

and environmental reasons it is essential to reduce the number of reaction

steps for any synthesis. To shorten the synthetic procedure the promising

strategy is to carry out a Domino reaction, commonly referred to ‘multistep

one-pot reaction’.37,38 Such reactions are attractive because they minimize

waste and reduce processing times. In this chapter, we a ligand-free and Cu-

free heterogeneous Pd/C catalyst system is described to activate aryl bromides

and chlorides by one-pot HALEX-Sonogashira reaction (eqn. 3).


108


In late 1980s, Bozell and Vogt39 reported an interesting two stage process

where they activated chloroarenes using NaI for Heck reactions catalysed by

bimetallic Pd(dba)2/NiBr2. Inspired by this system, we tried the HALEX

reaction to activate 4-chlorobenzonitrile 1 using KI as iodide source in the

presence of Pd/C catalyst. A mixture containing 1, 3 equiv of KI and 0.03 equiv

of Pd/C (pellets) in DMF was heated at 130 C under N2 for 48 h. The reaction

progress was monitored by GC. We were excited to observe 64% conversion of

1 to 4-Iodobenzonitrile 2 was observed after 48 h. Further reaction for 24 h did

not improve the yield. No conversion was observed at 110 C even after 3 days.

In another experiment we carried out Sonogashira coupling of 2 with

phenylacetylene 3 using the same catalyst and the solvent. In a typical

reaction, 1.5 equiv of 3 and one equiv of aryl halide 2 were mixed in the

presence of 2.5 equiv KF and 0.03 equiv of Pd/C pellets at 130 ºC under N2.

Quantitative yield of 4-cyanodiphenylacetylene 4 was obtained within 8 h.

After reaction completion, the catalyst was separated and the substituted

diphenylacetylene 4 was isolated and analyzed by GC/MS.

These reactions can be considered as a sequential two-step procedure to obtain

a Sonogashira coupling product. In principle, it should be possible to carry out

a one pot reaction, where the in situ formed aryl iodide via HALEX reaction

can readily couple with phenylacetylene to give desired coupling product. We

then examined this possibility using aryl halide 1, alkyne 3, KI, KF and Pd/C

in DMF under similar reaction conditions and mol ratios of reagents as

mentioned above. Note that no ligands or Cu co-catalysts were used as

opposed to the Pd/C system described recently.31 After 48 h, we obtained a

34% yield of substituted diphenylacetylene 4. Additionally, 2-3% of

dehalogenation of aryl halide and 5–6% of homocoupling of phenylacetylene

was also formed. However, we did not observe any aryl fluoride, which can


109

form via halogen exchange between aryl chlorides and KF in presence of phase

transfer agents.40 Note that when the stirring speed was kept below 300 rpm

the reaction failed, probably due to mass transfer limitations. Therefore, all

further reactions were carried out at sufficiently high stirring speed.

One-pot HALEX-Sonogashira reaction under various conditions

To optimize our system and find an efficient protocol for Sonogashira coupling,

we studied the effect of various parameters such as type of base, presence of

water, iodide source and catalyst. The coupling of 4-chlorobenzonitrile 1 with

phenylacetylene 3 to give diphenylacetylene 4 was used as a model reaction.

Table 1 shows the results obtained for various bases, amount of water added

to DMF and different iodide sources. Choosing the right base is crucial to the

success of the reaction. We obtained low yields with inorganic bases such as

KOH, NaOH, acetate and carbonate, both in presence or absence of water

(entries 1–5). Surprisingly, the most commonly used bases

tetrabutylammonium acetate (TBAA) and Et3N were not effective (entries 7

and 8), whereas the best results were obtained with tetrabutylammonium

fluoride (TBAF) and KF (entries 6 and 9). This indicates that the presence of

fluorides is necessary to achieve good yields.

We used a DMF/H2O mixture to dissolve the bases that were not soluble in

pure DMF, assuming that this might improve the yield. Indeed, in the case of

KF the yield of 4 was nearly doubled when the DMF/H2O ratio was

maintained at 3:1 (Table 1, entry 12). However, increasing the amount of

water decreased the yield and the reaction in pure water failed completely

(entries 10, 11 and 13). This agrees with the trend reported for Sonogashira

coupling using DMF/H2O solvent in presence of heterogeneous Pd-modified

zeolites.18 We also observed that the presence of water led to 5–8%

dehalogenation, giving 4-cyanobenzene. Arai and Zhao41 observed significant

amount of dehalogenation of chlorobenzene in the Heck reaction using a Pd/C


110

catalyst. They suggested that this reaction is likely to occur heterogeneously

on the surface of Pd/C, whereas leached molecular Pd species are responsible

for desired cross-coupling product. This may also apply to our system, with the

DMF/H2O combination acting as a source of formic acid and ultimately

hydrogen.42-44

Table 1. One-pot HALEX-Sonogashira reaction catalysed by Pd/Ca

Cl CN CN+

Entry Iodide source Base Solvent Yield of 4 (%)b

1 KI KOH DMF 15

2 KI KOH DMF/H2O (1:1)c 22

3 KI NaOH DMF/H2O (1:1) c 14

4 KI NaOAc DMF/H2O (1:1) c 8

5 KI K2CO3 DMF/H2O (1:1) c 10

6 KI TBAF DMF 51

7 KI TBAA DMF 6

8 KI Et3N DMF 3

9 KI KF DMF 34

10 KI KF DMF/H2O (1:1) c 41

11 KI KF DMF/H2O (2:1) c 49

12 KI KF DMF/H2O (3:1) c 58

13 KI KF H2O 0

14 none KF DMF/H2O (3:1)c <1

15 NaI KF DMF/H2O (3:1) c 43

16 TBAI KF DMF 2

17 CuI KF DMF/H2O (3:1) c 4d

aReaction conditions: 1.0 mmol 4-chlorobenzonitrile, 1.5 mmol

phenylacetylene, 2.5 mmol base, 3.0 mmol iodide source, 3 mol% Pd/C, 5 mL

solvent, N2 atmosphere, 130 ºC, 48 h (the reaction time was not optimised). b

GC yield of 4, corrected for the presence of an internal standard. c 5–8%

dehalogenation of 1 was also observed. dcomplete conversion of

phenylacetylene to homocoupling product.


111

Next we tested different iodide sources for this reaction. KI was the most

efficient, followed by NaI, whereas Bu4NI and CuI gave less than 5% yield. In

case of CuI the starting alkyne 3 was completely consumed via the competitive

Hay coupling pathway. Control experiments confirmed that no product was

formed without iodide source, affirming that the cross-coupling proceeds via

HALEX reaction.

Table 2. Screening of various catalysts for coupling of phenylacetylene and 4-

chlorobenzonitrilea

Entry Catalyst (3 mol%) Yield of 4 (%)b

1 Pd/C (pellets) A1 58

2 A1 + 5 mol% CuI 20c

3 A1 + 5 mol% NiCl2 41

4 Pd/C (powder) A2 18

5 Pd(dba)2 + 5 mol% CuI 12c

6 Pd/Al2O3 5

8 Pd/BaSO4 0

9 Pd(OAc)2 4

a Reaction conditions were same as in table 1. b GC yield of 4, corrected for the

presence of an internal standard. c 45–50% of homocoupling product was also

observed.

We also screened several commercially available catalyst and co-catalyst

combinations (table 2). Nevertheless, among the screened catalysts only 5 wt%

Pd/C (pellets, from Ventron) A1 was found to be most effective (entry 1). It is

known that a CuI co-catalyst can enhance the product yield for Sonogashira

coupling of bromides or/and chlorides. In our case, however, we observed a

deleterious effect on the yield in presence of 5 mol% CuI, with formation of


112

45 50% of the homocoupling (Hay coupling) product (entry 2). A similar

suppression of catalytic activity and oligomerisation/dimerisation of alkyne

was also reported elsewhere.18,26,45 NiCl2 is generally used as a catalyst for

activating chlorides towards the HALEX reaction,35 but using it along with A1

too did not improve the yield (entry 3). 5 wt% Pd/C (powder, from Fluka) A2

gave only moderate yield (entry 4). This was surprising because one imagines

that powdered catalysts should offer less diffusion resistance for the reactants

compared to pellets, leading to higher activity. We measured the surface areas

of both the catalysts and found that it was higher for catalyst A1 (1039 m2/g)

compared to A2 (824 m2/g), which explains our results. Other catalysts gave

very low yields (entries 5 9).

One-pot HALEX-Sonogashira reaction scope and limitations

We then examined the scope and limitations of this domino HALEX-

Sonogashira protocol. As TBAF and KF were equally effective, various

substrates were tested with both bases (Table 3). We were able to cross-couple

aryl chlorides with phenylacetylene in moderate to good yields and bromides

in good to excellent yields. In the case of aryl chlorides, the highest yield (68%)

was observed for p-CF3-C6H4-Cl (entry 2) reflecting the strong electron

withdrawing effect. The decrease in the yields of aryl chlorides was in

accordance with the decrease in the strength of the electron withdrawing

group (entries 1 4). Our attempts to couple electron-neutral and electron-rich

aryl chlorides failed even with 5 mol% Pd/C. For aryl bromides, a quantitative

yield for the electron-neutral p-C6H5-Br (entry 7) and a good yield for the

moderately electron-donating p-CH3-C6H4-Br (entry 9) were obtained. Both

bases gave similar yields for all the substrates. Control experiments carried

out using chlorobenzene and KI in presence of Pd/C at 130 ºC confirmed that

no HALEX product, i.e. iodobenzene, was formed. This is the reason for the

failure of subsequent Sonogashira reaction when using deactivated aryl

chlorides. Although the yields are not excellent, they are higher than any


113

reported for heterogeneously catalysed Sonogashira coupling of aryl chlorides.

Moreover, this is the first demonstration of activating aryl chlorides using a

ligand-free and Cu-free Pd/C catalyst.

Table 3. Pd/C catalysed coupling of various aryl halides with

phenylacetylenea

Entry Substrate Yield (%)b

KF based

Yield (%)b

TBAF basee

1 NC Cl 58 (43c) 51

2 F3C Cl 68 62

3 ClH3COC 31 35

4 ClOHC 20 18

5 Cl 0 0

6 H3C Cl 0 0

7 Br >99 (82c) 82

8 BrH3CO 8 0

9 H3C Br 62 46

a Reaction conditions: 1.0 mmol substrate, 1.5 mmol phenylacetylene, 2.5

mmol base, 3.0 mmol KI, 3 mol% Pd/C, solvent 5 mL, N2 atmosphere, 130 ºC,

48 h (time was not optimised). b GC yield of 4, corrected for the presence of an

internal standard. c isolated yields. d DMF/H2O (3:1) as solvent. e pure DMF as

solvent.

Pd/C Catalyst reusability

The reusability of the Pd/C A1 catalyst was also examined for the coupling of


114

1 with 3 using KF as the base in DMF/H2O (3:1). After the first run the

catalyst was separated by simple vacuum filtration, washed with acetone and

dried at 50 ºC under vacuum for 4 h. The dried catalyst was then reused

without any further activation. The same procedure was repeated for all

further cycles (Figure 1). The catalyst showed a slight decrease in the activity

after the first cycle, but retained its activity in all further cycles.

0

10

20

30

40

50

60

70

1 2 3 4 5 6

Reaction cycles

CN

-C6H

4-C

l co

nver

sion

/ %

Figure 1. Recycling experiments for Pd/C in Domino HALEX-Sonogashira

reaction.

Possible variation using catalytic KI

An attractive variation on this one-pot process would be to use KI in catalytic

amounts. If we can initiate the HALEX reaction using a catalytic amount of

KI, the resulting iodide 2 would then readily react with 3 to give the

Sonogashira product 4 plus HI. This acid could be neutralized by excess KOH

releasing KI back to the system and closing the cycle (scheme 1). This cycle

can continue until the aryl chloride is consumed. We investigated this

approach under various conditions but unfortunately we failed as yet to obtain

any Sonogashira product. Although in theory the acid-base reaction step looks

simple, it is possible that under our reaction conditions this step fails. One

reason for this may be the low solubility of KOH and/or the reactants in the

DMF/H2O (3:1) solvent. We could not find an optimum ratio of DMF/H2O


115

where both KOH and the reactants were completely soluble.

KI

IR

HI

ClR

KClPd/C

Ph

Pd/C

PhR

KOH

H2O

Scheme 1. A variation on the one-pot HALEX-Sonogashira reaction using

catalytic KI.

Conclusion

In conclusion, we have demonstrated that it is possible to activate aryl

chlorides and bromides via a one-pot consecutive HALEX-Sonogashira

process, using Pd/C catalysts under ligand-free and Cu-free conditions. The

yields are good and the catalysts separation is simple and quantitative. This

can provide an attractive alternative to the homogeneous Pd complexes

generally used for activating these halides.

Experimental


1H NMR spectra were recorded in CD2Cl2 on a 300 MHz Varian Inova

instrument. Chemical shift values are in ppm relative to Me4Si. Melting points

were measured on a Gallenkamp melting point apparatus and are


116

uncorrected. GC analysis was performed using an Interscience GC-8000 gas





spectral properties to those of authentic samples. Samples for GC were

washed with an equivalent amount of water, extracted with hexanes and

filtered through an alumina plug prior to injection. GC conditions: isotherm at

105 ºC (2 min); ramp at 30 ºC min 1 to 280 ºC; isotherm at 280 ºC (5 min). All

reactions were carried out under N2 atmosphere. 5 wt% Pd/C pellets A1 were

obtained from Alfa-Ventron and 5 wt% Pd/C powder A2, 5 wt% Pd/Al2O3 and

10 wt% Pd/BaSO4 were purchased from Fluka. The textural analysis of the

catalysts (A1 and A2) was performed by means of nitrogen adsorption at 77K,

using a Sorptomatic 1990 of CE Instruments. The isotherms were both of type

I, indicating a microporous structure. The monolayer equivalent surface area

was calculated according to Horvath Kawazoe equation.46 All other chemicals

were purchased from commercial firms and were used as received.

Halogen exchange reaction of 4-Chlorobenzonitrile using KI

A Schlenk-type glass reactor equipped with a rubber septum, reflux condenser

and a magnetic stirrer was evacuated and refilled with N2. The reactor was

then charged with Pd/C (3.0 mol%) and KI (0.50 g, 3.0 mmol) in DMF. 4-

Chlorobenzonitrile (1.0 mL, 1.00 M, 1 mmol) was added and the mixture was

stirred at 130 ºC for 48 h under a slight N2 overpressure. Reaction progress

was monitored by GC.

Pd/C catalysed coupling of phenylacetylene with iodobenzonitrile

The reactor was charged with Pd/C (3.0 mol% Pd relative to aryl halide),

phenylacetylene (2.0 mL, 1.0 M, 1.5 mmol) and KF (0.14 g, 2.5 mmol) in

DMF/H2O (1:1). 4-Iodobenzonitrile (1.0 mL, 1.00 M, 1 mmol) was added and


117

the mixture was stirred at 130 ºC for 8 h under a slight N2 overpressure.

Reaction progress was monitored by GC.

Screening of catalysts and substrates for one-pot HALEX-Sonogashira

reaction

Sets of 16 reactions were performed using a Chemspeed Smartstart 16-

reactor block, modified in-house for efficient reflux and stirring. The reactors

were charged with Pd catalysts (3.0 mol%), phenylacetylene (2.0 mL, 1.0 M,

1.5 mmol), base (2.5 mmol), iodide source (3.0 mmol) and aryl halide (1.0 mL,

1.00 M, 1 mmol). The reactors were evacuated and refilled with N2 three times

and the mixture was stirred at 130 ºC for 48 h under a slight N2 overpressure.

Reaction progress was monitored by GC (pentadecane internal standard).

Pd/C catalysed one-pot HALEX-Sonogashira reaction

Example (1) 4-cyanodiphenylethyne from 4-chlorobenzonitrile. A

Schlenk-type glass reactor equipped with a rubber septum, reflux condenser

and a magnetic stirrer was evacuated and refilled with N2. The reactor was

then charged with Pd/C (3.0 mol%), phenylacetylene (0.41 g, 4.0 mmol), KF

(0.37 g, 6.3 mmol) and KI (1.30 g, 7.8 mmol). 4-chlorobenzonitrile (0.36 g, 2.6

mmol) was added and the mixture was stirred at 130 ºC for 48 h under a slight

overpressure of N2. After 48 h the reaction mixture was poured into a

separatory funnel, diluted with water (20 mL) and extracted with hexanes (3

15 mL). The organic layers were combined, dried over anhydrous MgSO4 and

concentrated under vacuum at 25 ºC to yield 0.15 g of yellow product (43 wt. %

yield based on 4- chlorobenzonitrile). The crude material was recrystallised

from hot ethanol to give a light yellow solid, mp = 107–109 ºC.34 1H NMR: H

7.61 (m, 4H), 7.53 (d, 2H, J = 8.2 Hz), 7.42 (m, 3H). Good agreement was found

with literature values.34


118

Example (2) 4-diphenylacetylene from 4-bromobenzene. Reaction and

work-up were performed as above, but using 4-bromobenzene (0.40 g, 2.6

mmol) to give 0.33 g of product (82.5 wt. % yield based on 4-bromobenzene).

The crude material was recrystallised from hot ethanol to give a white

needles, mp = 57–58 ºC. 1H NMR: H 7.61 (m, 4H), 7.40 (m, 6H). Good

agreement was found with literature values.7

Catalyst reusability

For reusability studies the catalyst used in a preparative scale was separated

using a vacuum filter, washed with acetone (3 10 mL) and reused after

drying at 50 ºC. All further runs were similar to that described for the fresh

catalyst. Reaction samples were analysed by GC.

Pd/C catalysed one-pot HALEX-Sonogashira reaction using catalytic

KI

The reaction set-up and the pre-reaction procedure were similar to that used

in domino HALEX and Sonogashira reaction performed on a preparative scale.

The reactor was then charged with Pd/C (3.0 mol%), phenylacetylene (0.41 g,

4.0 mmol), KF (0.23 g, 4.0 mmol) and KI (0.02 g, 0.13 mmol, 5 mol%). 4-

chlorobenzonitrile (0.36 g, 2.6 mmol) was added and the mixture was stirred

at 130 ºC for 48 h under a slight overpressure of N2. Reaction progress was

monitored by GC.

References


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(4) Erdélyi, M.; Gogoll, A. J. Org. Chem. 2001, 66, 4165.


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(5) Leadbeater, N. E.; Tominack, B. J. Tetrahedron Lett. 2003, 44, 8653.

(6) Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org. Chem. 1993, 58,4716.

(7) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315.

(8) Kang, S. K.; Yoon, S. K.; Kim, Y. M. Org. Lett. 2001, 3, 2697.

(9) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843.






(15) Choudary, B. M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc. 2002, 124, 14127.

(16) Böhm, V. P. W.; Herrmann, W. A. Eur. J. Org. Chem. 2000, 3679.

(17) Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 5752.

(18) Djakovitch, L.; Rollet, P. Adv. Synth. Catal. 2004, 346, 1782.

(19) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 4176.

(20) Alami, M.; Crousse, B.; Ferri, F. J. Organomet. Chem. 2001, 624, 114.

(21) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642.

(22) Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2005, 46, 1717.

(23) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.; Lee, H. M.; Yang, C. L.; Nolan, S. P. J.Organomet. Chem. 2002, 653, 69.

(24) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729.

(25) Köllhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem. Int. Ed. 2003, 42, 1056.

(26) Gelman, D.; Buchwald, S. L. Angew. Chem. Int. Edit. 2003, 42, 5993.



(29) (a) Papp, A.; Miklos, K.; Forgo, M.; Molnar, A. J. Mol. Catal. A: Chem. 2005, 229, 107. (b) Horniakova, J.; Raja, T.; Kubota, Y.; Sugi, Y. J. Mol. Catal. A: Chem. 2004,217, 73. (c) Corma, A.; Garcia, H.; Leyva, A.; Primo, A. Appl. Catal. A 2004, 257, 77. (d) Yamada, Y. M. A.; Takeda, K.; Takahashi, H.; Ikegami, S. J. Org. Chem., 2003, 68, 7733. (e) Biffis, A.; Zecca, M.; Basato, M. Eur. J. Inorg. Chem. 2001, 1131. (f) Augustine, R. L.; Oleary, S. T. J. Mol. Catal. A 1995, 95, 277. (g) Conlon, D. A.; Pipik, B.; Ferdinand, S.; LeBlond, C. R.; Sowa Jr., J. R.; Izzo,B.; Collins, P.; Ho, G. J.; Williams, J. M.; Shi, Y. J.; Sun, Y. K. Adv. Synth. Catal., 2003, 345, 931.

(30) Heidenreich, R. G.; Köhler, K.; Krauter, J. G. E.; Pietsch, J. Synlett 2002, 1118.

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Chapter 7 Trapping metal nanoclusters in ‘soap and water’ soft crystals

121


Trapping metal nanoclusters in ‘soap and water’ soft

crystals*

Abstract

Stable metal nanoclusters (~2 nm in diameter) coated with hydrophobic coronas are

easily trapped in self-assembled ‘soft crystal’ hexagonal phase gels made of water and

surfactants. The system’s crystal structure and phase behaviour are studied in detail.

High-energy x-ray scattering and cross-polarised optical microscopy experiments

show that the clusters are tightly confined within the tubes. The thermal gel-fluid

transitions of the hexagonal phase are investigated, and it is shown that the

hexagonal phase can melt and re-crystallize repeatedly. The melt/gel cycles enable

easy trapping of various metal clusters in pre-prepared hexagonal phases.

* Part of this work has been published: F. Bouchama, M. B. Thathagar, G. Rothenberg, D. H. Turkenburg and E. Eiser, Langmuir, 2004, 20, 477. ChemPhysChem, 2003, 4, 526.

= Cu, Pd, Ag, Au, Ru

N+

N+

+N

+N

+N


122

Introduction

During the past decade, nanomaterials science evolved to an active research

field that spans many areas of physics and chemistry.1-11 The possibilities

range wide: nanomagnets will store information for superfast computers,12

nanowires will string together nanoelectronic circuits,13,14 and nanomachines

will bring about a revolution in modern medicine.15 Caveat emptor, however,

before investing in nano-futures: To become a part of everyday life,

nanomaterials and nanomachines will have to be inexpensive and easily

manufactured. There is a gap, for example, between assembling metal

nanowires using STM tips and their large-scale manufacturing.

One way to bridge this gap is to use a self-assembly approach, utilising the

periodicity on the nanometer scale of ‘soft solids’, such as liquid crystals.16 The

direct hexagonal phase that self-assembles from water/surfactant mixtures is

a good example.17,18 High concentrations of surfactants in water yield

spherical micelles that, in the presence of an alcohol co-surfactant, elongate to

form long tubes that pack in hexagonal order. The result is a ‘soft crystal’ gel

(see Figure 1) that is stable, well defined, and inexpensive. Such gels were

used to grow large iron and cobalt nanocluster wires, and noble metal

clusters,19,20 and as lyotropic cages for ferrous oxide fluids.21-23

In this chapter, we show a simple and general method to confine very small

metal clusters in hexagonal micellar rods. Here we present a detailed study of

the system’s crystal structure and phase behavior, and demonstrate that

melting the hexagonal phase facilitates the incorporation of “hydrophobized”

metal clusters. High-energy X-ray scattering measurements and other optical

techniques provide evidence that the nanoclusters are indeed embedded inside

the hexagonal phase. Finally, we discuss the possibility of growing metal

nanowires by self-assembly from tightly confined clusters.


123

Ag Au None Pd


Ag Au None Pd


Figure 1. Soft crystal gels containing metal nanoclusters (left) and cartoon

showing the incorporation of the clusters (middle) with their hydrophobic

coronas into the hexagonally arranged micellar tubes (right).


Self-assembly of the hexagonal phase

The direct hexagonal phase was prepared by mixing sodium dodecyl sulfate

(SDS) and water at a 1:2.5 ratio with 5 wt% n-pentanol as co-surfactant. In

pure water the SDS molecules form almost spherical micelles with an average

diameter of 3.6 nm.24 On addition of pentanol the average ratio between

headgroup-surface and tail-volume of the mixed micelles changes, favoring the

formation of wormlike micellar tubes.25 At high concentrations, these tubes

align to form a hexagonal phase. Earlier, Ramos et al.23 studied the pseudo-

ternary phase diagram of SDS/water, pentanol, and cyclohexane, where latter

is the lipophilic swelling agent. Here we are interested in how this phase

diagram changes as we replace the oily phase by toluene, because this solvent

is essential for trapping the metal nanoclusters inside the wormlike micelles

(the clusters are not sufficiently stable in other nonpolar solvents).

The hexagonal phase samples were prepared at 40 C in sealed vessels. As

pentanol concentrations increased, the wormlike micelles began growing

spontaneously, yielding a rigid, viscoelastic gel. The ternary phase diagram of

SDS, water, and pentanol displays a region where the wormlike micelles are

arranged in a hexagonal order. This region is characterized by a homogeneous


124

powder-crystalline phase.26 Further addition of pentanol changes the

curvature of the micelles even more, leading to a transition from the

hexagonal to a lamellar phase.† Adding toluene to the system extends the

hexagonal domain in the phase diagram in a similar way to cyclohexane.

However, this domain is slightly smaller than when using cyclohexane as a

swelling agent21,23 (the maximum swelling that can be obtained with toluene is

25 weight %). Figure 2 shows the partial phase diagram of the pseudo-ternary

SDS+water/pentanol/toluene system. The phase boundary that marks the

wormlike hexagonal phase was verified by cross-polarized optical microscopy.

Only the hexagonal phase region was studied, as our objective was to confine

nanoparticles in the well-defined cylindrical micellar structure. This phase is

a clear gel that does not separate even after centrifuging for 5 min at 200 g.

Pentanol SDS

0 20 40 60 80 100

80 20

Pentanol

TolueneSDS + Water

Hexagonal phase

Pentanol SDSPentanol SDS

0 20 40 60 80 100

80 20

Pentanol

TolueneSDS + Water

Hexagonal phase

0 20 40 60 80 100

80 20

Pentanol

TolueneSDS + Water

Hexagonal phase

Figure 2. Partial phase diagram showing the hexagonal phase region (shaded

area, top, the SDS:water ratio is 1:2.5 w/w) and structural parameters for the

aligned tubes (bottom).

The self-assembled cylinders are arranged on a hexagonal lattice with a lattice

constant d0. One can swell this pure hexagonal phase by either increasing the

† Samples that became fluid due to such a hexagonal-to-lamellar transition were not used for doping with metal clusters.


125

cylinders’ diameter (e.g. by adding a hydrophobic agent that dissolves in the

tubes), or by diluting the system with water. In the latter case the tube

diameter stays constant but the inter-rod spacing increases. Increasing the

tube diameter, however, does not necessarily lead to the increase of the lattice

spacing d0. The cylinders can be swollen with toluene up to a value of 25 wt%.

The growth of the hexagonal structure in time was monitored using cross-

polarised optical microscopy. Figure 3a–d shows the time-resolved

development of a ‘non-swollen’ hexagonal texture. The transition from a

micellar liquid to a hexagonal gel is rapid. Initially, the sample is

homogeneously gray with small spherulites (Figure 3a). On preparation of the

hexagonal gel, the transition from the spherical micelle solution to the hard

gel occurs within a few seconds. This suggests that the wormlike micelles grow

fast and that it is their geometric extension that leads to the gel transition.

Once formed, however, the alignement of the long tubes into a well-defined

hexagonal phase slows dramatically because of the geometric constraints

posed by the tubes. This is reflected in the large gray domains representing an

isotropic distribution, and the few small nuclei (seen as spherulites) of

hexagonal symmetry. In time, the domains grow at the expense of the

isotropic phase , and merge to form a network (see Figures 3b and 3c where

the time differences a b and b c are 1 and 5 minutes, respectively). After

two days the numerous micron-sized grains grow to form fewer and larger

spherulites (Figure 3d, see also Figure 9). This texture is common to rod-like

and helical lyotropic liquid crystals such as DNA27 and polypeptides.28 It

corresponds to an orientation of the tubes parallel to the confining glass plates

caused by the anisotropy of the anchoring energy. As the in-plane orientation

of the particles is not constrained, we observe different orientations in the fan-

shaped texture. Striations that are due to a slight cooperative undulation of

the lyotropic tubes are also observed. On average, the tubes are oriented

perpendicular to the striations.28,29


126

25 m25 m

Figure 3. Cross-polarised optical micrographs of a lyotropic hexagonal phase, showing the formation and

growth of the striations. (a) Fresh sample. (b) after 12 h, (c) after 24 h, (d) after 48 h. The samples’

composition was SDS/water (1:2.5 w/w) plus 4 wt% 1-pentanol. The striations result from slight

cooperative undulations of the cylinders, that is typical for a ‘soft’ hexagonal texture.

The growth of the birefringent domains is due to the continuous growth of the

wormlike micelles, reflecting the higher energy cost to form the hemisphere-

like endcaps.30 This illustrates an important difference between the hexagonal

phase and dilute solutions: The distribution of the lengths of wormlike

micelles in dilute solutions is large, with a standard deviation in the order of

the square root of the mean aggregation size.25 There is a maximum length,

however, beyond which wormlike micelles will break up due to thermal

fluctuations. In contrast, the cylinder length can grow as large as the

container size.

Thermal gel-fluid transitions of the hexagonal phase

The ‘empty’, non-swollen hexagonal phase is stable at room temperature up to

about 50–55 C. Above 55 C, the gels become fluid (no birefringent texture

can be observed by cross-polarised microscopy). However, when cooled back

down to 25 ºC, the fluid regains its liquid-crystalline structure and gel-like

properties. Figure 4 shows the SAXS intensity spectra of gel samples

measured from 24.0 C up to 59.7 C. These were obtained by azimuthal

integration of the corresponding 2D spectra shown in figure 5.


127

1.0 1.5 2.0 2.5 3.00.0

3.0x103

6.0x103

9.0x103

Inte

nsity

(a.u

.)

q-vector

24.0 oC 44.8 oC 49.7 oC 59.7 oC

1.0 1.5 2.0 2.5 3.00.0

3.0x103

6.0x103

9.0x103

Inte

nsity

(a.u

.)

q-vector

24.0 oC 44.8 oC 49.7 oC 59.7 oC

Figure 4. X-ray scattering intensities I(q) of an ‘empty’ hexagonal phase at

different temperatures, obtained by azimuthal integration of the 2D SAXS-

spectra shown in Figure 5. Sample composition is as in Figure 3.

24°C

59.7°C

44.8°C

54.7°C

49.7°C

27.3°C

24°C

59.7°C

44.8°C

54.7°C

49.7°C24°C24°C

59.7°C59.7°C

44.8°C44.8°C

54.7°C54.7°C

49.7°C49.7°C

27.3°C

Figure 5. 2D SAXS-spectral images of an ‘empty’ hexagonal phase over the

temperature range 25–55 ºC. Sample composition is as in Figure 3.


128

At 24.0 C, the SAXS experiments performed on freshly prepared samples

show a typical scattering pattern for a hexagonal symmetry with a Bragg peak

ratio of 2:3:1 (q0 = 1.22 nm–1; q1 = 2.12 nm–1; q2 = 2.44 nm–1). This pattern

corresponds to a powder crystalline sample with randomly oriented grains,

where the intensity is uniformly distributed along diffraction rings. When the

sample is heated to 49.7 C the peaks shift to higher values and broaden while

a preferred orientation of the sample appears in the 2D spectrum as

reinforcement along the qx-axis. This means that the rods align in the real

space perpendicular to the beam and to the x-axis. Indeed, as the gel is heated,

its viscosity reduces due to the increased breaking-rate of the wormlike

micelles with the temperature.31 The wormlike micelles become shorter and

hence increasingly mobile up to 49.7 ºC, but the ratio between the consecutive

diffraction peaks remains that of a hexagonal order. This continuous

shortening of the rods with the temperature may lead to a phase transition

when the melting point is reached, from an ordered hexagonal phase through

an intermediate nematic and finally to an isotropic liquid phase. When the

system is heated above 55 ºC all order is lost, and the 2D spectrum displays a

very broad isotropic ring (Figure 5) typical for liquids. When the system is

cooled down back to 27.3 ºC, the system recovers its hexagonal structure

(Bragg peaks at 1.24, 2.15, and 2.48 nm–1, see Figure 3b at 27.3 ºC) but its

lattice parameter is slightly smaller. This effect is, most likely, due to

evaporation of part of the water during heating.

It is interesting to note in Figure 5 that at 27.3 ºC the newly formed powder-

crystalline x-ray diffraction pattern is rather grainy. This suggests that the

sample forms a few large, homogeneous domains. Although not shown here,

similar behavior was found in the optical microscopy experiments, where

under crossed polarizers, the birefringent texture of the hexagonal phase

disappears on heating the sample above 50°C and reappears on cooling.


129

The reversible thermal gel-fluid transition of the hexagonal phase is simply a

direct consequence of the system being in thermodynamical equilibrium.

However, the fact that we can melt the gels is a great advantage, because we

can add materials of interest to the hexagonal phase after it has been already

prepared. The gel phase is highly viscous and difficult to work with – it takes

many days for nanoclusters to diffuse into the micelles. By melting the system

we overcome this problem, rendering the mixing almost instantaneous!

Doping the hexagonal phase with metal nanoclusters

Pd, Ru, Ag, Au, and Cu nanoclusters were prepared by extracting the metal

salt precursors into toluene with tetraoctylammonium bromide (TOAB),

followed by reduction with NaBH4.32 TOAB forms a stabilizing hydrophobic

shell (ca. 1.2 nm thick33) around the metal clusters. This ‘hairy shell’ is similar

to the hydrophobic environment of the core of the wormlike micelles.34,35

Depending on the metal precursor, the metal core diameter ranged between

1.5 and 2.5 nm. Thus the average total diameter of the stabilised clusters was

ca. 4.4 nm.‡

The doped quaternary systems show the existence of a birefringent phase,

with a texture characteristic of a hexagonal phase. The cross-polarised images

are similar to those observed for non-doped samples, with the typical

striations of the undulating ordered wormlike micelles. At this concentration,

the presence of the metal particles within the phase does not destabilise its

order. Moreover, neither phase separation of the gels, nor aggregation of the

metal clusters was observed after centrifuging the doped gels for 15 min at

200 g.

‡ In all of the doped systems, the hexagonal phase was made from SDS:water 1:2.5 w/w, with 4 wt% pentanol and swollen with 5 wt% toluene containing metal clusters. This low swelling ratio was chosen in order to tightly confine the clusters in the tubes.


130

Figure 6 shows the SAXS intensity spectra measured for both non-doped and

doped samples for two concentrations of Pd clusters. We observe a typical

scattering pattern for hexagonal symmetry with a Bragg peak ratio of 2:3:1

(q0 = 1.16 nm–1; q1 = 2.03 nm–1; q2 = 2.34 nm–1). Samples Pd nanoclusters show

higher scattering intensities compared to the ‘empty’ ones. In addition, the

higher the concentration of Pd nanoclusters is, the higher the overall

scattering intensity. This is to be expected.§

1.0 1.5 2.0 2.5 3.00

1x104

2x104

3x104

Inte

nsity

(a.u

.)

q-vector

non doped doped c1 doped c2

q0

q1

q2

1.0 1.5 2.0 2.5 3.00

1x104

2x104

3x104

Inte

nsity

(a.u

.)

q-vector

non doped doped c1 doped c2

q0

q1

q2

q0

q1

q2

Figure 6. X-ray scattering intensities I(q) of ‘empty’ and palladium-doped

hexagonal phases at two different metal concentrations: c1 = 5 mol/mL and c2

= 15 mol/mL of palladium nanoclusters in toluene. Intensities were obtained

by azimuthal integration of the 2D-spectra shown in the inset for c2. The

arrows correspond to the Bragg diffraction peaks q0 = 1.16 nm–1, q1 = 2.03 nm–

1 and q2 = 2.34 nm–1. The hexagonal order is not destabilized or deformed by

the presence of nanoclusters within the phase.

§ The increased scattering intensity reflects the metals’ higher electron density when compared to the H, O, and C atoms that make up the water/surfactant background. As x-rays only interact with the electrons of the scattering medium, the scattering intensity is proportional to the electron densities in the system. This is why the contrast in systems made of light atoms is enhanced by the addition of heavy ions. The more heavy ions in the system, the stronger the contrast (assuming, as is the case here, a constant scattering volume).


131

We also see that independent of the metal-cluster concentration, the location

of the Bragg peaks and the full-width at half maximum intensity (6 10–3 Å–1)

is unchanged. This indicates that the lattice spacing of the doped phase, d, is

not different from the non-doped phase, d0, and that the long-range positional

order is not disturbed by the presence of the nanoclusters. Furthermore,

comparing the asymmetry in the 2D-SAXS spectra (Figure 6, inset) with the

micrograph results we see that the rod-like micelles form large homogeneous

domains. These domains are often oriented with the rods parallel to the cell

surfaces; however, in some cases we also observed a perpendicular

arrangement. All these results indicate that the presence of the nanoclusters

does not disturb the structure of the wormlike hexagonal phase.

Although this method gives some quantitative information on the structure it

is not specific enough for unambiguous determination of the exact nature of

the phase. It gives the size of the repeat unit, d, but not the direct location of

the clusters. When the system is doped with metal nanoclusters, two

situations can be considered: either the clusters are located inside the tubes

(Figure 7, left), or that the clusters are at the interstitial spaces of the

hexagonal packing with their hydrophobic coronas interdigitised with the

surfactant tails on the walls of the tubes (Figure 7, right). The former case will

give rise to the same hexagonal lattice diffraction as the surfactant phase,

with higher scattering intensities of the latter. The latter alternative will give

a honeycomb lattice that has a triangular lattice in the reciprocal room. The

real lattice spacing would thus be larger than the one of the hexagonal order

of the micelles, which would show up as diffraction peak at lower q-values.**

As the scattering intensities obtained for the 'empty' and 'doped' hexagonal

** SDS can also form spherical micelles, which may form a monolayer on top of the hydrophobic corona of the TOAB molecules with the heads facing the aqueous background. High diffusion coefficients would allow a constant exchange of SDS molecules between the wormlike micelle and the cluster shell.The clusters could thus remain in the interstitial positions, forming a honeycomb structure. This structure is also hexagonal, but it lacks the central lattice site. The smallest repeat unit has to be a hexagonal ring – not a rombohedral unit as in a true hexagonal structure. Thus, although the scattering image of both structures would display a hexagonal pattern, the extinction rules are different and the intensity of different orders would be different, as would the shortest scattering vector q.


132

phase show the same profiles with diffraction peaks at the same position, we

believe that the nanoclusters are indeed situated inside the tubes.

Figure 7. Schematic representation of the two possible arrangements for the

cluster-doped hexagonal phase. (left) the nanoclusters are located inside the

wormlike micelles; (right) the clusters are located inside the interstitial spaces

of the hexagonal structure with their lipophilic coronas inter-digitized with

the surfactant tails molecules on the walls of the tubes. The SAXS results and

the microscopy experiments point the alternative on the left as the correct

structure.

It is also possible to discriminate the two situations by using simple geometric

considerations. The position of the first peak, q0, is related to the distance

between the centers of adjacent tubes, d, through 0

23

2q

d . With q0 = 1.16

nm–1 (Figure 5) we obtain d = 6.25 nm. Eq 1 relates the tube radius, R, to the

lattice parameter, d, where p is the volume fraction of the polar medium

including the water but as well the polar ‘heads’ of surfactants and co-

surfactants.

21

)1(2

3pdR (1)

Assuming that all surfactant and co-surfactant molecules are located at the


133

interface, we estimate the volume fraction of the organic medium to be

62.01 po and obtain R = 2.6 nm, and l = d-2R = 1.0 nm, with l being

the distance between tubes. This l is too small: there is no room for the

particles to sit in the interstices. Therefore, to host 4.4 nm diameter size nano-

clusters without deformation of the hexagonal order, the only possible

structure is a direct wormlike hexagonal phase with the clusters incorporated

inside the non-polar tubes.

Solubility and phase separation experiments further support our thesis that

the clusters are located inside the tubes. When water was mixed with metal

cluster suspensions in toluene a typical macroscopic oil/water phase

separation was observed. Although our metal clusters are too small to show

typical colors due to their plasmon-absorption, a dispersion of these clusters in

toluene is colored. The interface between the colored oil phase and the

colorless aqueous phase stayed sharp for weeks, and both phases retained

their refractive index. This phase separation prevailed also when small

concentrations of SDS were added in water. Based on this observation, and

the SAXS and micrograph measurements, we conclude the clusters do not

dissolve in the pure micellar SDS/water phase.

One-dimensional confinement of metal nanoclusters

The small tube radius indicates that the clusters are tightly confined inside

the tubes and their hydrophobic coronas are interdigitized with the surfactant

tails on the tube walls. This means that at this swelling ratio, the clusters are

free to move only in one dimension. This concept is general and can be applied

to many metal clusters. Figure 8 shows the SAXS intensity spectra for the

hexagonal phase doped with Ru, Ag or Au clusters. The location of the peaks

shows no variation irrespective of the metal, and their ratio of 2:3:1 (q0 =

1.22, q1 = 2.11, and q2 = 2.44 nm–1) does not change. Doping with Cu and Pt


134

(similar images, not shown) gave similar results. Regardless of the metal, the

hexagonal structure is thus the same and the nanoclusters are confined inside

the wormlike micelles in one dimension.

1.0 1.5 2.0 2.5 3.00

1x104

2x104

Inte

nsity

(a.u

.)

q-vector

Ru Ag Au

1.0 1.5 2.0 2.5 3.00

1x104

2x104

Inte

nsity

(a.u

.)

q-vector

Ru Ag Au

Figure 8. X-ray scattering intensities I(q) of doped hexagonal phases

containing different metals: Ru, Ag, Au. The sample composition is

SDS+water 1:2.5 w/w, 4 wt% 1-pentanol and 5 wt% toluene containing 5

mol/mL metal nanoclusters.

However, a specificity of the metal was observed on the alignment of the phase

along the surfaces of the cell. It appeared that the hexagonal phase doped with

Ru evolves into much larger domains, with the rod-like micelles standing

perpendicular to the cell walls. This ordering is illustrated in Figure 9, where

we present the 2D spectra of a hexagonal phase doped with Ru and one doped

with Au, immediately after confining the phase in mica windows (Figure 9,

left) and after 60 days (Figure 9, right). After 60 days, the 2D-SAXS image of

the Ru-doped phase displays the signature of a twinned single crystal (the

twinning is observed as a double Bragg-peak), whereas, the Au-doped sample

shows no real change in the ordering of the sample after the same aging time.


135

Furthermore, all other metal-doped samples also showed the initial alignment

parallel to the cell walls at all times. This shows that our approach to trap

various metal nonoclusters is general, although slight variations in the

alignment behavior are observed for different metals.

0 days 60 days

Ru

Au

Ru

Au

0 days 60 days

Ru

Au

Ru

Au

Figure 9. 2D SAXS spectra of hexagonal phases doped with ruthenium

clusters (top) and gold (bottom) clusters. Two ageing times are shown:

immediately after preparation (left) and after 60 days (right). The Ru-doped

samples age with much larger domains with the wormlike micelles standing

perpendicular to the cell walls.

An interesting question that remains open is whether this concept can be also

used to make ultrathin nano-wires by cold-welding. Pure metals have typically

high surface tensions and therefore high melting points. However, when the

metal grain size (or cluster size) is < 10 nm, the metal is no longer a bulk


136

entity. Instead, as metals tend to exhibit surface melting, liquid-like disorder

can be observed in small metal clusters at temperatures well below the

melting point, as these particles have a large surface-to-volume ratio. Small

clusters of ductile metals such as Au, Pd, Cu and Ag tend to have a reduced

surface free-energy density and a reduced melting point, enabling the nano-

clusters to cold-weld together (this does not pertain to particles covered with

metal oxide layers).25,36 By confining the nano-clusters to cylindrical micelle

rods, we may succeed in directing their cold-welding so that they grow into

anisotropic clusters, in a similar process as described by Tang et al.38

Experiments on the same metal clusters in bulk toluene show that the nano-

particles tend to aggregate into large metal clusters. This implies that cold-

welding between the clusters can take place, although thee hydrophobic

coating can be a problem (in most cases, aggregation of nanoclusters is due to

their poor passivation by surface ligands, and well-passivated nanoclusters

are not expected to fuse together without any external driving force). Catalysis

is another area in which the potential of this nanostructured materials can be

explored.

Conclusions

Self-assembly is an attractive synthesis concept for nanostructured materials,

and can, in the case of metal quantum dots and SDS/water soft crystals, be

applied on gram scale using simple equipment. For various metals, cluster

confinement is so tight that interdigitising of the hydrophobic coronas with

the tube walls is evident. The fact that the hexagonal phase can easily be

melted and recrystallised within a narrow temperature range (25–55 ºC) can

facilitate future applications of these systems where metal clusters are

confined in one dimension. Furthermore, the seemingly endless growth of the

cluster-doped hexagonal phase may open avenues to synthesise directed

strucutres and arrays that have nanometric as well as micrometric

dimensions.


137


High-energy small-angle X-ray scattering (SAXS) measurements were

performed on the BM26 High Brilliance Dutch-Belgium beam line (DUBBLE)

at the European Synchrotron Radiation Facility (ESRF, Grenoble). The

sample to detector distance was fixed at 3.3 m. The energy of the X-ray

photons was 18 keV ( = 0.69 Å, exposure time 5 min). A differential scattering

calorimetry cell (Linkam optical DSC600) was used to allow simultaneous X-

ray scattering and temperature measurements. This setup was used for all

SAXS measurements, except long-term aging measurements of Ru-doped and

Au-doped samples that were performed in-house.

The in-house SAXS experiments were performed using a rotating anode

(Rigaku, ultraX 18S) with a copper target ( = 1.54 Å). The 2D-image plate

detector (MAR345) can be placed after the sample at separations ranging from

0.2 m to 1.5 m (typical distance 1.16 m, unless noted otherwise), allowing also

for wide-angle scattering measurements. For separations larger than 1 m, a

vacuum pipe with Kapton windows was placed between the sample and the

detector to minimize air scattering. The scattering wave vectors ranges

between 0.5 and 10 nm–1, the instrumental width being approximately 5 10–2

nm–1. The samples were placed between two 30 µm thick mica sheets spaced

by a 1 mm glass object plate with a 5 mm wide window in its center holding

the sample. The sample cells were sealed with vacuum grease (Glisseal, Borer

Chemie). Typical exposure times were 30 min to 1 h.

Cross-polarised optical microscopy was performed using an Olympus BH-2

microscope coupled to a Leica DM-IRB digital camera. Samples were placed

between glass plates and sealed with vacuum grease to enable aging

observations. Centrifuging was performed using an Eppendorf 5412 centrifuge

at 200 g. Unless noted otherwise, chemicals were purchased from commercial

sources (>99% pure) and used as received. Sodium dodecyl sulfate (SDS), 1-


138

pentanol and toluene were purchased from Acros. All aqueous solutions were

made with Millipore water. Pd, Au, Ag, or Ru clusters and the soft crystal gels

doped with these clusters were prepared as previously published.32, 22

Preparation of the ‘empty’ (undoped) hexagonal phase

Sodium dodecyl sulphate (SDS, 0.090 mmol, 26.00 g) was mixed with water

(65.00 g) at 70 ºC until a homogeneous clear solution containing SDS micelles

(1:2.5 w/w SDS:H2O) was obtained. This stock solution was used in all of the

experiments. Toluene (0.16 mL, 0.14 g) was added dropwise at 50 ºC to 2.50 g

of this stock solution to swell the micellar phase. Then, the cosurfactant 1-

pentanol (0.13 mL, 0.11 g) was added dropwise to the swollen micellar phase

to give a clear gel of hexagonally ordered wormlike micelles.

The doped hexagonal phase was prepared using the same procedure as above

except that an equivalent amount of toluene containing the stabilized metal

nanoclusters was used.

Synthesis of the metal nanoclusters

Example. Palladium nanoclusters isolated and redispersed in toluene. A

Schlenk-type vessel equipped with a rubber septum and a magnetic stirrer

was evacuated and refilled with N2. PdCl2 (0.2 mmol, 35.4 mg),

tetraoctylammonium bromide (TOAB, 0.2 mmol, 109.3 mg) and toluene (50

mL) were injected into the vessel and 0.25 mL of 26.0 mM aqueous NaBH4

was added dropwise over 1 h to reaction mixture at 20 ºC. The mixture was

stirred for another 2 h to obtain the clusters as a black suspension in the

toluene phase. The phases were then separated and the toluene phase

containing the clusters was dried under vacuum (0.1 KPa, 40 ºC) to give the

clusters as a dry black powder. The clusters were then weighed and re-

dispersed in an exact volume of toluene to give the desired concentration.


139

Nanocluster suspensions of Au, Ag, Ru and Cu were prepared in a similar

manner using HAuCl4, AgNO3, RuCl3, and CuCl2 as presursors. The

suspensions were prepared in concentrations of 0.030 M, 0.075 M, and 0.15 M.

In situ synthesis of the nanoclusters inside the hexagonal phase

Example. Palladium nanoclusters. 2.5 g of an ‘empty’ hexagonal phase was

prepared as above and then melted at 55 ºC. A mixture of TOAB (0.016 mmol,

8.7 mg) and PdCl2 (0.016 mmol, 2.8 mg) in toluene was added to the colorless

viscous liquid and stirred until a homogeneous orange-colored phase was

obtained. Ca. 0.1 mL of 26.0 mM aqueous NaBH4 was added and the liquid

changed color immediately turned to transparent carbon black. The sample

was then cooled down to 20 ºC to regain its original gel-like form.

The in situ synthesis of gold nanocluster was performed in a similar manner

using HAuCl4 as the presursor.

Notes on interpretation of SAXS and microscopy experiments

SAXS measurements

The scattering pattern of a hexagonal phase exhibits 3 Bragg peaks with

position ratios 1: 3: 4: 7. The position of the first peak q0 is related to the

distance between the centers of adjacent tubes, dc, through 0

23

2q

dc . Using

geometrical considerations, we can relate the radius of the tubes r to the

lattice parameter dc and the volume fraction of the polar medium p (eq S1,

where p includes the water and the polar ‘heads’ of surfactants and co-

surfactants).†† Assuming a direct contact between the tubes, 2

~ cdr , and

substracting the layer of the hydrophilic SDS head-group (about 0.6 nm) we

†† Cf. with Ramos, L.; Fabre, P.; Ober, R. Eur. Phys. J. B, 1998, 1, 319–326, who suggest an inter-rod separation of ~1.5 nm.


140

estimate the volume fraction of the organic (nonpolar) medium to be

58.01 po .

)1(2

3pcdr (S1)

In general, three geometries can be envisaged for lyotropic hexagonal

phases: (i) direct (nonpolar tubes in a polar medium); (ii) inverse (polar tubes

in a nonpolar medium); and (iii) complex (a bicontinuous phase). A detailed

study of the shape factor of the scattering spectra can give indications on the

nature of the phase. This method is not specific enough for unambiguous

determination of the phase’s nature, but it does indicate, for all three

hypotheses, the size of the lyotropic elements.

Cross-polarised micrographs

The doped quaternary system shows the existence of birefringent phases

whose texture are characteristic of a hexagonal phase. The observed texture

between the crossed polarizers that forms spontaneously between the plane

glass boundaries is commonly referred to as fan-shaped.‡‡ It indicates that the

tubes orient parallel to the glass plates, which can be explained in terms of an

anchoring energy. However, the orientation of the tubes that locally defines

the optical axis is two-fold degenerate in the plane, giving domains of different

orientations observed in the fan shaped texture. The presence of striations

(the thin stripes) is a positive identification of the hexagonal phase. These

striations, typical of a hexagonal phase, are due to a slight cooperative

undulation of the lyotropic tubes. The average orientation of the tubes is

perpendicular to the striations.

‡‡ Livolant, F.; Bouligand, Y. J. Physique, 1986, 47, 1813–1827.


141

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Summary

Biaryls (Arl–Ar2) and their homologues are an important class of organic compounds; the biaryl unit is represented in several types of compounds of current interest including natural products, polymers, advanced materials, liquid crystals and molecules of medicinal interest. Three powerful catalytic methods to synthesize these biaryl units are the Heck, Suzuki and Sonogashira coupling reactions. The catalysts for these processes are usually homogeneous palladium-ligand complexes that are often laborious to synthesize and/or air sensitive. Moreover, their stability is a major concern and separation from the product mixture is often difficult and costly. Alternatively, it is possible to use metal nanoclusters to catalyze these reactions, a ligand-free option that may be attractive also for large-scale production. The aim of this research has been to synthesize, characterise and develop new metal nanocluster catalysts for cross-coupling reactions. Furthermore, the much debated mechanism of cluster catalysis in cross-coupling reactions has also been investigated. By understanding this mechanism, we hope to design ‘atom economical’ and ‘selective’ cluster catalysts in future.

Chapter 1 starts with a general introduction into the field of nanoclusters involving synthetic pathways, stabilising mechanism, and their application as catalysts in variety of reactions. Furthermore, the research concerning transition metal catalysed C–C bond formation reactions is discussed in detail, with special emphasis on the Heck, Suzuki and Sonogashira coupling reactions.

Combining two or more metals may tune the catalytic activity, selectivity and stability, and some combinations may exhibit synergistic effects. This was the main motivation behind chapter 2. In this chapter the mixed metal nanoclusters were synthesized and used as catalysts in Suzuki cross-coupling reaction. A mixture design is applied to test the singular and the combined catalytic effects of copper with three noble metals (palladium, platinum and ruthenium). The 15 cluster combinations were prepared by reducing the metal chloride precursors in DMF using tetraoctylammonium formate (TOAF). From screening of all 15 cluster catalysts Cu and bimetallic Cu/Pd clusters are found to be good catalysts for Suzuki cross-coupling. The activity of Cu/Pd clusters is comparable to pure Pd, which illustrates synergistic effect between Cu and Pd. The Cu/Pd catalyst is applied to a range of iodo- and bromoaryl substrates, and gave moderate yields using chloroaryl substrates. Cluster activity and stability is found to depend strongly on the preparation method

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and the reaction conditions. The mechanism of cluster deactivation and the sensitivity of the cluster-catalysed reaction to substituent effects are studied and discussed.

The discovery of Cu clusters as good catalyst for Suzuki cross-coupling reaction prompted us to test these clusters in Sonogashira reaction. Chapter 3deals with application of Cu clusters as catalysts in the cross-coupling of alkynes and aryl halides to give the corresponding disubstituted alkynes. No palladium, ligand, or co-catalyst is needed, and products were isolated in good isolated yields (80–85%) and high selectivity. The clusters are simple to prepare, stable and can be applied to a variety of iodo- and bromoaryls. We also tested the reusability of the Cu clusters in the coupling of phenylacetylene with p–I–C6H4–CF3. The clusters could be used three times without deactivation, giving a final TON of 73. Mechanistic pathways for homocoupling and cross-coupling of alkynes are examined by comparing the activity of different catalyst and co-catalyst combinations.

The high activity of metal clusters in the cross-coupling reactions led us to think that if catalysis occurs on the clusters’ surface, selective heating of the catalytic sites could give higher substrate conversion and/or better product selectivity. The clusters are small pieces of metal, so they could be selectively heated in solution using microwave (m/w) irradiation. Chapter 4 describes the system where microwave irradiation is used to create ‘hot spots’ on metal clusters in solution, facilitating catalytic cycles in which these clusters participate. An 8×12 parallel screening system is built based on this concept, and tested using the Heck reaction as a case study. Cu and Ru clusters are not active in the Heck reactions, and the activity of Cu/Pd clusters is lower than that of pure Pd clusters. However, activity of in-situ prepared Pd clusters is higher compared to pre-prepared Pd clusters. The spatial reproducibility of this system is examined and the pros and cons of using monomode and multimode setups are also discussed.

Nanometric Pd clusters can exhibit catalytic activities comparable to those of traditional Pd complexes in the Heck, Suzuki and Sonogashira cross-coupling. The mechanism for heterogeneous Pd catalysts in these reactions is clear, but little is known about how cluster catalysts work in the liquid phase. Chapter 5answers the question of whether Pd clusters are the actual catalysts or mere reservoirs for Pd species in the so-called ‘cluster-catalyzed cross-coupling’. This chapter consist of two sections:

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Section A deals detailed kinetic analysis and transmission electron microscopy (TEM), which shows that a soluble species must be present in the system when Pd nanoclusters are used as catalysts. The coupling of phenylacetylene with 4-bromobenzonitrile is used as a model reaction. Various Pd clusters show similar kinetic profiles to that of a homogeneous Pd(dba)2 complex. We also studied the effect of various counteranions on the catalytic activity, using clusters prepared from Pd(NO3)2, PdCl2 and Pd(OAc)2. The activity is dependent on coordinating ability of anions to the cluster surface that affects the clusters’ stability. Most importantly, TEM analysis of samples taken before, during, and after the reaction shows that the cluster size decreases during the reaction. Based on these findings, we presented a possible two-path mechanism for Sonogashira cross-coupling reactions in the presence of Pd nanoclusters.

Section B describes results obtained using in-house built two compartment membrane reactor, which is designed to separate Pd clusters (size, 15 nm) from reaction mixture by a nano-porous membrane. The Heck coupling of iodobenzene with n-butylacrylate in presence of Na(OAc) is used as model reaction. Experiments were planned such that the membrane with 5 nm pores will allow only leached Pd species from the Pd clusters side to diffuse into the reaction mixture side which can then initiate the catalytic cycle to form the desired product. The kinetic analysis on the reaction mixture side revealed that the product is formed in good yield, proving that the leached Pd species are responsible for clusters catalysis. For large scale application of Pd clusters in liquid phase reactions, this system might be practical as it provides a controlled supply of catalytic species for the reactants leaving the rest of the Pd clusters for next cycle.

In most cases aryl iodides are used as coupling partners to the alkynes in Sonogashira reaction. However for practical purposes, the less reactive bromo- and chloro-aryls are attractive because of their lower cost and wider availability compared to iodides. In chapter 6, the advantages of combining heterogeneous catalysis and aryl chloride substrates for cross-coupling are described. A heterogeneous Pd/C catalyst is used for activating aryl bromides and chlorides via a one-pot Halogen Exchange (HALEX)-Sonogashira reaction. No ligand or co-catalyst is required, and the cross-coupling products are obtained in moderate to good yields. The influence of the solvent, base, iodide source and catalyst is evaluated. The catalyst is reusable for at least six consecutive reaction cycles. A variation on this one-pot reaction using catalytic amounts of KI is also proposed.

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Besides my main project on cluster catalysis, I also studied the synthesis of new nano-materials. Nano-materials have wide range of applications: nanomagnets for superfast computers, nanowires to string together nanoelectronic circuits and nanomachines for modern medicine. Such materials are synthesised by very sophisticated and expensive techniques, e.g. STM tips, lithography, or chemical vapour deposition (CVD). However, to manufacture them in bulk will demand simple methods. In chapter 7, we show a simple and general method to confine very small clusters in hexagonal micellar rods. Stable nanoclusters (~2 nm in diameter) of copper, silver, gold, palladium, and ruthenium coated with hydrophobic coronas are easily trapped in self-assembled ‘soft crystal’ hexagonal phase gels made of water and surfactants. The system’s crystal structure and phase behaviour are studied in detail. High-energy x-ray scattering and cross-polarised optical microscopy experiments show that the clusters are tightly confined within the tubes. The thermal gel-fluid transitions of the hexagonal phase are investigated, and it is shown that the hexagonal phase can melt and recrystallise repeatedly. The melt/gel cycles enable easy trapping of various metal clusters in pre-prepared hexagonal phases. The possibility of using these nano-structures in catalysis and making nanowires is also discussed.

Conclusion and outlook

The objectives set at the onset of this work have been met. We have shown that metal nanoclusters are highly effective cross–coupling catalysts and also revealed the true nature of Pd cluster catalysis in C–C bond formation reactions. Metal nanoclusters may have a high impact in catalysis field, and perhaps provide new possibilities normally inaccessible with conventional catalysts. They are attractive as catalysts because:

1) They display unique catalytic properties that are different from traditional homogeneous and heterogeneous catalysts.

2) They also have large number of co-ordinatively unsaturated surface atoms, which can lead to high catalytic activity either via leached species or surface reaction.

3) Moreover, their synthesis is simple and straightforward with possibility to easily tailor the size, shape and composition to specific requirements.

In general, reproducibility in the properties of nanoclusters (size, dispersity and performance), and recovery and reuse without lose of activity are of paramount importance. Efforts to deal with more reactions will be significant, but the reuse of the metal clusters should be the subject of highest priority for future research.

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Samenvatting

Biaryls (Arl-Ar2) en hun homologen zijn een belangrijke klasse van organische verbindingen; de biaryl eenheid is aanwezig in verscheidene typen producten, die van belang zijn en voorkomen in natuurlijke producten, polymeren, geavanceerde materialen, vloeibare kristallen en medicijnen. Drie krachtige katalytische methoden om deze biaryl eenheden samen te stellen zijn de Heck, Suzuki en Sonogashira reacties. De katalysatoren voor deze processen zijn gewoonlijk homogene palladium-ligand complexen die vaak moeizaam te maken zijn. Ze zijn meestal gevoelig voor lucht en vaak ook instabiel. Voorts is de scheiding van het productmengsel vaak moeilijk en kostbaar. Een alternatief is het gebruik van metaal nanoclusters om deze reacties, via een ligand-vrije route te katalyseren. Zo’n alternatief kan ook aantrekkelijk zijn voor productie op grote schaal. Het doel van dit onderzoek is geweest nieuwe metaal-nanocluster-katalysatoren voor cross-koppelingreacties samen te stellen en te karakteriseren. Het veel bediscussieerde mechanisme van de cross-koppelingreacties is ook onderzocht. Door begrip van dit mechanisme te begrijpen, hopen wij 'atoom economische' en 'selectieve' cluster katalysatoren te kunnen ontwerpen.

Hoofdstuk 1 begint met een algemene inleiding over de syntheseroutes voor nanoclusters, de mogelijkheden om de clusters te stabiliseren en hun gebruik voor diverse reacties. Voorts wordt het onderzoek over overgangsmetaal katalysatoren voor C C bindingsvormingsreacties bediscussieerd, met speciale nadruk op de Heck, Suzuki en Sonogashira reacties.

Met het combineren van twee of meer metalen kan de katalytische activiteit, de selectiviteit en de stabiliteit beter afgestemd worden, en sommige combinaties kunnen synergistische effecten vertonen. Dit is het belangrijkste uitgangspunt van hoofdstuk 2. In dit hoofstuk worden gemengde metaal nanoclusters en het gebruik daarvan als katalysatoren in de Suzuki-reactie besproken. Een statistische benadering met mengsels is toegepast om de enkelvoudige en de gecombineerde katalytische effecten van koper met drie edele metalen (palladium, platina en ruthenium) te testen. Van alle 15 clusterkatalysatoren bleken Cu en de bimetaal clusters van Cu/Pd goede katalysatoren voor de Suzuki-reactie te zijn. De activiteit van de clusters van Cu/Pd is vergelijkbaar met die van zuiver Pd, dit illustreert het synergistisch effect tussen Cu en Pd. De Cu/Pd-katalysator is toegepast op diverse iodo- en bromoaryl substraten. Matige opbrengsten werden gevonden voor chloroaryl substraten. Het mechanisme van cluster deactivering en de gevoeligheid van

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de cluster-gekatalyseerde reactie, beïnvloed door substituenten, zijn bestudeerd en besproken.

De ontdekking van Cu-clusters als goede katalysatoren voor de Suzuki reactie heeft ons ertoe aangezet deze clusters in de Sonogashira reactie te testen. Hoofdstuk 3 behandelt de toepassing van de Cu-clusters als katalysatoren in de cross-koppeling van alkynen en arylhalogeniden tot de overeenkomstige digesubstitueerde alkynen te geven. Er is geen palladium, ligand, of co-katalysator nodig, en de producten konden met goede opbrengsten en hoge selectiviteit geïsoleerd worden. De clusters zijn eenvoudig te bereiden, ze zijn stabiel en kunnen toegepast worden op een verscheidenheid van iodo en bromoarylverbindingen. Het mechanisme voor de homokoppeling en cross-koppeling van alkynen is onderzocht door de activiteit van verschillende combinaties van katalysatoren en co-katalysatoren te vergelijken.

De hoge activiteit van metaal clusters in de cross-koppeling reacties bracht ons ertoe te vermoeden dat, als de katalyse op het oppervlakt van de clusters plaatsvindt, selectief verwarmen van de katalytische centra hogere substraatomzetting en/of betere productselectiviteit zouden kunnen geven. De clusters zijn kleine stukken metaal en zij zouden selectief in een oplossing verwarmd kunnen worden gebruik makend van magnetronstraling. Hoofdstuk4 beschrijft het systeem waarin magnetronstraling wordt gebruikt om 'hot spots' op metaal clusters die zich in de oplossing bevinden te creëren, dit vergemakkelijkt katalytische cycli waaraan deze clusters deelnemen. Een 8×12 parallel onderzoekssysteem is opgebouwd dat gebaseerd is op dit concept, dit werd getest met de Heck reactie als modelreactie. Activiteit van insitu voorbereide Pd-clusters is hoger dan die van vooraf gemaakte Pd-clusters. De reproduceerbaarheid van dit systeem met betrekking tot de plaats in de magnetron is onderzocht en de voors en tegens van het gebruiken van “monomode” en “multimode” instellingen worden besproken.

Pd-clusters kunnen katalytische activiteiten vertonen die vergelijkbaar zijn met die van traditionele Pd-complexen in cross-koppelingreacties zoals de Heck, Suzuki en Sonogashira reactie. Het mechanisme voor heterogene Pd- katalysatoren in deze reacties is bekend, maar er is weinig bekend over werking van de clusterkatalysatoren in oplossing. Hoofdstuk 5 beantwoordt de vraag of Pd-clusters de daadwerkelijke katalysatoren zijn, of dat ze optreden als reservoirs voor Pd-species in de zogenaamde 'cluster-gekatalyseerde cross-koppelingsreactie'. Dit hoofdstuk bestaat uit twee secties:

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In Sectie A worden gedetailleerde kinetische analyses en transmissie elektronen microscopie (TEM) besproken. Hierin wordt aangetoond dat opgelost Pd in het systeem aanwezig moet zijn indien Pd-clusters worden gebruikt voor de Sonogashira koppelingsreactie. Diverse Pd-clusters vertonen dezelfde kinetische profielen als de homogene complexe Pd(dba)2. TEM analyse van monsters genomen voor, tijdens en na de reactie tonen aan dat de clustergrootte tijdens de reactie afneemt. Gebaseerd op deze resultaten wordt een twee-weg mechanisme voor Sonogashira reacties in aanwezigheid van Pd-clusters voorgesteld.

In Sectie B worden de resultaten beschreven die verkregen zijn met behulp van een zelfgebouwde reactor. Deze reactor bevat twee compartimenten die gescheiden worden door een membraan met 5 nm poriën. Dit membraan is in staat afzonderlijke Pd-clusters (grootte, 15 nm) te scheiden van het reactiemengsel. De Heck koppeling van iodobenzeen met n-butylacrylaat in aanwezigheid van Na(OAc) is gebruikt als modelreactie. Aan een kant van de membraan bevindt zich het reactiemengsel en aan de andere kant de Pd-clusters. Daardoor zijn alleen opgelost Pd-species in staat de reactie te katalyseren. De analyse aan de kant van het reactiemengsel toonde het product in goede opbrengst aan, daarmee bewijzend dat de uitgeloogde Pd-species verantwoordelijk zijn voor clusterkatalyse.

In de meeste gevallen worden aryljodiden gebruikt als koppelingpartners met alkynen in de Sonogashirareactie. Echter, voor praktische doeleinden zijn de minder reactieve broom- en het chloor-arylen, aantrekkelijk vanwege hun lagere kosten en ruimere beschikbaarheid in vergelijking met iodiden. In hoofdstuk 6, worden de voordelen van de combinatie heterogene katalyse en aryl chloride substraten voor cross-koppeling reacties beschreven. Een heterogene Pd/C katalysator wordt gebruikt voor het activeren van arylbromiden en chloriden via een “één-pot uitwisseling van het halogeen” (HALEX)-Sonogashira reactie. Hierbij zijn geen ligand of co-katalysator vereist en de cross-koppelingproducten worden in gematigde tot goede opbrengsten verkregen. De invloed van het oplosmiddel, het loog, de jodidebron en de katalysator worden besproken. De katalysator is opnieuw te gebruiken voor ten minstens zes opeenvolgende reactiecycli. Een variatie op deze één-potsreactie met behulp van katalytische hoeveelheden KI wordt ook voorgesteld.

Naast het hoofdproject van cluster katalyse, werd ook de synthese van nieuwe nano-materialen bestudeerd. De nano-materialen hebben een breed toepassingsgebied: nano-magneten voor supersnelle computers, nano-draden

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voor nano-electronische circuits en nano-machines voor de moderne geneeskunde. Dergelijke materialen worden nu samengesteld met behulp van zeer verfijnde en dure technieken, b.v. STM tips, lithografie, of chemical vapor deposition (CVD). Echter, om deze in grote hoeveelheden te vervaardigen, zijn eenvoudige methoden vereist. In hoofdstuk 7 wordt een eenvoudige en algemene methode beschreven om zeer kleine clusters in hexagonale micellaire buisjes in te sluiten. Stabiele nanoclusters (~2 nm in diameter) van koper, zilver, goud, palladium en ruthenium die met een hydrofobe corona zijn bedekt, worden gemakkelijk opgesloten in een self-assembled ‘soft crystal’ hexagonal phase gels die van water en surfactant zijn gemaakt. Een kristalstructuur en het gedrag van het systeem zijn in detail bestudeerd. High-energy X-ray scattering en cross-polarised optical microscopy experimenten tonen aan dat de clusters stevig opgesloten zijn binnen de buizen. De mogelijkheid om deze nano-structuren in de katalyse te gebruiken en ook voor het maken van nanodraden wordt besproken.

Conclusie en vooruitzichten

Aan de doelstellingen, die bij het begin van dit werk zijn vastgesteld, is beantwoord. Wij hebben aangetoond dat metaal-nanoclusters hoogst efficiënte cross-koppelingkatalysatoren zijn en ook is het mechanisme van Pd-cluster katalyse in deze reacties bewezen. Nanoclusters van het metaal kunnen een grote invloed op de katalyse hebben, en misschien nieuwe, voor conventionele katalysatoren ontoegankelijke, paden betreden. Zij zijn aantrekkelijke katalysatoren met hun unieke eigenschappen omdat:

1) Zij vertonen de eigenschappen van zowel de traditionele homogene als de heterogene katalysatoren.

2) Zij hebben een groot aantal coordinatief onverzadigde oppervlakte-atomen, die tot hoge katalytische activiteit kunnen leiden via uitgeloogde species of oppervlaktereactie.

3) Bovendien, hun eenvoudige synthese geeft de mogelijkheid de grootte, de vorm en de samenstelling gemakkelijk aan aan te passen aan de specifieke vereisten.

In het algemeen zijn de reproduceerbaarheid van de eigenschappen van nanoclusters (grootte, dispersity en prestaties), de terugwinning en het hergebruik, zonder verlies van activiteit, van essentieel belang. In het toekomstig onderzoek zullen de inspanningen om meer reacties te vinden significant zijn, maar het hergebruik van de metaalclusters verdient de hoogste prioriteit.

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Acknowledgements

The acknowledgement have finally been reached, this means that I am almost done. Personally, I always enjoy reading the acknowledgements in a dissertation. They help to add a human side to the (usually technical) contents. Having said that, I now have to come up with something that I would enjoy reading myself, so here it goes.

Past four years have been quite an adventure, including coming to Holland, the loss of my brother (Niraj), few cross-country trips, marriage and at last, the completion of this thesis. Along the way, a number of people made my research work possible, enjoyable, and thoroughly rewarding.

First, I gratefully and sincerely thank my co-promoter, Dr. Gadi Rothenberg, for his encouragement and direct supervision throughout my PhD. I still remember that he called at my home (in Mumbai) on 13th August 2001 for the interview and just with that telephonic conversation he accepted me for this project. I thank him for the trust he showed in me and for giving me this opportunity to do research with him. Being his first student, I have learnt a lot from him apart from the scientific and good article writing skills. His never ending energy and drive to make things happen has made him one of my role models. He has imbibed in me, the qualities of confidence, perseverance, commitment towards one’s work and handling of many things at a time, which I believe, would help me throughout my career. He has always treated me as a friend/brother and helped me during my ups and downs in research and also personal life. Especially in the crucial first year of my PhD, when I had to go back to India for family matters he said, “don’t worry, go home, they need you, I will take care of everything”. It was a great relief. Without his support this thesis would not have been possible.

Many thanks to Prof. Cornelis J. Elsevier, for being my promoter, for his support, and for giving me the freedom to do this research work. I am fortunate that I could freely discuss scientific problems with him whenever required. His support and motivation for completing this thesis was priceless. I also express my gratitude to Prof. Alfred Bliek for his assitance during first year of my PhD. I would also like to thank Dr. Erika Eiser and Dr. Fatima Bouchama, for the fruitful and enjoyable collaborative work on nanomaterials (resulted in chapter 7) and hope we continue with such projects in future. I also thank Dr. Hans-Werner Fruhauf for his valuable suggestions during group meetings and Dr. Frantisek Hartl for very enthusiastic discussions. I am thankful to Dr. Jan van Maarseveen, as he was always ready to talk chemistry and I got few ideas and solutions from those discussions and to Prof. Paul Kamer who helped me understand the homogeneous catalysis during the catalysis course. Dr. Patricia Kooymann from National centre for HREM from TU-Delft is acknowledged for measuring TEM samples and for the collaboration. Dr. J. E. ten Elshof from Twente University deserves a great deal of appreciation for making a membrane which helped us understand the mechanism behind cluster catalysis. I cannot thank enough to Dr. Sudip Mukhopadhyay, Dr. Ashutosh Joshi and Dr. Pradeep Goel for bringing me in contact with Gadi and consequently changing my career.

I would also like to thank all the committee members (prof. dr. H. Bönnemann, prof. dr. J. G. de Vries, prof. dr. P. C. J. Kamer, prof. dr. P. J. Schoenmakers and dr. E.

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Eiser) for spending their precious time to read my thesis and also for their useful comments.

To successfully complete this work the contribution from technical and administrative department was very important. I therefore thank Marjo Mittelmeijer, Lars van der Zande, Jurriaan Beckers (now PhD student), Paul Collignon & Hans Agema (from electronic workshop), Dorette Tromp, Jan-Meine Ernsting, Petra Aarnoutse, Hans Boelens and Taasje Mahabiersing for their excellent technical support and useful discussions. Apart from technical help, Marjo also helped me for the summary translation in Dutch and Jurriaan was always ready to help with any problems I faced during my PhD, special thanks to you both. Thanks to the people from mechanical workshop (Wietze Buster, Theo Nass, Co Zoutberg & Daan de Zwarte) and glass blower department (Bert van Groen) for fabricating strange reactors and glasswares within few days after ordering. Dean Dr. Rob Zsom, Fred van den Aardweg, Maureen Sabander, Renate Hippert, Karen Tensen, Peter Scholts, Britta Duiker, Loes Swaning and Petra Hagen are also acknowledged for their administrative support. Also I want to express my gratitude to ICT department for solving computer related problems, especially Jaap Kuijsten and Gooitzen Zwanenberg. Ankie, Marijke and Stephan from the library, thanks for delivering articles and books borrowed from other libraries. Thanks Nicole for supplying endless number of coffees. Allemal bedankt voor alles..

All my friends (Susana, Laura, Enrico, Alex (Portuguese), Anil, Erdny, Tony, David, Alex (French), Pablo, Liu, Maikel (Verouden), Jeroen, Erica, Luc, Anthony, Frederic, Nacho, Jurriaan, Jitte) have spent a lot of time with me during the last four years. It was a fine feeling to be the friend of people from so many countries, so many cultures and I have to say that the Holland was a window to the world for me. All of them deserve great thanks for support, nice discussions concerning everything and for making my stay enjoyable in Amsterdam. Susana- from the day one in Amsterdam you have shared your views with me on critical issues on Dutch life (which made my life easier here). You and Laura were always there for me during my good or bad times and always kept the atmosphere alive within our group. Laura, you are very nice and funny person and we made a great p…o team, you know what I mean. You both are on the top of the ‘blacklist’ and hence you are my paranymfs (paraffins). Enrico, I enjoyed your animal (monkey) instincts, you always tend to make people laugh somehow. Alex, what should I say about you? Annoyer…Yes if you talk about History, otherwise I believe you are great person with loads of knowledge. Anil, I enjoyed our cooking, watching movies and you getting drunk, I had a great time with you. Erdny, you helped me several times but I cannot forget favor where you introduced me to Miss Lopez for the housing. Tony, after you joined as post-doc in the group you have given me good advices regarding job search and IND related questions. David & Pablo, you both were ever ready to help if I need anything (chairs, bowls, plates, etc) in my house when there were some occasions. Alex (French), it was great partying with you and moreover you were enthusiastic to assist me on mechanism project even though you didn’t had time, it was pity that NMR work was not successful. Liu, I like the Chinese food you make and the way you take the things innocently. Frederic & Nacho, two invited scholars from abroad made our group look bigger then it was and I had great fun with you both. Jeroen, it was nice working with you on Hydrosilation project but unfortunately results were not so great. Erica and Jitte, chemistry discussions with you both were very interesting and helpful.

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Maikel and Anthony, you have also given me useful suggestions whenever required.Thanks a lot to all of you for the help and contributions you all made during these years.

Thanks also go to the former members of the chemical engineering department, in particular Ye & Florin (former officemates), Snezana, Hessel, Amedeo and Bart for their timely help and support. I wish to thank all students (Jia, Pat, Eveline, Romilda, Daan) who have worked closely with me and contributed to the findings presented here. They did great work and it would have been a lot less fun without them.

Thanks to ultimately cool NIOK & NCCC partying group, Kazu (Samurai and camera man!!), Francesca, João, Hans, Khaled, Nilesh, Charl, Sune, Tatyana, Vinit, Elena, crazy Susana, Laura (Lolita..), Enrico, Anil (Gaikwad), Alex (french), Christiano, Kumar.……., for all the fun we had together. These are unforgettable memories for me and you all deserve one more party…so be ready. Anil (Suthar), Kavita, Bapat, Navin, Ambreesh, Nirja, Sachin, Lekhraj, Shuyog, Saneep, Zulfi and Indians from Groningen (Sameer, Anant, Anil, Vinay…it’s a big list) - thank you all for everything.

Outside university, Miss Lopez (I lived in her house for 3 years) deserves special thanks as she never made me feel that I am in a different country and has always treated me like a son. She has done so many favours on me that it will be hard to repay them. Thanks also to her husband Armando who is a funny and nice person with whom I had very nice time. My flatmate and one of my best friends, Marco, has also contributed a lot in my personal life and wish to thank him for everything.

Most importantly, I owe a debt of gratitude to my wonderful parents, Bhupendra and Malti Thathagar, for instilling within me the importance and value of higher education and hard work. Their love and affection has helped me to achieve the goals that I have set throughout my career. For this thesis work, my wife, Kanchan, has seen and felt up and down moments. There are not enough words to appreciate her understanding, her confidence in me and my abilities, and most importantly her patience for meeting me only once a year during this period. Thanks a million……….for being there for me all the time. My brother, Gaurang, also deserves a special thanks for taking care of our parents and Niraj when I was not in India. My friends (Jayesh, Mahesh & Tushar) in India are also acknowledged for their help whenever our family required. Thanks to Karira (in-laws) and Lalwani family for their support and encouragement.

I wish you all good luck with everything you do and hope we all be in touch with each other in future.

Mehul

Acknowledgements

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Curriculum Vitae

Mehul B. Thathagar was born on 15 November, 1976 at Bhavnagar, India. In

1978 he and his family moved to Bombay (now Mumbai), one of the most crowded and

happening cities in India. He completed his schooling in 1995 with excellent grades

that allowed him to choose to pursue medicine or engineering degree. Since his father

was a textile chemist, he was always fascinated by chemical technology and hence he

decided to go for chemical engineering degree from University of Mumbai, India. In

1999 he carried out a final year project on “Manufacture of H-acid, a dye

intermediate”, at Zenith Ltd. and obtained first class Bachelor’s degree in chemical

engineering. In the same year he appeared for Graduate Aptitude Test in

Engineering (GATE), an all India entrance examination for admission to Master’s

degree program. The high GATE score ascertained him admission with Junior

Research Fellowship in one of the top institutes in India, University Institute of

Chemical Technology (U.I.C.T). He got the real feel of research in the final year of

Masters’ degree, under the supervision of Prof. G. D. Yadav. He completed the project

on “Kinetic studies of esterification reaction using solid acid catalysts” and was

awarded ‘A’ grade for this research work. In September 2001, he obtained Master’s in

chemical engineering with distinction and ranked 3rd among 40 students.

Instead of trying his hands in industry he decided to do research abroad. He

started applying for PhD positions and luckily he was offered to pursue PhD in two

countries (Holland and Australia). However, he chose to join University of

Amsterdam, Holland because of interesting research topic. He worked under Dr. Gadi

Rothenberg and Prof. Cornelis. J. Elsevier and conducted research on “Novel

nanocluster catalysts for C C coupling reactions”. Besides his main project on cluster

catalysis, he was also actively involved in several collaborative projects on

‘Developing new nano-materials’ with Dr. Erika Eiser. He has presented his research

work in numerous national and international meetings and has attended several

summer schools. In 2003, he was awarded ‘Best PhD lecture’ at NCCC IV and has

also received two travel grants to attend conference in Italy and USA. Till now, he

has published 12 articles in international peer-reviewed journals and one is

submitted. One of his articles in JACS was featured in Science as Editors choice and

articles in ChemPhysChem and Org. Biomol. Chem. were featured on issue covers

(see publication list). He will defend his thesis on 21 February 2006 and hopefully

will become Dr. Mehul B. Thathagar.

CV

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List of publications

157

Articles in peer-reviewed journals

1. M. B. Thathagar, A. ten Elshof and G. Rothenberg, ‘Pd nanoclusters in C C coupling reactions: A proof of leaching’, submitted.

2. L. Durán Pachón, M. B. Thathagar, F. Hartl and G. Rothenberg, ‘Palladium-coated nickel nanoclusters: New Hiyama cross-coupling catalysts’, Phys. Chem. Chem. Phys., 2006, 8, 151. Featured as a hot article.

3. M. B. Thathagar and G. Rothenberg, ‘Tandem one pot Pd/C catalyzed ‘Domino’ HALEX and Sonogashira reactions: A Ligand-free and Cu-free alternative’, Org. Biomol. Chem., 2006, 4, 111. Featured on issue cover.

4. M. B. Thathagar, P. J. Kooyman, R. Boerleider, E. Jansen, C. J. Elsevier, G. Rothenberg, ‘Pd nanoclusters in Sonogashira cross-coupling: A true catalytic species?’, Adv. Synth. Catal., 2005, 347, 1965.

5. D. H. Turkenburg, A. A. Antipov, M. B. Thathagar, G. Rothenberg, G. B. Sukhorukov, and E. Eiser, ‘Palladium nanoclusters in microcapsule membranes: From synthetic shells to synthetic cells.’, Phys. Chem. Chem. Phys., 2005, 7, 2237.

6. M. B. Thathagar, J. Beckers and G. Rothenberg ‘Nanocluster-based cross-coupling catalysts: A high-throughput approach’, Catal. Org. React., 2005, 104, 211.

7. M. B. Thathagar, J. Beckers and G. Rothenberg, ‘Palladium-free and ligand-free Sonogashira cross-coupling’, Green Chem., 2004, 6, 215.

8. J. Wang, H. F. M. Boelens, M. B. Thathagar and G. Rothenberg, ‘In situ spectroscopic analysis of nanocluster formation’, ChemPhysChem, 2004, 5, 93. Featured on the issue cover.

9. F. Bouchama, M. B. Thathagar, G. Rothenberg, D. H. Turkenburg and E. Eiser, ‘Self-assembly of a hexagonal phase of wormlike micelles containing metal nanoclusters’, Langmuir, 2004, 20, 477.

10. E. Eiser, F. Bouchama, M. B. Thathagar and G. Rothenberg, ‘Trapping metal nanoclusters in ‘soap and water’ soft crystals’, ChemPhysChem, 2003, 4, 526.

11. M. B. Thathagar, J. Beckers and G. Rothenberg, ‘Combinatorial design of copper-based mixed nanoclusters: New catalysts for Suzuki cross-couping’, Adv. Synth. Catal., 2003, 345, 979.

12. M. B. Thathagar, J. Beckers and G. Rothenberg, ‘Copper-catalysed Suzuki cross-coupling using mixed nanocluster catalysts’, J. Am. Chem. Soc., 2002, 124, 11858. Featured in Science as Editor’s Choice, see Science, 2002, 297, 2171.

13. G. D. Yadav and M. B. Thathagar, ‘Esterification of maleic acid with ethanol over cation-exchange resin catalysts’, React. Funct. Polym., 2002, 52, 99.

List of publications

158

Contributions to conferences

1. L. Durán-Pachón, M. B. Thathagar, F. Hartl and G. Rothenberg, ‘Pd-coated Ni nanoclusters: New Hiyama coupling catalysts’, ISHHC XII, (Florence, Italy), 2005, 127.

2. M. B. Thathagar, P. J. Kooyman and G. Rothenberg, ‘Palladium clusters in cross-coupling: active species or catalyst reservoir?’, ISHHC XII, (Florence, Italy), 2005, 228.

3. M. B. Thathagar, P. J. Kooyman and G. Rothenberg, ‘Cluster-catalysed cross-coupling: Homogeneous or heterogeneous?’, NCCC VI, (Noordwijkerhout, The Netherlands), 2005,295.

4. M. B. Thathagar, J. Beckers and G. Rothenberg, ‘Nanocluster-based cross-coupling catalysts: A high-throughput approach.’, 20th ORCS conference, (South Carolina, USA), 2004.

5. M. B. Thathagar, J. Wang, H. F. M. Boelens and G. Rothenberg, ‘Understanding nanocluster formation using in situ spectroscopy’, NCCC V, (Noordwijkerhout, The Netherlands), 2004, 115.

6. J. Beckers, M. B. Thathagar and G. Rothenberg, ‘Mixed metal colloid hydrogenation catalysts’, NCCC V, (Noordwijkerhout, The Netherlands), 2004, 168.

7. M. B. Thathagar and G. Rothenberg, ‘C-C coupling using mixed metal nanoclusters’, NanoCat summer school, (Turin, Italy), 2003. Poster selected for the lecture.

8. M. B. Thathagar, J. Beckers and G. Rothenberg, ‘Discovery of copper-based mixed nanocluster Suzuki catalysts using combinatorial approach’, NCCC IV, (Noordwijkerhout,The Netherlands), 2003, 118. Awarded best PhD lecture.

9. F. Bouchama, M.B. Thathagar, E. Eiser and G. Rothenberg, ‘Metal nanoclusters trapped in a hexagonal surfactant phase.,’ Statistical Physics Conference, (Lunteren, The Netherlands), 2003.

News article about my research

1. Cross-coupling with copper nanoparticles. G. Chin, Science, 2002, 297, 2171.

Feature in Science, 2002, 297, 2171.

Cover of ChemPhysChem, January 2004.

Cover of Org. Biomol. Chem., January 2006.

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