KTH

Royal Institute of Technology

KD200X - Master Thesis

Towards nickel boride catalyzed

C-C coupling reactions

Author:

Agnes Lako

Supervisor:

Professor Peter Diner

July 10, 2017

Abstract

This thesis focuses on the study of nickel boride as a catalyst in various coupling

reactions. The nickel boride catalyst was investigated in three different coupling re-

actions, the experiments aimed at understanding the activity and catalytic properties

of nickel boride.

We successfully synthetized the nickel boride catalyst, alongside with the cobalt

and iron boride. Different methods of preparation were compared and we concluded,

that the differences in the preparation, such as solvent and atmosphere, influence the

activity of the catalyst in coupling reactions. We found that the most suitable solvent

for preparing nickel boride is anhydrous methanol, thus we proceeded our research

with this catalyst.

In the case of the Sonogashira cross-coupling we found that the homocoupling of the

acetylene starting material is a side reaction we could not exclude. However, with the

proper solvent it is possible to shift the reaction towards homocoupling, without the

formation of the heterocoupling product. Thus, we decided to investigate the Glaser

homocoupling between acetylenes. In the case of the Sonogashira coupling only TLC

was used to examine the reaction mixture. However, in the case of Glaser coupling,

after pre-investigations we developed a gas chromatography method for analyzing the

reaction mixtures. We learned, that the homocoupling only results in trace amounts

(2-4%) of product. Previous investigations in our research group showed, that the

nickel boride could catalyze Suzuki-Miyaura-type couplings. Examining this reaction

all three metal borides were tested; however the reactions only led to the desired

product with nickel boride. Analyzing the reaction with gas chromatography we

learned that the choice of solvent influences the stability of the starting materials and

the formation of side products. Reactions with different starting materials, in different

solvents, with different bases were analyzed. The effect of microwave irradiation was

also examined. Based on the results we concluded, that with nickel boride it is not

possible to achieve high yields in coupling reactions.

Keywords

nickel catalysis, coupling reactions, cross-coupling, homocoupling

I

List of Abbreviations

Ni(CO)4 Nickel tetracarbonyl

Ni(cod)2 Bis(cyclooctadiene)nickel(0)

Ni(PPh3)4 Tetrakis(triphenylphosphine)palladium(0)

Ni(bipy)Et2 Diethyl(2,2’-bipyridyl)nickel(0)

Ni(dppe)Et2 Diethyl[1,3-bis(diphenylphosphino)ethan]nickel(0)

NiCl2(dppp) Dichloro(1,3-bis(diphenylphosphino)propane)nickel(II)

NiCl2(PPh3)2 Dichloridobis(triphenylphosphane)nickel(II)

Ni2B Nickel boride

NiCl2 Nickel chloride

NaBH4 Sodium borohydride

XRD X-ray diffraction

XPS X-ray photoelectron spectroscopy

HRTEM High-resolution transmission electron microscopy

TEM Transmission electron microscopy

DDT 1,1’-(2,2,2-Trichloroethane-1,1-diyl)bis(4-chlorobenzene)

CH3OH Methanol

THF Tetrahydrofuran

CuI Copper(I) iodide

(PPh3)2PdCl2 Bis(triphenylphosphine)palladium(II) dichloride

Pd(OAc)2 Palladium(II) acetate

(CH3CN)2PdCl2 Bis(acetonitrile)dichloropalladium(II)

Na2PdCl4 Sodium tetrachloroplatinate

PS Poly(styrene)

PEG Poly(ethylene glycol)

DMF Dimethyl formamide

CoBr2 Cobalt(II) bromide

[bmim]OH 1-Butyl-3-methylimidazolium hydroxide

OTf Triflate

II

CsF Ceasium fluoride

PPh3 Triphenylphosphine

K2CO3 Potassium carbonate

TLC Thin layer chromatography

NMR Nuclear magnetic resonance spectroscopy

DMAc Dimethylacetamide

DEE Diethyl ether

KOtBu Potassium tert-butoxide

Na2CO3 Sodium carbonate

K3PO4 Tripotassium phosphate

GC Gas chromatography

UV Ultraviolet

TEMPO (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl

FeCl3 Iron(III) chloride

III

Contents

1 Introduction 1

1.1 Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1.1.1 Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

1.1.2 Heterogeneous catalysts . . . . . . . . . . . . . . . . . . . . . 3

1.1.3 Transition metal catalysts . . . . . . . . . . . . . . . . . . . . 3

1.1.4 Nickel as catalyst . . . . . . . . . . . . . . . . . . . . . . . . . 3

1.1.5 Nickel boride . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1.1.5.1 Structure . . . . . . . . . . . . . . . . . . . . . . . . 7

1.1.5.2 Nickel boride promoted organic reactions . . . . . . . 8

1.2 Coupling reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

1.2.1 Sonogashira reaction . . . . . . . . . . . . . . . . . . . . . . . 13

1.2.1.1 Mechanism . . . . . . . . . . . . . . . . . . . . . . . 14

1.2.1.2 Recent advances and developments . . . . . . . . . . 15

1.2.2 Glaser reaction . . . . . . . . . . . . . . . . . . . . . . . . . . 17

1.2.2.1 Mechanism . . . . . . . . . . . . . . . . . . . . . . . 18

1.2.2.2 Recent advances and developments . . . . . . . . . . 19

1.2.3 Suzuki-Miyaura reaction . . . . . . . . . . . . . . . . . . . . . 21

1.2.3.1 Mechanism . . . . . . . . . . . . . . . . . . . . . . . 22

1.2.3.2 Recent advances and developments . . . . . . . . . . 23

1.3 The aim of this thesis . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

2 Experimental work 26

2.1 Synthesis of nickel boride catalyst . . . . . . . . . . . . . . . . . . . . 26

2.1.1 Preparation of metal borides . . . . . . . . . . . . . . . . . . . 26

2.1.2 Nickel boride applications . . . . . . . . . . . . . . . . . . . . 27

2.2 Sonogashira coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

2.3 Glaser coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

2.3.1 Solvent screening . . . . . . . . . . . . . . . . . . . . . . . . . 30

IV

2.3.2 Base screening . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

2.3.3 Analysis with gas chromatography . . . . . . . . . . . . . . . 32

2.3.4 Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

2.4 Suzuki-Miyaura coupling . . . . . . . . . . . . . . . . . . . . . . . . . 36

2.4.1 Catalyst investigations . . . . . . . . . . . . . . . . . . . . . . 36

2.4.1.1 Initial reactions with contaminated chemicals . . . . 36

2.4.2 Gas chromatography method . . . . . . . . . . . . . . . . . . 42

2.4.3 Solvent screening . . . . . . . . . . . . . . . . . . . . . . . . . 42

2.4.4 Base screening . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

2.4.5 Alternative starting materials . . . . . . . . . . . . . . . . . . 45

2.4.5.1 Reaction with different halides . . . . . . . . . . . . . 45

2.4.5.2 Reaction with phenylboronic acid pinacol ester . . . 46

2.4.6 Temperature studies . . . . . . . . . . . . . . . . . . . . . . . 48

2.4.7 Microwave reactions . . . . . . . . . . . . . . . . . . . . . . . 49

3 Conclusion and outlook 50

4 References 52

A Appendix 64

A.1 General methods and chemicals . . . . . . . . . . . . . . . . . . . . . 64

A.2 Preparations of metal borides . . . . . . . . . . . . . . . . . . . . . . 64

A.2.1 Method A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

A.2.2 Method B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

A.2.3 Preparation of nickel boride on filtering paper . . . . . . . . . 65

A.3 Sonogashira coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

A.3.1 Characterisation of 4-methylbiphenyl . . . . . . . . . . . . . . 65

A.3.2 Characterisation of 1,4-diphenylbutadiyne . . . . . . . . . . . 65

A.4 Glaser coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

A.4.1 Solvent screening method . . . . . . . . . . . . . . . . . . . . 65

A.4.2 GC method . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

A.4.3 GC chromatograms of the reaction components . . . . . . . . 66

V

A.4.4 GC calibration curve for 1,4-diphenylbutadiyne (product) . . . 68

A.5 Suzuki-Miyaura coupling . . . . . . . . . . . . . . . . . . . . . . . . . 69

A.5.1 Method for the catalytic investigations of metal borides . . . . 69

A.5.2 Characterisation of 3-methylbiphenyl . . . . . . . . . . . . . . 69

A.5.3 GC method . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

A.5.4 GC chromatograms of the reaction components . . . . . . . . 70

A.5.5 GC calibration curves . . . . . . . . . . . . . . . . . . . . . . 71

A.5.6 Biphenyl GC calibration . . . . . . . . . . . . . . . . . . . . . 73

A.5.7 Solvent screening method . . . . . . . . . . . . . . . . . . . . 74

A.5.8 Preparation of the phenylboronic acod pinacol ester . . . . . . 74

A.5.9 Method for microwave reactions . . . . . . . . . . . . . . . . . 75

VI

1 Introduction

Over the years, societies have become aware of the damaging effects of some chem-

ical practices and the need to protect the environment. In the past, few were aware

of the negative effects our lifestyle might have on the environment, and rather saw

only the positive potential for creating new, useful materials and products. The term

chemical pollution contains the damages caused by the agriculture (such as pesticides

and fertilizers) and household chemicals; however, the major part of chemical pollu-

tion is caused by the industries and factories in the form of hazardous waste, metals

and solvents. As the 12 principles of Green Chemistry state, it is better to prevent

waste than to treat or clean up waste after it has been created. Therefore, wherever

practicable, synthetic methods should be designed to use and generate substances

that possess little or no toxicity to human health and the environment. In addition,

starting materials from renewable sources are preferred. Green chemistry searches

for alternative, environmentally friendly reaction media. Alcohols and esters are con-

sidered as recommended solvents; however, in the case of the widely applied dipolar

aprotic solvents, such as dimethylformamide and dimethyl sulfoxide substitution is

requested. The pollution and waste produced by the environmentally harmful chem-

icals that were used in stoichiometric amount has become a serious issue; therefore,

catalytic reagents became superior to stoichiometric reagents. Green chemistry also

aims to increase reaction rates and lower reaction temperatures. Catalytic reactions

allow milder reaction conditions, such as lower temperature and pressure, resulting

in a better selectivity.

1.1 Catalysis

The term ”catalyst” was first introduced in 1835 by Berzelius who stated in his

yearly report that ”it is then shown that several simple and compound bodies, soluble

and insoluble, have the property of exercising on other bodies and action very different

from chemical affinity. The body effecting the changes does not take part in the

reaction and remains unaltered through the reaction. [...] I will therefore call it

1

the ”Catalytic Force” and I will call ”Catalysis” the decomposition of bodies by

this force.” [1] In 1894, Ostwald gave the first modern definition: ”Catalysis is the

acceleration of a chemical reaction, which proceeds slowly, by the presence of a foreign

substance” [2]. For his work on catalysis, Ostwald was awarded the 1909 Nobel

Prize in Chemistry. Later studies proved that catalysts lower the activation barrier

and thereby increase the rate of the reaction without themselves undergoing any

permanent chemical change. In the 20th century, a wide range of applications were

discovered, such as the hydrogenation of ethylene over nickel and cobalt catalysts by

Sabatier [3], and the synthesis of ammonia from the elements by Haber [4].

1.1.1 Classification

Catalysts are often divided into groups called homogenous catalysts and heteroge-

neous catalysts. A homogenous catalyst (e.g. metal salts of organic acids, organometal-

lic complexes, and carbonyls of cobalt, iron, and rhodium) resides in the same phase

as the reactants. Heterogeneous catalysts are often inorganic solids such as metals,

oxides, sulfides, and metal salts, but they may also be organic materials such as ion

exchangers and enzymes and reside in different phase from the reagents, often being

insoluble solids [5]. Each class has its own advantages and disadvantages; however,

the use of heterogeneous catalyst are more common due to their low cost, ease of

separation from products, high stability, and an ability to be recycled. A specific

advantage of the heterogeneous catalyst is that it can be used in a continuous pro-

cess operation, instead of in a batch-type process where it must be separated in an

individual step from the reaction product. At the same time, heterogeneous catalyst

can only react with reagents at the interface of the two phases, which result in slower

rates because of the low effective concentration. Throughout the years, heterogeneous

catalysis is used in more than 80% of current bulk chemical processes in the chemical

and petrochemical industries [6].

2

1.1.2 Heterogeneous catalysts

The most important group of catalysts consists of the solid catalysts and these

materials are used in important industrial large-scale processes, such as conversion

of chemicals, fuels and pollutants [7]. The group of solid catalysts can be divided

into several families such as: unsupported (bulk) catalysts (metal oxides, simple

binary oxides, complex multicomponent oxides, metals and metal alloys, ion-exchange

resins, metal salts); supported catalysts (support: silica, carbon, silicon carbide);

confined catalysts (ship-in-a-bottle catalyst: metal complexes in zeolite cages), hybrid

catalysts, polymerization catalysts, and several others [8].

1.1.3 Transition metal catalysts

Historically, non-catalytic routes were used for syntheses of fine chemicals; however,

because of environmental and economic considerations such as low price, high quality

and availability of materials the use of catalytic routes are preferred. With transition

metals (Pd, Pt, Rh, Fe, Co, Ru, Ni) a great variety of chemical reactions can be car-

ried out, for example: hydrogenation, izomerization, dehydrogenation, asymmetric

synthesis, oxidation, C-C coupling [9]. Considering the chemo-, regio- and stereose-

lective properties of these catalysts, transition metals make it possible to synthetize

asymmetric molecules selectively.

1.1.4 Nickel as catalyst

The first report of organonickel chemistry dates back to 1890, when Mond et al.

first isolated nickel tetracarbonyl [10]. Nickel got more attention in 1940 with the

discovery of the Reppe catalysts and from the 1960s the number of publications in

this field seems to rise [11]. Compared to other transition metals, the advantage of

using nickel as a catalyst is its low cost; moreover, the difference between the prices

in the past 10 years got more significant (Table 1). However, certain disadvantages

of nickel and its derivatives are associated with toxicity, human carcinogenesis, and

skin allergies [12].

3

Table 1: Price comparison of Ni, Pd and Pt and their dichlorides

(Aldrich Catalog) [12]

Ni

(99.99)aPd

(99.95)abPt

(99.99)ab

2004

(EUR/g−1)

5.4 62.9

[11.5]

83.1

[15.4]

2017

(EUR/g−1)

1.43 81.9

[57.3]

142.1

[99.4]

NiCl2

(99.99)

PdCl2

(99.999)

PtCl2

(99.9)

2004

(EUR/g−1)

26 120.0

[4.6]

250.8

[9.6]

2017

(EUR/g−1)

35.4 125.0

[3.5]

311.0

[8.8]

a Figures in parenthesis refer to the purity in %.b Figures in square brackets refer to price rates relative to nickel com-

pounds.

It has been well documented, that organonickel complexes are suitable for organic

transformations in catalytic as well as stoichiometric systems, especially for carbon-

carbon formation [11], [13]. Nickel can possess two stable oxidation states, the +2 and

the zerovalent state, both states are suitable to develop active organonickel complexes.

Nickel(0) complexes [Ni(CO)4 (1), Ni(cod)2 (2), Ni(PPh3)4 (3), Ni(bipy)Et2 (4),

Ni(dppe)Et2, (5)] (Figure 1) have been utilized as stoichiometric reagents for ho-

mocoupling of organic halides (Figure 2) [14] and they promote the intramolecular

coupling of organic halides with enolates and enones [15]. Other application is the

catalytic co-oligomerization of unsaturated hydrocarbons [11].

4

Ni

CO

OC CO

CONi

PPh3

Ph3P PPh3

PPh3Ni

N

N

Et

Et

Ni Ni

Ph2P

PPh2

Et

Et

1 2 3 54

Figure 1: Nickel(0) complexes

O

OBr

Br

Ni(CO)4O

O

N

Br BrNi(cod)2

PPh3n

Nn

Figure 2: Reactions with nickel(0) complexes

Dialkylnickel(II) complexes have the formula of NiR2L2, for example NiCl2(dppp)

(6) and NiCl2(PPh3)2 (7) (Figure 3), and can be used for catalytic cross-coupling

reactions [16]. Using chiral phosphine ligands (8) gives the possibility of asymmetric

synthesis (Figure 4) [17].

P

Ni

P

Cl Cl

Ni

Cl

Ph3P Cl

PPh3

6 7

Figure 3: Dialkylnickel(II) complexes

5

Cl

Cl

+ 2 BuMgBr NiCl2(dppp)

MgCl + BrNiBr2-L*

L* =Me2N

tBu

PPh2

H

8

Figure 4: Dialkylnickel(II) complexes and their reactions

(π-Allyl)nickel(II) complexes are derived from allyl halides and have been uti-

lized a stoichiometric reagents for allylation of organic halides [18] and ketons [19].

Nickelacycle complexes can be used for cyclization of unsaturated organic molecules

[20].

1.1.5 Nickel boride

In 1945, Schlesinger observed that although the alkali borohydrides reduced a cer-

tain number of salts to the metallic state (silver, mercury, bismuth salts, etc.), but

they only gave the corresponding borides with nickel or cobalt salts [21]. Schlesinger

and co-workers compared the prepared black precipitate with Raney nickel and found

that the new catalyst is neither ferromagnetic nor pyrophoric and decomposes slower

in hydrochloric acid. With analytical investigations, they determined the formula of

the catalyst: the boron to nickel ratio is virtually constant and always corresponds

to the presence of one boron atom for two nickel atoms. Therefore, the authors con-

cluded that the catalyst is nickel boride (Ni2B). In 1952, Paul et al. examined the

reactivity of nickel boride in different hydrogenation reactions with safrole, furfural

and benzonitrile [22]. They found that the nickel boride catalyst has the activity

at least equal to and often superior to that of Raney nickel. Given the low cost,

abundance, corrosion resistance, high efficiency and ease of fabrication, nickel boride

6

is one of the best alternatives to noble metal hydrogen evolution catalysts.

The industrial synthesis of borides usually involves reduction of metal oxides using a

mixture of boron carbide and carbon; electrolysis; or direct reaction of the elements.

4 NaBH4 + 2 NiCl2 + 9 H2O Ni2B + 3 H3BO3 + 4 NaCl + 12.5 H2O

Schlesinger discovered that the catalyst can be generated easily by using nickel(II)

salts (mainly NiCl2) with aqueous sodium borohydride [23].

1.1.5.1 Structure

Investigations using different solvents such as N,N -dimethylformamide, N,N -dime-

thylacetamide, diglyme, alcoholic or ether solvents showed that small variations in

the method of preparations can significantly affect the activity, selectivity, physical

and chemical properties of nickel boride. The unusual structure of the nickel boride

catalyst gained more attention which resulted in detailed studies. Maybury, Mitchell,

and Hawthorne analyzed nickel boride prepared in ethanol under nitrogen atmosphere

using excess NaBH4, and concluded that Ni2B inadequately represents its composition

[24]. Glavee et al. compared the product of the reaction using inert atmosphere

(diglyme) and open air (water). With XRD and X-ray power diffraction analysis

they concluded that the resulting product in the case of water solvent is noncrystalline

Ni2B with small quantities of metallic Ni and Ni3B while in the case of the dyglime

the product is a mixture of the above listed three components [25]. Legrand et al.

synthetized the catalyst with the help of reverse micelles. After the formation of

nickel metal nanoparticles with the addition of sodium borohydride nickel boride

nanoparticles were obtained. As XPS is nondestructive, it allowed the investigation

of the nanoparticles. From the XPS, they concluded that nanoparticles made under

nitrogen are Ni2B while the catalyst made on open air is a mixture of Ni metal and

Ni-B with an undetermined stoichiometry. The analysis proved that regardless the

chemical process, the nanoparticles contain boron bound nickel and also borate [26].

In 2002 Geng et al. examined the nanostructure of the nickel boride catalyst with

HRTEM and observed an ultra-fine crystalline structure; the material consists of

7

very small nickel single crystals from clusters as host that hold guest boron species

captive with their interstitial sites. This allows the extremely small size and very

high surface area [27]. Zeng and co-workers synthetized the nickel boride catalyst

by electroless plating technique and the TEM image revealed that the Ni-B particles

were amorphous with flower inner structure which formed during the preparation

process and they confirmed with HRTEM that there are no small crystallites in the

big particles, contradicting Geng’s findings [28].

1.1.5.2 Nickel boride promoted organic reactions

The literature only presents examples that use nickel boride as a reducing agent;

however, a wide range of substrates can be used and it gives a remarkable variety of

products depending on the reaction conditions [29].

Brown et al. observed, that nickel boride can act as a more reactive catalyst

than Raney Ni towards less reactive alkenes (e.g. cyclopentene, cyclohecene and

cyclooctene) [30], [31]. Belisle et al. reported a method for hydrogenation of α,β-

unsaturated ketones and aldehydes using ex situ generated nickel boride (Figure 5)

[32].

CHONi2B, H2

MeOH

CHO

Figure 5: Hydrogenation of α,β-unsaturated aldehyde

With in situ formed nickel boride in methanol, several quinolines, isoquinolines

and quinoxalines were converted to their tetrahydro-derivatives at room temperature

(Figure 6) [33]. In order to get good to excellent yields (83-94%), high excess of sodium

borohydride is necessary; however, using quinolines as starting materials requires only

sub-stoichiometric amounts of nickel chloride (0.35 eq.). Kudo et al. also reported

mechanistic investigations which revealed that in these cases complexes between the

nickel chloride and heterocyclic compounds were reduced by sodium borohydride.

8

N

N

N

N

NiCl2/NaBH4

MeOH

NiCl2/NaBH4

MeOH

NiCl2/NaBH4

MeOH

NH

NH

NH

HN

Figure 6: Reduction of heterocycles

Sodium borohydride itself is not able to reduce unactivated alkyl halides. However,

Dennis and Copper reported the reductive force of the combination of NiCl2 and

NaBH4 in alcohol. The disposal of organochlorine pesticides, such as DDT (9) and

2,4-DB[4-(2,4-dichlorophenoxy)butanoic acid] (10) is difficult, but with the use of

nickel boride both compounds can be extensively dechlorinated (Figure 7) [34].

CCl3

Cl Cl

O

Cl

Cl

COOH

9 10

Cl

Cl

Cl

Cl

Cl

NaBH4, (Ni2B)2H3

MeOH, EtOH or i-PrOH

Cl

Cl

Figure 7: Toxic polychlorinated hydrocarbon pesticides and their reductions

Pharmaceutically active compounds often bear amino groups and the reduction of

aromatic nitro compounds to amines is an important synthetic reaction. Kudo and

Nose reported a method using NiCl2 with NaBH4 in methanol to reduce nitroarenes

9

to anilines in good yield [35]. Osby and Ganem found that the same system rapidly

reduces a variety of nitro compounds at room temperature (Figure 8) [36].

NiCl2/NaBH4

MeOHR NO2 R NH2

R = aryl, alkyl, allyl

Figure 8: Reduction of nitroarenes and nitroalkanes

Other nitrogenous functional groups, such as nitroso (11), azoxy (12), azo (13),

hydrazo (14) and hydroxylamines (15) (Figure 9) also can be reduced using the nickel

boride catalyst. Aromatic compounds bearing these groups can be transformed to

anilines in acidic or basic media [35].

NO

NN

O

NN

HNNH

11 12 13 14

NHO

15

Figure 9: Nitrogeneous functional groups

The NiCl2/NaBH4/CH3OH system can be used for the reductive removal of allylic,

propargylic and benzylic groups from acetate esters (Figure 10). Comparing nickel

boride with Raney nickel, the former proved to be superior for reductive removal while

the latter was more efficient in deoxygenations [37]. Russel et al. reported that in

unsaturated aldehydes both the carbonyl and the olefinic group can be hydrogenated

[38].

O

ONiCl2/NaBH4

MeOH

Figure 10: Example of ester reduction

10

Truce and Perry reduced thioketals and thioacetals with the same catalyst system

and successfully desulfurized the organic structures [39]. The reductive desulfurization

of thioethers is also a possibility with nickel boride; Euerby and Waigh reported the

selective reduction of alkylthio derivatives of benzaldehyde and benzyl alcohol to give

good yields of benzyl alcohol, while with Raney nickel the main product is toluene

(Figure 11) [40].

NH

PhSMe

NiCl2/NaBH4

MeOHNH

Ph

Figure 11: Desulfurization of thioethers

In 1984, Back reported a convenient method for selective reductive deselenization

of alkyl, allyl and alkenyl selenides with the NiCl2/NaBH4/CH3OH/ THF system.

Under these conditions no alkene reduction was observed; moreover, sulfones ketones

and acetates also remained untouched (Figure 12) [41], [42].

SeX

10NiCl2/NaBH4

MeOH-THF

X10

X = Cl, CN, COOMe, SPh, Ts

Figure 12: Example for deselenization

As the different type of reductions indicate, nickel boride behaves differently under

different reaction conditions. The influencing factors are:

1. the NiCl2/NaBH4 molar ratio,

2. the preparation of the catalyst, the type of the nickel salt,

3. the solvent or solvent mixture,

4. the temperature.

11

These findings indicate that the range of application could be widened and other type

reactions could also be conducted with this type of catalytic system.

1.2 Coupling reactions

A coupling reaction is a general term for a variety of reactions where two organic

fragments are coupled in the presence of a metal catalyst. In most cases the C-C

single bond is formed by the reaction of an organometallic (R-M) and an organic

halide (R’-X) [43].

R M + R’ Xcatalyst

R R’ + M X

Based on the reagents, coupling reactions can be divided into two groups. In the

case of heterocoupling two different fragments are coupled. Grignard published the

first so called cross-coupling reaction in 1900 and was awarded the 1912 Nobel Prize in

Chemistry for this work [44]. Several other cross-couplings have been reported since,

such as the Kumada, Sonogashira, Negishi, Stille, Suzuki and Hiyama coupling. In

1994, Buchwald and Hartwig reported a new kind of cross-coupling, in which case a

new N-C single bond is formed (Figure 13) [45], [46]. In 2010, for developing palladium

catalyzed cross coupling reactions Richard F. Heck, Ei-ichi Negishi and Akira Suzuki

were awarded the Nobel Prize in Chemistry [47]. Homocoupling couples two identical

partners, which narrows down the possible outcomes of a reaction; consequently, this

group was reported earlier. In 1855, Wurtz published the reaction of two halides in

the presence of Na as reducing agent (Figure 13) [48].

12

R MgBrR

1

O

R2+

R1 R 2

RHO

Ar MgBr + Ar XPd or Ni

Ar Ar

R+H R’Pd cat., CuI

baseR R’

R ZnX + R XPd or Ni cat.

R R

H+/H2O

R SnR3 + R XPd cat.

R R

R B(OR)2 + R XPd or Ni cat.

R R

R SiR3 + R XPd cat.

R Rbase

base

+ R X R RR XNa

Grignard

Kumada

Sonogashira

Stille

Negishi

Suzuki-Miyaura

Hiyama

Wurtz

Buchwald-HartwigR2N H + R XPd cat.

R2N R

X

or Fe cat.

Figure 13: Different homo- and heterocoupling reactions

1.2.1 Sonogashira reaction

The Sonogashira reaction is the most widely used method for synthesis of sub-

stituted alkynes (Figure 14) and reflects typical properties of Pd-catalyzed cross-

coupling reactions, due to the availability of starting materials, mild coupling condi-

tions, and the ability to tolerate a large variety of functional groups. The reaction re-

quires catalytic amounts of palladium as catalyst and copper(I)-iodide as co-catalyst.

The use of copper makes it possible to use milder conditions as the ones earlier re-

ported by Heck and Cassar [49].

13

R-X + H R’Pd cat., CuI

baseR R’

R = aryl, vinyl

R’ = aryl, alkenyl, alkyl, SiR3

X = I, Br, OTf

Figure 14: General Sonogashira reaction

1.2.1.1 Mechanism

The mechanism of the Sonogashira reaction has not yet been established clearly,

there has been evidence from recent studies of cross-coupling reactions that suggest

a more complex mechanism [50]. Nonetheless, the general outline of the mechanism

involves a sequence of oxidative addition, transmetalation, and reductive elimination,

which are common to palladium-catalyzed cross-coupling reactions. However, the

precise role of the copper co-catalyst and the structure of the catalytically active

species remain uncertain. The mechanism displayed in Figure 15 includes the catalytic

cycle itself, the preactivation step and the copper mediated transfer of acetylide to

the Pd complex and is based on proposals already made in the early publications of

Sonogashira [51].

The most commonly used palladium source is (PPh3)2PdCl2 (1), which was orig-

inally employed by Sonogashira himself. Pd(OAc)2, (CH3CN)2PdCl2, or Na2PdCl4

with at least two equivalents of a tertiary phosphine can also be used to form the

catalytically active species in situ. The active catalytic complex is still the subject of

some debate, but is classically thought be the coordinatively unsaturated 14-electron

Pd(0)L2 (4) [51]. With all Pd(II) salts the initial step leading to the catalytically

active species is preactivation of the catalyst, i.e. reduction of Pd(II) to Pd(0). As

a side reaction reductive elimination from the cis-diacetylide (2) can result in the

respective butadiyne (3). Alternatively, generation of 4 from Pd(II) proceeds via

reductive elimination of 6. From 4 oxidative addition of aryl or vinyl halides re-

sults in a Pd(II) intermediate (5); this is considered as the rate-determining step.

The copper-supported alkynylation leads to the alkynylpalladium(II) derivative (6),

14

Pd

L Cl

ClL

CuX

RCu

RH

HX-amine

Pd

L

L

R

R

R R

L2Pd0

R'X Pd

L X

R'L

L2Pd

H

R

Pd

L

R'L

R

CuX

RCu

RH

HX-amine

RR'

transmetallation

reductive elimination

oxidative addition

preactivation

II

II

II

II

(1)

(2)

(3)

(4)

(5)

(6)

(7)

Figure 15: Mechanism of the Sonogashira reaction for Pd/Cu-catalyzed cross-coupling

which regenerates the catalytic species (4) by reductive elimination of the coupled

products (7).

There are many variables that dictate the overall efficiency of the catalytic cycle,

including ligand(s), amine base, copper salt, solvent, other ’additives’, and the elec-

tronic and steric characteristics of the organic electrophile and alkyne.

1.2.1.2 Recent advances and developments

Recently microwave heating proved to be able to accelerate chemical reactions

frequently delivering high yields in just a few minutes as opposed to hours with con-

ventional heating. A microwave-enhanced Sonogashira reaction in the presence of

(PPh3)2PdCl2 and CuI was presented by Erdelyi and Gogoll and applied to the cou-

15

pling of aryl iodides, bromides, triflates, and activated aryl chlorides with trimethylsi-

lylacetylene (Figure 16) [52].

Ar + H SiMe3

Pd(Ph3)2Cl2, CuI

Et2NH, DMFAr SiMe3X

t = 5-25 min 80-99%

Figure 16: Microwave-assisted Sonogashira reaction

Heterogeneous polymer-supported catalysts have also attracted considerable in-

terest: Merrifield resin (Figure 17 A) [53] and PS-PEG resin (Figure 17 B) [54] have

both shown to be applicable as support for the cross-coupling of iodoarenes with

alkynes at moderate temperatures.

Based mainly on economic considerations, different attempts have been made to

replace the expensive noble metal palladium by using a cheaper metal [55]. Research

on the use of different copper-based catalysts has been rather frequent in recent years

[56]. CuI and triphenylphosphane (Figure 17 C) [57]; simple copper(II) acetate (Fig-

ure 17 D) [58] and some copper complexes (Figure 17 E) [59] have also been used

in Sonogashira reactions. Colacino et al. reported ligand-free procedures involving

copper salts as catalysts (Figure 17 F) [60]. Iron also has been used as catalyst in the

cross-coupling reaction; however, the influence of palladium impurities in the coupling

process is still a question (Figure 17 G) [61]. Other catalysts based on cobalt (Figure

17 H) [62] and gold (Figure 17 I) [63] have been reported to catalyze Sonogashira

reactions, too. Vechorkin et al. reported Ni-catalyzed Sonogashira coupling of non-

activated, β-H-containing alkyl halides. The coupling is tolerant to a wide range of

functional groups, including ether, ester, amide, nitrile, keto, heterocycle, acetal, and

aryl halide, in both coupling partners (Figure 17 J) [64].

16

O

Cl

NPd

NN

Cl

Ph3P

NH

O

PPh2

Pd

Cl

CuI

dioxane

Ar + H Ar Ar ArX

A B

C D E

Et3N

H2O

CuI

KOH

PPh3

H2O

Cu(OAc)2

Et3N

Cs2CO3

DMEDA

Cu(DMEDA)2]Cl2·H2O

dioxane

F G H I J

CuI

K2CO3

PEG

CuI, Fe(acac)3

K3PO4

DMSO

CuI, nano-Co

K2CO3

PPh3

NMP

PPh3AuCl

K3PO4

o-xylene

CuI, (MeNH2)NiCl

Cs2CO3

dioxane

Figure 17: Advances in Sonogashira reaction

1.2.2 Glaser reaction

Homocoupling of terminal acetylenes first described by Glaser in 1869 [65] occurs in

presence of a base, a copper(I) salt (usually CuCl) and oxygen (Figure 18). Natural

products often consist of di- and polyacetylenic structures, such as the polyacetylenes

from Chrysanthemum leucanthemum, Bidens aurea and Artemesia capillaris [66].

Therefore, there is a rapidly growing interest of material sciences in conjugated oligo-

and polyacetylenes [67]. Whereas Glaser-type oxidative coupling opens efficient syn-

17

thetic pathways toward symmetrical diynes, its performance in heterocoupling is poor.

HR2CuCl, O2

baseR R

Figure 18: General Glaser reaction

1.2.2.1 Mechanism

Although acetylenic homo- and heterocouplings have been widely used in different

fields of organic synthesis, their exact mechanism is still obscure. Because of the

difficulty of kinetic studies, owing to the rapid reaction rates observed for the bro-

moalkynes commonly employed, several mechanistic hypotheses have been postulated

[67]. Studies have shown the strong dependency of the mechanism on the experimen-

tal setup, suggesting highly complex coherences and interactions. All currently known

mechanisms of oxidative acetylenic homocouplings are very specific to single reaction

conditions, e.g. pH or oxidation state of the used copper salt.

Studies by different research groups indicate that both Cu+ and Cu2+ ions are in-

volved in the coupling process [67]. Whereas copper(II) serves as the direct oxidizing

agent, the role of copper(I) seems more versatile. Hay and co-workers found that

he copper(II) carboxylates are the only copper(II) salts that are catalysts for the

reaction, but they proved to be far inferior in catalytic activity to copper(I) salts [68].

A very reasonable role of copper(I) in the coupling process seems to be inter-

mediate formation of non-reactive copper-π-complexes (1) (Figure 19). Coordina-

tion of cuprous ions activates the corresponding alkyne units toward deprotonation.

Bohlmann and co-workers assumed that this activation process can be the initial

step in the formation of dinuclear copper(II) acetylide complexes (4) [69]. 1 stepwise

displaces the negatively charged counter ions of copper(II) salt dimers (2). The din-

uclear copper(II) acetylide complex which finally results (4) collapses to the coupled

product (5) under reductive elimination of copper(I).

18

CuX HR

R

Cu

X

Cu

Cu

X

B B

BB

2+

CuX

Cu

Cu

X

B B

BB

2+

R

Cu

Cu

B B

BB

2+

R

R

R

Cu

CuX

R R

HX

(1)

(2)

(3)

(4)

(5)

HX-BB

B = base

Figure 19: Proposed mechanism of the Glaser reaction by Bohlmann et al.

However, the current mechanistic understanding of copper-mediated oxidative acetylenic

couplings is unsatisfactory, the mechanistic idea of Bohlmann et al. described above

still provides the most accepted picture for Glaser-type oxidative acetylenic homo-

couplings.

1.2.2.2 Recent advances and developments

Glaser-type homocouplings have been applied to the synthesis of numerous aliphatic

and aromatic diynes, because of the tolerance of a large variety of functional groups.

Their synthetic capacity has been impressively demonstrated in the synthesis of

the conjugated organic oligomers and polymers [49] in polymer and supramolecular

chemistry. Complex molecular architectures, such as: conjugated macrocycles (dehy-

drobenzoannulenes, graphdiyne subunits, π expanded radialene macrocycles); macro-

cyclic oligothiophenes; pyridine containing macrocycles; macrocyclic and dendrimeric

19

polyynes; shape persistent macrocycles; rotaxanes and catananes; cyclophanes; ferro-

cenophanes; fullerenol derivatives; molecular cages are formed from simple building

blocks [70].

CuI, I2

Na2CO3

DMF

CuAl-LDH

TMEDA

acetonitrile

Cu/SiO2

piperidine

toluene

HR2 R R

A B C D

E F G H

CuI-USY

DMF

CoBr2, ZnBr2, Zn

PhNO2

acetonitrile

Cu(OAc)2

NaOAc

PEG

CuI

[bmim]OH

CuCl2, Ni(NO3)2·6H2O

TMEDA/Et3N

PEG/MeOH

Figure 20: Glaser reaction developements

Efforts have been made to develop new methods with milder conditions. Jia et

al. developed a facile and simple CuI/iodine-mediated pathway (Figure 20 A) for

the homocoupling reaction and proposed a mechanism that involves the formation of

alkynylcopper intermediate, which undergoes oxidative dimerisation with iodine [71].

Jiang et al. investigated the use of CuAl-LDH (copper(II) in the host layers of layered

double hydroxide or hydrotalcites) (Figure 20 B) [72]. Zeolites modified with cuprous

ions in DMF offer another alternative catalyst; a large number of alkynes, including

those containing carbohydrate moieties could be coupled (Figure 20 C) [73]. Instead

of copper salts, copper immobilised on a functionalised silica support also serves as an

efficient heterogeneous catalyst (Figure 20 D) [74]. Glaser-type coupling of terminal

alkynes was also attempted with cobalt catalysts: with a suspension of CoBr2, Zn

powder and nitrobenzene which can be used as a stoichiometric oxidant. In contrast

to the classical Glaser coupling reaction, the cobalt-catalysed reaction was performed

under reductive conditions (zinc powder) (Figure 20 E) [75].

Efforts have been made to replace the traditional solvents with green solvents such as

supercritical fluids, ionic liquids, water, etc. and even solvent free conditions would

20

be attractive. Zhang et al. reported that polyethyleneglycol could be an alternative

as the reaction system could be readily recycled more than five times (Figure 20

F) [76]. Ionic liquids allow the recycling and reuse of this catalytic system with

simple procedures, and thus pave the path for green synthesis. Ionic liquid, such

as [bmim]OH has also been tried as a solvent under atmospheric conditions for the

homocoupling of acetylenes (Figure 20 G) [77].

Microwave irradiation can also be applied for better efficiency in macrocyclisation.

Bedard and co-workers managed to reduce the reaction time from 48 hours to 1-6

hours (Figure 20 H) [78].

1.2.3 Suzuki-Miyaura reaction

The cross-coupling of organoboron reagents with organic electrophiles in the pres-

ence of a base and a Pd catalyst is commonly referred to as the Suzuki-Miyaura

reaction (Figure 21) and has proved to be one of the most popular cross-coupling

methodologies. The original version, first reported in 1979, was the palladium(0)-

catalysed coupling of a vinyl boronate with an aromatic iodide or bromide [79].

B(OH)2 + XR Pd cat.

base R

Figure 21: General Suzuki-Miyaura reaction

Organoboron coupling partners show a number of advantageous properties over

other organometals: organoborons have a much lower toxicity than organostannane

reagents, they are stable to water and air, which makes their isolation and storage

possible. Many organoboron building blocks are nowadays commercially available

and they have remarkable tolerance against various functional groups along with

their insensitivity to steric effects. Alkynylboron and aromatic boron compounds

both can be used as reagents, making the synthesis of conjugated alkadienes and

biaryls possible. Suzuki and co-workers also discovered that the reaction provides the

expected coupled products regio- and stereoselectively in high yields [80] [81].

Boronic acids are one of the most readily available kinds of boron reagent for the

21

Suzuki coupling. They are; however, complicated by the fact that they are often in

equilibrium with their anhydrides, the boroxines. In addition, the boronic acids can

have a tendency to undergo protio-deboration, resulting in the decomposition of the

startin material and the need to employ excess boronic acid in the coupling reaction.

Esters of boronic acids, especially the pinacol esters, are widely used and can be

easily prepared from the boronic acid [43]. Alkynylboranes are valuable intermediates;

however, owing to their pronounced Lewis acidity, alkynylboranes can easily hydrolyze

under basic aqueous conditions, which severely complicated their early application in

coupling reactions [82].

1.2.3.1 Mechanism

The general catalytic cycle for Suzuki cross-coupling involves the three fundamental

steps: oxidative addition, transmetalation, and reductive elimination as demonstrated

in Figure 22 [83].

In most cases the oxidative addition is the rate determining step of the catalytic

cycle; the relative reactivity decreases in the order of I >OTf >Br >Cl. During this

step, the palladium catalyst is oxidized from palladium(0) to palladium(II). The pal-

ladium catalyst (1) is coupled with the aryl halide (2) to yield an organopalladium

complex (3). The reaction with the base gives intermediate 4 which undergoes trans-

metalation with the previously activated organoboron compound (5). The base that

was added in the prior step is exchanged with the substituent on the organoboron

species to give the new palladium(II) complex (6). The organoboron compounds do

not undergo transmetalation in the absence of base; and therefore, the role of the

base is believed to be the activation of the organoboron compound as well as facili-

tate the formation of 4 from 3 [84]. The final step is the reductive elimination step

where the palladium(II) complex (6) eliminates the product (7) and regenerates the

palladium(0) catalyst (1).

22

transmetalation

reductive elimination

oxidative addition

LnPd0

LnPdX

XR

R

B(OH)2

LnPd

R

R

NaOH

NaXLnPd

OH

R

B(OH)3

NaOH

Na

B(OH)4Na

(1)

(2)

(3)

(4)

(5)

(6)

(7)

Figure 22: Mechanism of the Suzuki-Miyaura reaction forming biaryls

1.2.3.2 Recent advances and developments

Typically, cross coupling reactions are run in organic solvents. However, Suzuki

couplings can be performed in heterogeneous or purely aqueous conditions as organob-

oranes are water soluble and compatible with water soluble, inorganically supported,

ligand-free Pd-catalysts; making the reaction milder and greener [80]. Pd(OAc)2 in a

mixture of water and poly(ethylene glycol) is shown to be an extremely active catalyst

for the Suzuki reaction of aryl iodides and bromides. The reaction can be conducted

under mild conditions without the use of phosphine ligand in high yields, and the

Pd(OAc)2-PEG can be reused without significant loss in activity [85].

Suzuki couplings have been used in the synthesis of complex molecules. For exam-

23

ple, coupling of two large fragments of the epothilone A structure was accomplished

in this way (Figure 23). The advantage of this type of reaction is that the desired

intermediate was successfully obtained in the presence of numerous stereocenters and

functional groups, because of the stereoselectivity [86].

N

S

I

OAcOTBS

OTBSOBn

+

N

S

OAc

OTBSOBn

OTBS

9-BBNTHF

Pd(dppf)Cl2Cs2CO3DMF/H2O

1.

2.

Figure 23: Suzuki reaction in the synthesis of epothilone A

Various catalysts have been developed for metals other than palladium, especially

nickel. The use of nickel catalysts has allowed for electrophiles that proved challenging

for the original Suzuki coupling using palladium, including substrates such as phenols,

aryl ethers, esters, phosphates, and fluorides [87].

Wu et al. reported the that dendritic phosphine-stabilized nickel nanoparticles

were found to be a highly active and recyclable catalyst for Suzuki coupling reac-

tions, especially those extended to aryl chloride substrates, affording the biaryls in

moderate to good yields (Figure 24 A) [88]. Copper-catalysts’ attractive features are

being earth-abundant and inexpensive. Gurung and co-workers reported on a ver-

satile Cu-catalyzed cross-coupling of aryl- and heteroarylboronate esters with aryl-

and heteroaryl iodides that affords biaryl products in good to excellent yields. The

reaction proceeds under ligand-free conditions, with the assistance of CuI, CsF and

o-(di-tert-butylphosphino)-N,N -dimethylaniline (Figure 24 B) [89]. Han et al. found

that with the aid of sodium hydroxide gold nanoparticles can catalyze the synthesis

of biaryls in high yields. The reaction media is chosen as water instead of organic

24

solvent in consideration of the green-chemistry processes and low cost. Furthermore,

the catalyst could be reused without decreasing the yield (Figure 24 C) [90].

NMe2

P(tBu)2

NN

Pd

NCl Cl

Cl

iPr

iPr iPr

iPr

O

N

N

N

Pd

OAc

OAcO

O

OH

Si

OEt

N NN

N R

PdEDTA2-

R B(OR)2 + R X R R

G3DenP-Ni

K3PO4·7H2O

THF

A B C D

E

CuI, CsF

DMF/dioxane

Au

NaOH

H2O

K2CO3

K2CO3

EtOH

F

Na2CO3

H2O

Figure 24: Suzuki reaction recent developments

Microwave reactions have gained ground in the past decades because of their

ability to shorten reaction times. Nun and co-workers developed a solvent-free,

microwave-assisted Suzuki reaction with the aid of potassium carbonate and a new

palladium N-heterocyclic carbene catalyst (Figure 24 D) [91].

The use of supported catalysts makes both the purification process and the recy-

cling easier. Yang et al. developed al Merrifield resin immobilized phenanthroline-

palladium(II) complex which was found to be an efficient catalyst for Suzuki-Miyaura

cross-coupling reaction between arylboronic acids and a range of aryl halides under

mild reaction conditions. The catalyst exhibited both high catalytic activity and

stability; furthermore, the catalyst could be recycled at least 10 times without a sig-

25

nificant loss of catalytic activity (Figure 24 E) [92]. Wei and co-workers reported a

silica-immobilized system in an ionic liquid brush in water as solvent for coupling aryl

iodides and bromides with phenylboronic acid (Figure 24 F) [93].

1.3 The aim of this thesis

Transition metal-catalyzed cross-coupling reactions represent an important segment

of organic chemistry, since in these reactions new carbon-carbon bonds can be formed

allowing a simple way to build up molecules. This thesis is focused on the nickel

boride catalyst, and concerns with the possibility to widen the scope of reactions

in which nickel boride can be applied successfully. The aim is to investigate named

catalyst’s activity in three different coupling reactions, Sonogashira cross-coupling,

Glaser homocoupling and Suzuki-Miyaura cross-coupling.

2 Experimental work

2.1 Synthesis of nickel boride catalyst

Besides nickel boride, cobalt boride and iron boride have also been prepared, in-

vestigated and used in different reductions [96]. Based on this reports our group also

considered using these catalysts in the coupling reactions. Although all metal borides

have been prepared, in this work we only investigated thoroughly the behavior and

activity of the nickel boride.

2.1.1 Preparation of metal borides

The metal boride catalysts can be prepared in aqueous and non-aqueous media

[25]. In different solvents, the composition of the catalyst can vary. Nickel, cobalt

and iron boride had been prepared in anhydrous methanol and in water (Appendix

A.2). In all cases, the catalysts were forming with good yields; however, the difficulty

of collecting the magnetic particles resulted in some loss of material (Table 2).

26

Table 2: Preparation of metal borides

M2Cl + NaBH4solvent

M2B

Metal Prepared in Magnetic properties Isolated yield

Nickelmethanol non-magnetic 84%

water non-magnetic 91%

Cobaltmethanol non-magnetic 80%

water magnetic 75%

Ironmethanol magnetic 51%

water magnetic 67%

2.1.2 Nickel boride applications

To explore the catalytic activity of the nickel boride, different preparations have

been utilized in the reactions. In most reaction previously prepared (Appendix A.2.1)

catalyst has been used. In this case, we observed that by storing the catalyst, with

time the activity decreases until the nickel boride loses all catalytic activity. It is

also possible to buy nickel boride from Sigma-Aldrich; however, the commercially

available and the pre-prepared nickel boride have different appearances. While the

commercially available appeares metallic, the pre-prepared catalyst consists of black

particles. To prevent the degradation of the nickel boride, before starting the reac-

tions, the catalyst was freshly prepared on filtering paper (Appendix A.2.3).

In the case of alcoholic solvents it is possible to use in situ prepared catalyst; however,

the solubility of nickel chloride hexahydrate decreases when using bulkier alcohols.

2.2 Sonogashira coupling

As stated previously, there are a number of publications reporting successful Sono-

gashira couplings with the aid of nickel catalyst [64] and even ligand-free copper-

catalyzed procedures have been developed [60]. Our aim was to investigate, if nickel

27

boride can catalyze the Sonogashira reaction between an alkyne and an aryl halide.

Okuro and co-workers reported that the treatment of iodobenzene with phenylacety-

lene in DMF in the presence of catalytical amount of CuI, PPh3 and K2CO3 at 120 ◦C

for 16 hours gave diphenylacetylene almost quantitatively [94]. We chose this reaction

as starting point for our research (Figure 25).

+INi2B, CuI, K2CO3

DMF

Figure 25: Proposed Sonogashira reaction

Two parallel reactions were set up in DMF (Table 3, Entry 1-2). To the first

vial, only CuI as catalyst together with sodium borohydride, to the second vial also

pre-prepared nickel boride was added. Analyzing the reaction mixtures with TLC

(eluent: hexane), in both cases two new spots appeared, really close to each other.

After column chromatography (eluent: hexane), the unknown components were an-

alyzed via 1H-NMR and one of the components proved to be the expected product

(Appendix A.3.1). The structure of the other component could not be determined

due to impurities. However, both the product and the side product the could only be

obtained in trace amounts.

Based on the publication of Yi et al. [95], DMF was exchanged with a mixture of

DMAc and DEE (Table 3, Entry 3-4). To exclude the possibility of dehalogenation,

the activities of two starting materials (1-iodohexane and 4-iodotoluene) were com-

pared. Analyzing the reaction mixtures with TLC (eluent: hexane), in both cases the

yet unidentified new spot appeared and the spot of the cross-coupled product could

not be detected. The 1-iodotoluene stayed intact in the reaction mixture. After

column chromatography (eluent: hexane), the purified unknown component (white

chrystals) was analyzed via 1H-NMR and proved to be the homocoupled product of

phenylacetylene (Appendix A.3.2).

To determine, if nickel boride or copper iodide catalyzes the reaction, three reac-

tions were set up (Table 3, Entry 5-7). To the first vial only nickel boride catalyst,

28

Table 3: Sonogashira coupling investigations

+INi2B, CuI, K2CO3

DMF

Entry Catalyst Base Solvent Conditions ProductaSide

producta

1 CuI K2CO3 DMF 120 ◦C, 16 h x x

2 Ni2B/CuI K2CO3 DMF 120 ◦C, 16 h x x

3 Ni2B/CuI KOtBu DEE/DMAcb rt, 24 h x

4 c Ni2B/CuI KOtBu DEE/DMAcb rt, 24 h x

5 Ni2B KOtBu DEE/DMAcb rt, 24 h x

6 CuI KOtBu DEE/DMAcb rt, 24 h x

7 - KOtBu DEE/DMAcb rt, 24 h x

a determined with TLC.b DEE/DMAc (2 ml, 9:1).c 1-Iodohexane starting material.

Reaction conditions: 4-Iodotoluene (1 mmol), phenylacetylene (1 mmol), solvent (2 ml),

CuI (0.05 mmol, 0.05 eq.), Ni2B (0.12 mmol, 0.12 eq.) and K2CO3 (1.5 mmol, 1.5 eq.).

to the second vial only CuI catalyst were added as catalysts and to the third vial no

additional chemicals were added. Analyzing the reaction mixtures with TLC, in the

third case, without any metal no reaction occurred. In the other two cases, only the

homocoupling product could be detected, which suggests that copper alone also cat-

alyzes the homocoupling without the nickel catalyst, which is expected from previous

literature.

In conclusion, we found that both the cross-coupling and the homocoupling re-

actions proceed in DMF, and with appropriate solvents it is possible to shift this

balance towards the homocoupling product (Figure 26). Based on the results we de-

cided to exclude the aryl halide from the reaction mixtures and continue the work

with Glaser-type couplings.

29

+I

Ni2B, CuI,

KOtBu DMF

+

Ni2B, CuI,

KOtBuDEE-DMAc

Figure 26: The effect of solvents

2.3 Glaser coupling

Our aim was to achieve the homocoupling of phenylacetylene with the aid of nickel

boride (Figure 27). In the case of the initial screening reactions only TLC analysis

was used to detect the product.

2Ni2B, base

solvent

Figure 27: Glaser homocoupling model reaction

2.3.1 Solvent screening

To optimize the reaction, the effect of different solvents was investigated. The

solvents were chosen based on the literature and the principles of green chemistry

were also considered. The reaction was set up with seven different solvents (Table 4,

Appendix A.4.1).

30

Table 4: Glaser coupling solvent screening

2Ni2B, base

solvent

Entry Catalyst Base Solvent Conditions Producta

1 Ni2B KOtBu DEE/DMAcb rt, 24 h x

2 Ni2B KOtBu methanol rt, 24 h x

3 Ni2B KOtBu ethanol rt, 24 h x

4 Ni2B KOtBu butanol rt, 24 h

5 Ni2B KOtBu water rt, 24 h

6 Ni2B KOtBu acetonitrile rt, 24 h x

7 Ni2B KOtBu DMF rt, 24 h

a determined with TLC.b DEE/DMAc (1 ml, 9:1).

Reaction conditions: 4-Iodotoluene (0.25 mmol), phenylacetylene (0.25 mmol),

solvent (1 ml), Ni2B (0.03 mmol, 0.12 eq.) and KOtBu (0.5 mmol, 2.0 eq.).

In the cases of water, butanol and DMF no product was detected. Using alcohols

as solvents also resulted in trace amounts of the product. Based on the relative

intensity of the product spot compared to the phenylacetylene’s spot, the previously

tested DEE-DMAc and acetonitrile solvents proved to be the optimal conditions.

However, the TLC of the reaction mixture with the solvent DEE-DMAc showed more

side products. In conclusion, we chose acetonitrile for further reactions.

2.3.2 Base screening

Literature revealed that weaker bases can also be sufficient in Glaser couplings [71].

Therefore, other inorcanic bases (sodium carbonate and tripotassium phosphate) were

also tried as possible replacements for potassium tert-butoxide (Table 5).

31

Table 5: Glaser coupling base screening

2Ni2B, base

solvent

Entry Catalyst Base Solvent Conditions Producta

1 Ni2B KOtBu acetonitrile rt, 24 h x

2 Ni2B Na2CO3 acetonitrile rt, 24 h

3 Ni2B K3PO4 acetonitrile rt, 24 h x

a determined with TLC.

Reaction conditions: phenylacetylene (0.25 mmol), acetonitrile (1 ml), Ni2B

(0.03 mmol, 0.12 eq.) and base (0.5 mmol, 2.0 eq.).

Based on TLC analysis, in the case of sodium carbonate no reaction occurred,

while tripotassium phosphate proved to be a better option than potassium tert-

butoxide, since the reaction mixture contained less components, side products. With

a weaker base the possibility of side reactions is lower, thus we decided to continue

the research with tripotassium phosphate.

2.3.3 Analysis with gas chromatography

Gas chromatography is a common type of chromatography used in analytical chem-

istry for separating and analyzing compounds that can be vaporized without decom-

position. This method makes it possible to determine the concentration of different

components without the need of column chromatography or other time-consuming

workup. Out of these reasons, we chose GC to analyze our reaction mixtures.

As the first step, the starting material, and the product were injected on the GC in

order to develop a suitable method for the separation. As can be seen in Appendix

A.4.3, after the intense solvent peak, the starting material can be detected at 3.782

min. The peak of the product appeares at 14.720 min; however, the high boiling

point (200-210◦C) made it difficult to reduce the retention time. Anisole was used

as internal standard, with the retention time of 4.195 min. Because of the potential

32

overlap of the starting material’s and the standard’s peak, no further shortening of

the GC method was possible (Figure 28, Appendix A.4.2).

Figure 28: Calibration chromatogram (point 4)

In both cases a five-point calibration curve was made. The five samples contained

different amount of starting material and product, while the amount of standard was

kept constant. In the case of the starting material, the ratio of the phenylacetylene’s

peak area (As) and the anisole’s peak area (Aa) was calculated (Table 6).

33

Table 6: Calibration of phenyacetylene (s)

with anisole (a) as standard

Entry ns/na Concentration As/Aa

(-) (g/dm3) (-)

1 0.95 56.8 1.09

2 0.70 41.8 0.81

3 0.52 31.4 0.63

4 0.29 17.2 0.33

5 0.00 0.00 0.00

y = 0.8631x - 0.0044R² = 0.9995

0.00

0.20

0.40

0.60

0.80

1.00

0.00 0.20 0.40 0.60 0.80 1.00 1.20

ns/n

a [-

]

As/Aa [-]

Figure 29: Phenylacetylene calibration curve with anisole as standard

The diagram in Figure 29 represents the correlation between the As/Aa values

and the ns/na values. If the molar amount of standard is equal to the starting

material when starting the reaction, conversion can be directly calculated by using

the equation.

34

The same calibration was made for the product. The ratio of the product’s peak

area (Ap) and the standard’s peak area (Aa) was calculated (Appendix A.4.4). The

coupling reaction of two mols of starting material theoretically results in one mol of

product (Figure 27), thus multiplying the calculated np/na values with 2 gives the

GC yield of the product.

2.3.4 Reactions

With the new GC method, the previously reactions were repeated in order to more

accurately determine yields of the homocoupling product (Table 7, Entry 1). On TLC

an intense spot of the product appeared; however, with the GC method only 4% of

product was detected. This suggests that there is a large discrepancy between the

intensity of the product’s spot compared to the spot of the starting material and the

yield of the product.

Table 7: Glaser coupling reactions

2Ni2B, K3PO4

acetonitrile

Entry Ni2B Base Solvent Conditions Producta

1 pre-prepared K3PO4 acetonitrile 70 ◦C, 24 h 4%

2 pre-prepared K3PO4 acetonitrile rt, 24 h 2%

3 in situ formed K3PO4 acetonitrile rt, 24 h -

4 commercial K3PO4 acetonitrile rt, 24 h -

5 NiCl4 hexahydrate K3PO4 acetonitrile rt, 24 h -

6 b pre-prepared K3PO4 acetonitrile 60 ◦C, 2 h + 2 h -

a determined with GC.b microwave reaction.

Reaction conditions: phenylacetylene (0.5 mmol), acetonitrile (2 ml), Ni2B (0.06 mmol, 0.12

eq.), K3PO4 (1.0 mmol, 2.0 eq.) and anisole (0.5 mmol).

35

The effect of the catalyst and the possibility to increase the GC yield were investi-

gated with four parallel reactions (Table 7, Entry 2-5) In the case of catalyst-formation

in situ, NiCl2 hexahydrate did not dissolve in acetonitrile. However, with the addition

of NaBH4 black particles and gas evolution could be observed. On TLC (eluent: hex-

ane), in the first three cases the product’s spot appeared, while with GC the product

only in the case of the pre-prepared catalyst (GC yield: 2%) could be observed.

With a microwave reactor it is possible to shorten the reaction times by microwave

irradiation and heating. Therefor, we performed several reactions using microwave

irradiation (Table 7, Entry 6). After 2 hours of stirring at 60 ◦C, the product was

only detected with TLC (eluent: hexane); and after an additional 2 hours of heating,

only trace amounts of product could be detected with GC.

Based on the consequently low GC yields, we concluded, that using TLC for mon-

itoring the reaction is misleading, because of the strong conjugation in the molecule

(two benzene rings and triple bonds) leads to high UV intensity. As a result of the

developed GC method we can state, that the homocoupling product could be detected

only in trace amounts. Furthermore, the question also arises: is it really the Ni2B,

that is catalyzing the coupling, or other metal impurities cause the 2-4% product

formation?

2.4 Suzuki-Miyaura coupling

2.4.1 Catalyst investigations

2.4.1.1 Initial reactions with contaminated chemicals

As model reaction, the Suzuki-Miyaura coupling of phenylboronic acid and 3-

iodotol-uene was chosen, in the presence of potassium tert-butoxide (Figure 30, Ap-

pendix A.5.1). In the initial screening reactions, the conversion of the reactions was

only monitored with TLC.

36

+I

Bmetal boride, KOtBu

ethanol

HO

HO

Figure 30: Model reaction

Using nickel boride prepared in anhydrous methanol (Table 8, Entry 1), the re-

action mixture was analysed with TLC (eluent: hexane) after 24 hours. The 3-

iodotoluene’s spot disappeared from the mixture and the product’ spot appeared.

The reaction mixture was filtered through Celite and then evaporated. The crude

reaction mixture was purified with column chromatography using hexane as eluent

yielding 69% product. The purity was proved via 1H-NMR (Appendix A.5.2).

The reaction was repeated with all three metal borides prepared in water (Table

8, Entry 2-4). Based on TLC (eluent: hexane), the starting material disappeared in

all three cases. This extremely positive result generated the question if it is indeed

the catalyst driving the reaction, or maybe it is not needed. To examine this, two

reactions were set up (Table 8, Entry 5-6): in the case of the first one reagent ratios

were not altered and in the second one the 3-iodotoluene was used in excess. In both

cases the iodo-compound disappeared, and product was forming.

37

Table 8: Initial reactions with contaminated chemicals

+I

Bmetal boride, KOtBu

ethanol

HO

HO

Entry Catalyst Base Solvent Conditions Producta

1 Ni2Bb KOtBu ethanol 110 ◦C, 24 h 69% b

2 Ni2Bd KOtBu ethanol 110 ◦C, 24 h x

3 Co2Bd KOtBu ethanol 110 ◦C, 24 h x

4 Fe2Bd KOtBu ethanol 110 ◦C, 24 h x

5 Ni2Bb KOtBu ethanol 110 ◦C, 24 h x

6 f Ni2Bb KOtBu ethanol 110 ◦C, 24 h x

a determined with TLC.b prepared in anhydrous methanol.c isolated yield.d prepared in water.f 3-iodotoluene (1.5 mmol, 1.5 eq.), phenylboronic acid (1.0 mmol,), ethanol

(1 ml), Ni2B (0.12 mmol, 0.12 eq.) and KOtBu (3.0 mmol, 3.0 eq.).

Reaction conditions: 3-iodotoluene (1.0 mmol), phenylboronic acid (1.5

mmol, 1.5 eq.), ethanol (1 ml), Me2B (0.12 mmol, 0.12 eq.) and KOtBu (3.0

mmol, 3.0 eq.).

The literature reports metal-free biaryl coupling reactions with potassium tert-

butoxide as base [97] and direct C-H arylations of arenes promoted by mixed potas-

sium alkoxides [98]. There are reactions with radical mechanism in which cases where

the electron is the catalyst [99]. To investigate if the mechanism is radical of the

present model reaction, TEMPO and anthracene were added to the reaction mixture

(Table 9, Entry 1-2). The role of the radical scavenger TEMPO is to catch radicals

so the product cannot form. Alternatively, the aryl-halide could be deprotonated to

form a reactive benzyne. Therefore, anthracene can react with the aryl-halide in a

Diels-Alder reaction. As a result, in both cases the iodo-compound did not disappear

38

from the reaction mixture and the conversion decreased. These results supported the

theory of a radical mechanism.

To prove the mechanism, the product of the TEMPO and the radicals present in the

reaction mixture needed to be isolated. The reactions were repeated without adding

the phenylboronic acid (Table 9, Entry 3-4). In the case of TEMPO according to the

TLC only a really small new spot appeared, which could not be separated. Using

anthracene no reaction occurred. In the reaction of 3-iodotoluene with KOtBu no

homocoupling occurred. The radical mechanism could not be proved.

Table 9: Mechanistic investigations

+I

B

Ni2B, KOtBu

TEMPO or anthracene

ethanol

HO

HO

Entry Additional reagent 3-Iodotoluene Producta

1 b TEMPO present x

2 b anthracene present x

3 c TEMPO present traces

3 c anthracene present -

a determined with TLC.b 3-iodotoluene (1.0 mmol), phenylboronic acid (1.5 mmol, 1.5 eq.),

ethanol (1 ml), Ni2B (0.12 mmol, 0.12 eq.) and KOtBu (3.0 mmol,

3.0 eq.), 110 ◦C, 24 h.c 3-iodotoluene (1.0 mmol), ethanol (1 ml), Ni2B (0.12 mmol, 0.12 eq.)

and KOtBu (3.0 mmol, 3.0 eq.), 110 ◦C, 24 h.

Coupling reactions without transition metals could be really sensitive towards con-

taminations, since trace amounts of these metals can catalyze the reactions [100]. It

is important, to make sure that all materials used are contamination-free, thus we

decided to examine the starting materials used in the previous reactions.

Comparing the newly purchased (purity: 99.99%) and the old KOtBu (purity: ≥

39

97%), the reaction mixtures bear a different colour. In the case of the new one the

mixture turned yellow; however, in the case of the old one the mixture turned brown

with time. We decided to use freshly ordered base to avoid unnecessary contamina-

tions.

For the reactions three different bottles of phenylboronic acid were available: two

bottles from Fluka (an old one and a later ordered one) and one bottle from Sigma-

Aldrich (freshly ordered). In order to test the quality, in all three cases the model

reaction was executed with and without catalyst, too (Table 10).

Table 10: Phenylboronic acid investigations

+I

BNi2B, KOtBu

ethanol

HO

HO

Entry Distributor Catalyst present GC yielda

1Sigma-Aldrich

0%

2 x 5%

3Flukab

17%

4 x 12%

5Fluka

0%

6 x 9%

a self-developed GC method, explained later.b older bottle.

Reaction conditions: 3-iodotoluene (1.0 mmol), phenylboronic

acid (1.5 mmol, 1.5 eq.), ethanol (1 ml), Ni2B (0.12 mmol, 0.12

eq.) and KOtBu (3.0 mmol, 3.0 eq.), 110 ◦C, 24 h.

Using the phenylboronic acid, which was purchased earlier from Fluka, in both

cases comparable conversions were observed. In the cases of the other two bottles,

without catalyst no reaction occurred. The starting material, which gave reactions

without the presence of the catalyst, was used in the previous reactions. This results

might explain why all the catalysts gave the product in the model reaction; it is

40

possible that the old bottle contains palladium traces that are driving the reaction.

To avoid confusion, for further experiments only recently ordered starting material,

purchased from Sigma-Aldrich, was used.

This findings made it necessary to repeat the model reactions with the different

metal borides. Both he catalysts prepared in anhydrous methanol and in water were

used to explore the activities (Table 11).

Table 11: Repeated model reaction with metal borides

+I

Bmetal boride, KOtBu

ethanol

HO

HO

Entry Catalyst Prepared in GC yielda

1Ni2B

methanol 23%

2 water 6%

3Co2B

methanol 0%

4 water 0%

5Fe2B

methanol 0%

6 water 0%

a self-developed GC method, explained later.

Reaction conditions: 3-iodotoluene (1.0 mmol), phenylboronic acid

(1.5 mmol, 1.5 eq.), ethanol (1 ml), Me2B (0.12 mmol, 0.12 eq.), KOtBu

(3.0 mmol, 3.0 eq.) and dodecane (1.0 mmol), 110 ◦C, 24 h.

As can be seen in Table 11, only in the case of nickel boride product detected was

detected. The catalyst prepared in methanol gave a higher yield then the catalyst

prepared in water. This indicated the decision to only use nickel boride prepared in

methanol for further reactions.

41

2.4.2 Gas chromatography method

To be able to quantitatively analyze the reaction mixture and to determine the

yield and conversion, a GC method was developed (Appendix A.5.3). As internal

standard dodecane was chosen (Rt = 12.186 min) due to its assumed inactivity in the

model reaction. The starting material’s peak appears at 13.339 min, and the coupled

product’s retention time was 21.123 min (Appendix A.5.4). The calibration curve

for the starting material and the product was calculated with the same method that

was used for the Glaser coupling (2.3.3). The calibration point molar ratios and the

calibration curves can be seen in Appendix A.5.5. For the analysis of the reaction

mixture filtration was not enough, because not only the solid components, but also

the phenylboronic acid needed to be eliminated to not to cause any harm to the

column in the gas chromatograph. Therefore, silica plug was used with hexan-diethyl

ether (1:1) eluent. When checking the method, corrections were needed, because the

regression was not precise enough. The corected calibration curve contained three

new points, each with of 60% theoretical yield. With this regression line the expected

yields were calculated (Appendix A.5.4, Figure A.3).

Examining the chromatograms, in most of the cases an unidentified peak at 19.739

min was detected. The biphenyl was produced and injected to the GC and the results

confirmed that the homocoupling occurred as side reaction. To determine the amount

of the side product a calibration was done (Appendix A.5.6).

2.4.3 Solvent screening

In the model reaction ethanol was used as solvent. However, the literature reports

on several other methods with different solvents that bear different properties (polar,

apolar, protic and aprotic). Ten solvents were screened to see if higher conversion

could be obtained with these conditions (Table 12). For this screening a method for

a smaller scale was developed, where 2 ml sample holders with plastic caps were used

(Appendix A.5.7). The problem with this method was, that the evaporating solvents

could easily escape since the caps could not be sealed properly. This questions the

accuracy of the GC results.

42

Table 12: Suzuki-Miyaura reaction solvent screening

+I

BNi2B, KOtBu

HO

HO solvent

Entry Solvent Product Biphenyl 3-Iodotoluene

GC yield GC yield GC yield

1 PEGa 0% 0% 245%

2 toluene 0% 0% 97%

3 methanol 0% 0% 151%

4 tert-butanol 0% 0% 79%

5 THFa 4% 2% 5%

6 tert-amyl alcohol 7% 8% 72%

7 dioxane 7% 9% 60%

8 n-butanol 10% 0% 45%

9 ethanol 17% 0% 0%

10 acetonitrile 30% 36% 5%

11 DMFa 52% 0% 34%

a solvent is not appropriate for GC analysis, different workup was needed.

Reaction conditions: 3-iodotoluene (0.10 mmol), phenylboronic acid (0.15

mmol, 1.5 eq.), ethanol (400 µl), Ni2B (0.012 mmol, 0.12 eq.), KOtBu (0.3 mmol,

3.0 eq.) and dodecane (0.1 mmol), 110 ◦C, 24 h.

As can be seen in Table 12, in only one of these reactions was a higher product

yield than 50% observed. The main reason for the low yields is that there is a compet-

ing dehalogenation reaction, which results in the decomposition of the iodocompound.

This effect is extremely dominant in the case of THF and ethanol. The findings also

indicate that using tert-amyl alcohol, dioxane, and acetonitrile enhances the genera-

tion of the biphenyl side product. In the case of acetonitrile, the GC chromatogram

confirms that the reaction led to a mixture containing different kinds of undesired

side products. Using the listed solvents in Entry 1-4 did not lead to the desired prod-

43

uct. However, the calculations for the remaining starting material show that using

biphasic reactions (e.g. PEG) makes calculations more difficult considering that the

distribution of the internal standard in these two phases is unknown. Using DMF

lead to the highest conversion, although the reaction mixture was biphasic. Com-

paring the different alcohols confirms our theory that the solvent choice has a larger

effect on the outcome of this reaction. With methanol no product was observed, but

using n-butanol or ethanol led to the desired product. The difference in these two

cases is the decomposition of the starting material. Analyzing the chromatogram of

n-butanol shows that the starting material is more resistant towards dehalogenation

in this solvent. To summarize our results, we found that the most suitable solvent

for further optimizations is n-butanol.

2.4.4 Base screening

In several Suzuki-Miyaura reactions, potassium tert-butoxide is replaced with weaker

bases, such as potassium carbonate or potassium triphosphate. These two bases were

tested in four different solvents (based on the solvent screening in 2.4.3) (Table 13).

As can be seen in Table 13, only in two of the cases the cross-coupling reaction was

observed. Although dioxane gave 9% yield, the undesirable homocoupling occurred in

a higher degree. Using n-butanol as solvent also showes hat the less basic potassium

phosphate also gavealmost 20% yield of the product, while no homocoupling product

was detected.

44

Table 13: Base screening

+I

B

HO

HO

Ni2B, base

solvent

Entry Solvent Base Product Biphenyl

GC yield GC yield

1 acetonitrile

K2CO3

0% 0%

2 DMF 0% 0%

3 dioxane 0% 0%

4 n-butanol 0% 0%

5 acetonitrile

K3PO4

0% 21%

6 DMF 0% 0%

7 dioxane 9% 15%

8 n-butanol 19% 0%

a inconclusive results.

Reaction conditions: 3-iodotoluene (0.10 mmol), phenyl-

boronic acid (0.15 mmol, 1.5 eq.), solvent (400 µl), Ni2B (0.012

mmol, 0.12 eq.), base (0.3 mmol, 3.0 eq.) and dodecane (0.1

mmol), 110 ◦C, 24 h.

2.4.5 Alternative starting materials

2.4.5.1 Reaction with different halides

Chloro-, bromo- and iodotoluene have different reactivities based on the different

characteristics of the halogen substituents, where iodotoluene is more reactive than

chlorotoluene. The model reaction was set up with the three different starting mate-

rials, to investigate their behaviour in the coupling reaction (Table 14).

45

Table 14: Reaction with different halides

+X

B

HO

HOethanol

Ni2B, KOtBu

Entry Starting material Product Biphenyl Starting material

GC yield GC yield GC yield

1 3-iodotoluene 4% 0% 12%

2 3-bromotoluene 4% 0% -a

3 3-chlorotoluene 0% 0% -a

a starting material calibration would be needed.

Reaction conditions: 3-halogenotoluene (1.0 mmol), phenylboronic acid (1.5 mmol,

1.5 eq.), ethanol (1 ml), Ni2B (0.12 mmol, 0.12 eq.), KOtBu (3.0 mmol, 3.0 eq.) and

dodecane (1.0 mmol), 110 ◦C, 24 h.

With 3-chlorotoluene no reaction occurred, but 3-bromotoluene seems to have the

same reactivity as 3-iodotoluene. The problem using ethanol is that in the case of

3-iodotoluene the starting material decomposes, which could be avoided by using less

reactive halides. In this case, the reactivity of 3-iodotoluene in the coupling reaction is

needed due to the low yields. In the other two cases calibration is needed to determine

the amount of starting materials.

2.4.5.2 Reaction with phenylboronic acid pinacol ester

Protodeboronation is a well-known undesired side reaction, and frequently asso-

ciated with metal-catalysed coupling reactions that utilise boronic acids, like the

Suzuki-Miyaura coupling [101]. In this reaction the boronic acid undergoes protonol-

ysis in which a carbon-boron bond is broken and replaced with a carbon-hydrogen

bond (Figure 31).

46

OH

OH

B proton source H + B(OH)3

Figure 31: Protodeboronation reaction

Replacing the free hydroxylgroups in the phenylboronic acid is a possible solution

to avoid the protodeboronation side reaction. However, using protection groups also

alters the reactivity of said compounds. Our aim was to examine the reaction using

phenylboronic acid pinacol ester (Appendix A.5.8) to see if it has a positive effect on

the outcome of the reaction.

Four reactions were set up with using ethanol and butanol as solvents, KOtBu and

K3PO4 as bases (Table 15). Repleacing the phenylboronic acid with the pinacol ester

also allowed us to track the amount of both starting materials present in the reaction

mixture; the phenylboronic acid pinacol ester could be detected at 17.980 min.

Table 15: Reaction with phenylboronic acid pinacol ester

+I

BNi2B, base

solvent

O

O

Entry Solvent Base Product Biphenyl 3-Iodotoluene

GC yield GC yield GC yield

1 ethanolKOtBu

7% 0% 93%

2 butanol 0% 0% 90%

3 ethanolK3PO4

0% 0% 113%

4 butanol 0% 0% 108%

Reaction conditions: 3-iodotoluene (1.0 mmol), phenylboronic acid pinacol es-

ter (1.5 mmol, 1.5 eq.), ethanol (1 ml), Ni2B (0.12 mmol, 0.12 eq.) and KOtBu

(3.0 mmol, 3.0 eq.), 110 ◦C, 24 h.

According to the chromatograms, only in the case of ethanol and using KOtBu

47

can be the product detected. The 3-iodotoluene did not decompose in this case and

the other starting material also stayed intact. These results question if there is any

correlation between the protodeboronation and the dehalogenation side reactions.

2.4.6 Temperature studies

Literature reports of coupling reactions at different temperatures; since it effects the

stability of the starting materials. Also considering green chemistry it is also desired

to develop methods at as low temperatures as possible. Therefore, the reaction was

tested at higher (150 ◦C) and lower (80 ◦C) temperatures.

Decreasing the temperature to 80 ◦C gave no product, even though the starting

material stayed intact in the reaction mixture.

Table 16: Reaction at 150◦C

+I

B

HO

HO

Ni2B, base

solvent

Entry Solvent Base Product Biphenyl 3-Iodotoluene

GC yield GC yield GC yield

1 a ethanolKOtBu

4% 0% 0%

2 butanol 5% 0% 11%

3 a ethanolK3PO4

6% 0% 0%

4 butanol 27% 0% 0%

a evaporated solvent.

Reaction conditions: 3-iodotoluene (0.10 mmol), phenylboronic acid (0.15

mmol, 1.5 eq.), solvent (400 µl), Ni2B (0.012 mmol, 0.12 eq.), base (0.3 mmol,

3.0 eq.) and dodecane (0.1 mmol), 150 ◦C, 24 h.

The model reaction was set up at 150 ◦C in ethanol and butanol with potassium

tert-butoxide and potassium triphosphate as bases (Table 16). Based on the result

butanol appears to be a better choice for solvent, because even at 110 ◦C ethanol

48

evaporates from the vials; therefore, these results are not reliable.

In the case of butanol it is interesting to notice that using potassium triphosphate

led to 27% product. Using ethanol as solvent gave similar results. Repeating the

reactions in a larger scale (1.0 M) gave the same results. Using the phenylboronic

acid pinacol ester did not lead to product in any case.

2.4.7 Microwave reactions

As stated earlier, microwave irradiation can enhance the reaction and shorten the

reaction time. Using the same reaction conditions as in previous studies, reactions

were set up at 180 ◦C using phenylboronic acid and phenylboronic acid pinacol ester

in butanol (Table 17).

The reaction using phenylboronic acid pinacol ester resulted in less product (5%),

while with the phenylboronic acid 17% product could be obtained, with a minimal

amount of side product. In Entry 3 the catalyst was prepared before starting the

reaction and led to higher yield. However, no 3-iodotoluene could be detected with

the GC and therefore the yield could not be increased any further. It is important to

note, that working at elevated temperature (above the boiling point of the solvents)

the risk of explosion arises, since the vapour pressure can be significant inside the

microwave vials. During our work multiple reaction mixtures exploded at 180 ◦C;

therefore, we decided to lower the temperature.

49

Table 17: Microwave reactions

+I

Bbutanol

O

O

Ni2B, KOtBu

+I

B

HO

HO

Ni2B, base

butanol

Entry Starting Base Time Product Biphenyl

material GC yield GC yield

1phenylboronic

acid

K3PO4

1h 9% 15%

2 2h 12% 0%

3 a KOtBu 2h 17% 1%

4phenylboronic acid

pinacol esterKOtBu 3.5h 5% 0%

a with freshly made catalyst.

Reaction conditions: 3-iodotoluene (0.1 mmol), phenylboronic acid or phenyl-

boronic acid pinacol ester 0.15 mmol, 1.5 eq.), butanol (400 µl), Ni2B (0.012 mmol,

0.12 eq.), base (0.3 mmol, 3.0 eq.) and dodecane (0.1 mmol).

3 Conclusion and outlook

Based on the results presented in this work the conclusion can be made, that

nickel boride in general is an appropriate catalyst for various reductions; however,

for coupling reactions it is not suitable, exactly because of the reductive properties.

In all three cases, side reactions connected to reduction (such as alkyne to alkene

reduction and dehalogenation) could be observed. These side reactions appeared to

be faster than the coupling reactions, making it impossible to increase the yield. The

highest yield (52%) was obtained in the case of the Suzuki-Miyaura coupling reactions.

Nevertheless, the nature and activity of the nickel boride could be examined with the

more sensitive Suzuki-Miyaura reaction. We found, that exposing the catalyst to

50

air and oxygen significantly shortens the lifetime of nickel boride; this should be

considered while using the catalyst for different reactions. As an alternative, nickel

boride might be an efficient catalyst in reductive coupling reactions, but this theory

needs further investigations.

51

4 References

[1] Berzelius, J. J. (1835) Arsberattelsen om framsteg i fysik och kemi, Royal

Swedish Academy of Sciences

[2] Ostwald, W. (1894) Zeitschrift fur physikalische Chemie, 15: 705-706.

[3] Sabatier, P. and Senderens, J. B. (1902) Comptes Rendus de l’Academie des

Sciences 134: 514.

[4] Heinemann, H. (1997) ’Development of Industrial Catalysis’ in G. Ertl, H.

Knozinger, J. Weitkamp (eds.) Handbook of Heterogeneous Catalysis Vol. 1

Weinheim: Wiley-VCH

[5] Hartwig, J. F. (2009) Organotransition Metal Chemistry: From Bonding to

Catalysis Berkley

[6] Knozinger, H. (2009) Heterogeneous Catalysis and Solid Catalysts Weinheim:

Wiley-VCH

[7] Ertl, G., Knozinger, H. and Weitkamp, J. (1997) Hand- book of Heterogeneous

Catalysis, Vols. 1-5 Weinheim: Wiley-VCH

[8] Deutschmann, O., Knozinger, H., Kochloefl, K. and Turek, T. (2009) Het-

erogeneous Catalysis and Solid Catalysts Ullmann’s Encyclopedia of Industrial

Chemistry

[9] Beller, M. and Bolm, C. (2004) Transition Metals for Organic Synthesis, Vol.

1 2nd edn. Weinheim: Wiley-VCH

[10] Mond, L., Langer, C. and Quincke, F. (1890) ’L.-Action of carbon monoxide on

nickel’ Journal of the Chemical Society 57: 749-753.

[11] Jolly, P. W. (1975) The Organic Chemistry of Nickel: Organic Synthesis Else-

vier

52

[12] Tamaru, J. (2005) Modern Organonickel Chemistry Weinheim: Wiley-VCH

[13] Komiya, S. (1997) Synthesis of organometallic compounds Weinheim: Wiley-

VCH

[14] Corey, E. J. and Venkateswarlu, A. (1972) ’Protection of hydroxyl groups as

tert-butyldimethylsilyl derivatives’ Journal of the American Chemical Society

94(2): 667-668.

[15] Semmelhack, M. F., Chong, B. P., Stauffer, R. D., Rogerson, T. D., Chong, A.

and Jones, L. D. (1975) ’Total synthesis of the Cephalotaxus alkaloids. Problem

in nucleophilic aromatic substitution’ Journal of the American Chemical Society

97(9): 2507-2516.

[16] Kumada, M., Tamao, K. and Sumitani K (1978) ’Phosphine-nickel complex

catalyzed cross-coupling of Grignard reagents with aryl and alkenyl halides:

1,2-halides: 1,2-dibutylbenzene’ Organic Syntheses 58: 127.

[17] Hayashi, T., Konishi, M., Fukushima, M., Mise, T., Kagotani, M., Tajika,

M. and Kumada, M. (1982) ’Asymmetric synthesis catalyzed by chiral

ferrocenylphosphine-transition metal complexes. 2. Nickel- and palladium-

catalyzed asymmetric Grignard cross-coupling’ Journal of the American Chem-

ical Society 104(1): 180-186.

[18] Semmelhack, M. and Helquist, P. M. (1972) ’Reactions of aryl halides with

π-allylnickel halides: methallylbenzene’ Organic Syntheses 52: 115.

[19] Hegedus, L. S., Wagner, S. D., Waterman, E. L. and Siirala-Hansen, K.

(1975) ’Reaction of π-allylnickel bromide complexes with ketones and aldehydes.

Synthesis of α-methylene-γ-butyrolactone’ The Journal of Organic Chemistry

40(5): 593-598.

[20] Tamao, K., Kobayashi, K. and Ito, Y. (1988) ’Nickel(0)-promoted cyclization

of enynes with isocyanides: a new route to polycyclic cyclopentenone skeletons

Journal of the American Chemical Society 110(1): 1286-1288.

53

[21] Schlesinger, H. I. and Brown, H. C., 1945 Preparation of alkali metal compounds

US Patent 2.461.661

[22] Paul, R., Buisson, P. and Joseph, N. (1952) ’Catalytic Activity of Nickel

Borides’ Industrial & Engineering Chemistry 44(5): 1006-1010.

[23] Schlesinger, H. I., Brown, H. C., Finholt, A. E., Gilbreath, J. R., Hoekstra, H.

R. and Hyde. E. K. (1953) ’Sodium Borohydride, Its Hydrolysis and its Use as

a Reducing Agent and in the Generation of Hydrogen’ Journal of the American

Chemical Society 75(1): 215-219.

[24] Maybury, P. C., Mitchell, R. W. and Hawthorne, M. F (1974) ’Hydrogen

adducts of cobalt and nickel boride’ Chemical Communications 14: 534-535.

[25] Glavee, G. N., Klabunde, K. J., Sorensen, C. M. and Hadjipanayis, G. C. (1994)

’Borohydride Reduction of Nickel and Copper Ions in Aqueous and Nonaqueous

Media. Controllable Chemistry Leading to Nanoscale Metal and Metal Boride

Particles’ Langmuir 10: 4726-4730.

[26] Legrand, J., Taleb, A., Gota, S., Guittet, M.-J. and Petit, C. (2002) ’Synthesis

and XPS Characterization of Nickel Boride Nanoparticles’ Langmuir 18: 4131-

4137.

[27] Geng, J., Jefferson, D. A. and Johnson, B. F. G (2007) ’The unusual nanos-

tructure of nickel-boron catalyst’ Chemical Communications 9: 969-971.

[28] Zeng, M., Wang, H., Zhao, C., Wei, J., Qi, K., Wang, W. and Bai, X. (2016)

’Nanostructured Amorphous Nickel Boride for High-Efficiency Electrocatalytic

Hydrogen Evolution over a Broad pH Range’ ChemCatChem 8(4): 708-712.

[29] Khurana, J. M. and Gogia, A. (1995) ’Synthetically useful reactions with nickel

boride. A rewiev’ Organic Preparations and Procedures International 29(1): 1-

32.

54

[30] Brown, C. A. and Brown, H. C. (1963) ’The Reaction of Sodium Borohydride

with Nickel Acetate in Aqueous Solution–A Convenient Synthesis of an Active

Nickel Hydrogenation Catalyst of Low Isomerizing Tendency’ Journal of the

American Chemical Society 85(7): 1003-1005.

[31] Brown, C. A. and Ahuja, V. K. (1973) ’Catalytic hydrogenation. VI. Reac-

tion of sodium borohydride with nickel salts in ethanol solution. P-2 Nickel, a

highly convenient, new, selective hydrogenation catalyst with great sensitivity

to substrate structure’ The Journal of Organic Chemistry 38(12): 2226-2230.

[32] Belisle, C. M., Young. Y. M. and Singaram, B. (1994) ’Catalytic reaction. 1.

catalytic 1,4-hydrogenation of α,β-unsaturated aldehydes and ketones using SC-

1 nickel boride’ Tetrahedron Letters 35(31): 5595-5598.

[33] Nose, A. and Kudo, T. (1984) ’Reduction of Heterocyclic Compounds. II. Re-

duction of Heterocyclic Compounds with Sodium Borohydride-Transition Metal

Salt Systems’ Chemical and Pharmaceutical Bulletin 32(6): 2421-2425.

[34] Dennis, W. H., Cooper, W. J. (1975) ’Catalytic dechlorination of organochlorine

compounds. I. DDT.’ Bulletin of Environmental Contamination and Toxicology

14(6): 738-744.

[35] Nose, A. and Kudo, T. (1981) ’Reduction with Sodium Borohydride-Transition

Metal Salt Systems. I. Reduction of Aromatic Nitro Compounds with the

Sodium Borohydride-Nickelous Chloride System’ Chemical and Pharmaceuti-

cal Bulletin 29(4): 1159-1161.

[36] Osby, J. O. and Ganem, B. (1985) ’Rapid and efficient reduction of aliphatic

nitro compounds to amines’ Tetrahedron Letters 26(52): 6413-6416.

[37] Sarma, D. N., and Sharma, R. P. (1985) ’Nickel boride reductive cleavage of

allylic trimethylsilyl ethers’ Tetrahedron Letters 26(3): 371-372.

55

[38] Russel, T. W., Duncan, D. M. and Hansen, S. C. (1977) ’Catalytic reduction.

4. Hydrogenation of aldehydes over borohydride reduced nickel and palladium’

The Journal of Organic Chemistry 42(3): 551-552.

[39] Truce, W. E. and Perry, F. M. (1963) ’The Metalation and Alkylation of Mer-

captals’ The Journal of Organic Chemistry 28(4): 961-964.

[40] Euerby, M. R. and Waigh, R. D. (1986) ’A Convenient Procedure for the Re-

ductive Desulphurisation of Thioethers with Nickel Boride’ Synthetic Commu-

nications 16(7): 779-784.

[41] Back, T. G. (1984) ’A convenient procedure for the reductive deselenization of

selenides with nickel boride’ Chemical Communications 21: 1417-1418.

[42] Back, T. G., Collins, S., Gokhale, U. and Law, K.W. (1983) ’Selenosulfona-

tion of disubstituted acetylenes: reactions of corresponding vinyl selenoxides

and anomalous formation of a ketene diselenoacetal’ The Journal of Organic

Chemistry 48(24): 4776-4779.

[43] Bates, R. (2012) Organic Synthesis Using Transition Metals Weinheim: Wiley-

VCH

[44] Grignard, V. (1900) ’Sur quelques nouvelles combinaisons organomtaliques du

magnsium et leur application des synthses d’alcools et d’hydrocabures’ Comptes

Rendus de l’Academie des Sciences 130: 1322-1325.

[45] Paul, F., Patt, J. and Hartwig, J. F. (1994) ’Palladium-catalyzed formation of

carbon-nitrogen bonds. Reaction intermediates and catalyst improvements in

the hetero cross-coupling of aryl halides and tin amides’ Journal of the American

Chemical Society 116(17): 5969-5970.

[46] Guram, A. S. and Buchwald, S. L. (1994) ’Palladium-Catalyzed Aromatic Am-

inations with in situ Generated Aminostannanes’ Journal of the American

Chemical Society 116(17): 7901-7902.

56

[47] Seechurn, D. C. C. J., Kitching, M. O., Colacot, T. J. and Snieckus, V. (2012)

’Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to

the 2010 Nobel Prize’ Angewandte Chemie International Edition 51(21): 5062-

5085.

[48] Wurtz, A. (1855) ’Ueber eine neue Klasse organischer Radicale’ Annalen der

Chemie und Pharmacie 96(3): 364-375.

[49] Dyker, G. (2005) Handbook of C-H Transformations Vol. 2 Weinheim: Wiley-

VCH

[50] Negishi, E. (2002) Handbook of organopalladium chemistry for organic synthesis

Weinheim: Wiley-VCH

[51] Sonogashira, K., Tohda, Y. and Nobue, H. (1975) ’A convenient synthesis of

acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes,

iodoarenes and bromopyridines’ Tetrahedron Letters 16(50): 4467-4470.

[52] Erdelyi, M. and Gogoll, A. (2001) ’Rapid Homogeneous-Phase Sonogashira Cou-

pling Reactions Using Controlled Microwave Heating’ The Journal of Organic

Chemistry 66(12): 4165-4169.

[53] Brase, S., Dahmen, S., Lauterwasser, F., Leadbeater, N. E. and Sharp, E. L.

(2002) ’Polymer-Bound 1-Aryl-3-alkyltriazenes as Modular Ligands for Catal-

ysis. Part 2: Screening Immobilized Metal Complexes for Catalytic Activity’

Bioorganic & Medicinal Chemistry Letters 12(14): 1849-1851.

[54] Uozumi, Y. and Kobayashi, Y. (2003) ’The Sonogashira Reaction in Water via

an Amphiphilic Resin-supported Palladium-Phosphine Complex under Copper-

free Conditions’ Heterocycles 59(1): 71-74.

[55] Plenio, H. (2008) ’Catalysts for the Sonogashira Coupling - The Crownless

Again Shall Be King’ Angewandte Chemie International Edition 47(37): 6954-

6956.

57

[56] Evano, G., Blanchard, N. and Toumi, M. (2008) ’Copper-Mediated Cou-

pling Reactions and Their Applications in Natural Products and Designed

Biomolecules Synthesis’ Chemical Reviews 108(8): 3054-3131.

[57] Guan, J. T., Yu, G. A., Chen, L., Weng, T. Q., Yuan, J. J. and Liu, S. H.

(2009) ’CuI/PPh3-catalyzed Sonogashira coupling reaction of aryl iodides with

terminal alkynes in water in the absence of palladium’ Applied Organometallic

Chemistry 23(2): 75-77.

[58] Guo, S. M., Deng, C. L. and Li, J. H. (2007) ’Cu(OAc)2 catalyzed Sonogashira

cross-coupling reaction in amines’ Chinese Chemical Letters 18(1): 13-16.

[59] Zuidema, E. and Bolm, C. (2010) ’Sub-Mol% Catalyst Loading and Ligand-

Acceleration in the Copper-Catalyzed Coupling of Aryl Iodides and Terminal

Alkyenes’ Chemistry - A European Journal 16(14): 4181-4185.

[60] Colacino, E., Daich, L., Martinez, J. and Lamaty, F. (2007) ’Microwave-Assisted

Copper-Catalyzed Sonogashira Reaction in PEG Solvent’ Synlett (8): 1279-

1283.

[61] Mao, J., Xie, G., Wu, M., Guo, J. and Ji, S. (2008) ’Ligand-Free Iron/Copper

Cocatalyzed Alkynylation Coupling Reactions’ Advanced Synthesis & Catalysis

350(16): 2477-2482.

[62] Feng, L., Liu, F., Sun, P. and Bao, J. (2008) ’Sonogashira Reaction of Aryl

Halides with Terminal Alkynes Catalyzed by Cobalt Hollow Nanospheres’ Syn-

lett (9): 1415-1417.

[63] Garcia, P., Malacria, M., Aubert, C., Gandon, V. and Fensterbanck, L. (2010)

’Gold-Catalyzed Cross-Couplings: New Opportunities for C-C Bond Formation’

ChemCatChem 2(5): 493-497.

[64] Vechorkin, O., Barmaz, D., Proust, V. and Hu, X. (2009) ’Ni-Catalyzed Sono-

gashira Coupling of Nonactivated Alkyl Halides: Orthogonal Functionalization

58

of Alkyl Iodides, Bromides, and Chlorides’ Journal of the American Chemical

Society 131(34): 12078-12079.

[65] Glaser, C. (1869) ’Beitrage zur Kenntniss des Acetenylbenzols’ Chemische

Berichte 2(1): 422-424.

[66] McKillop, A. and Pattenden, G. (1977) ’Naturally occurring polyolefinic and

polyacetylenic compounds’ in McKillop, A. (ed.) Aliphatic Chemistry Vol. 5

201-239. Royal Society of Chemistry

[67] Simandi, L. I. (1983) in (Eds.: Patai, S.; Rappoport, Z.) The Chemistry of

Functional Groups, Supplement C, pt 1 Wiley, New York 529-534.

[68] Hay, A. (1960) ’Communications- Oxidative Coupling of Acetylenes’ The Jour-

nal of Organic Chemistry 25(7): 1275-1276.

[69] Bohlmann, F., Schonowsky, H., Inhoffen, E. and Grau, G. (1964) ’Polyacetylen-

verbindungen, LII. ber den Mechanismus der oxydativen Dimerisierung von

Acetylenverbindungen’ Chemische Berichte 97(3): 794-800.

[70] Sindhu, K. S. and Anilkumar, G. (2014) ’Recent advances and applications of

Glaser coupling employing greener protocols’ RSC Advances 4: 27867-27887.

[71] Li, D., Yin, K., Li, J. and Jia,X. (2008) ’CuI/iodine-mediated homocoupling

reaction of terminal alkynes to 1,3-diynes’ Tetrahedron Letters 49(41): 5918-

5919.

[72] Zhu, B. C. and Jiang, X. Z. (2007) ’A new CuAl-hydrotalcite catalyzed

homocoupling reaction of terminal alkynes at room temperature’ Applied

Organometallic Chememistry 21(5): 345-349.

[73] Kuhn, P., Alix, A., Kumarraja, M., Louis, B., Pale, P. and Sommer, J. (2009)

’Copper-Zeolites as Catalysts for the Coupling of Terminal Alkynes: An Effi-

cient Synthesis of Diynes’ European Journal of Organic Chemistry (3): 423-429.

59

[74] Gelderen, L. V., Rothenberg, G., Calderone, V. R., Wilson, K. and Shiju, N.

R. (2013) ’Efficient alkyne homocoupling catalysed by copper immobilized on

functionalized silica’ Applied Organometallic Chememistry 27(1): 23-27.

[75] Hilt, G., Hengst, C. and Arndt, M. (2009) ’The Unprecedented Cobalt-

Catalysed Oxidative Glaser Coupling under Reductive Conditions’ Synthesis

(3): 395-398.

[76] Lu, X., Zhang, Y., Luo, C. and Wang, Y. (2006) ’Efficient and Recyclable Re-

action System for the Homocoupling of Terminal Acetylenes’ Synthetic Com-

munications 36(17): 2503-2511.

[77] Ranu, B. C. and Banerjee, S. (2006) ’Homocoupling of Terminal Alkynes to

1,4-Disubstituted 1,3-Diynes Promoted by Copper(I) Iodide and a Task Specific

Ionic Liquid, [bmim]OH A Green Procedure’ Letters in Organic Chemistry 3(8):

607-609.

[78] Bedard, A.C. and Collins, S. K. (2012) ’Microwave accelerated Glaser-Hay

macrocyclizations at high concentrations’ Chemical Communications 48: 6420-

6422.

[79] Miyaura, N., Yamada, K. and Suzuki, A. (1979) ’A new stereospecific cross-

coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl

or 1-alkynyl halides’ Tetrahedron Letters 20(36): 3437-3440.

[80] Suzuki, A. (2004) ’Organoborane coupling reactions (Suzuki coupling)’ Proceed-

ings of the Japan Academy, Series B 80(8): 359-371.

[81] Suzuki, A. (2011) ’Cross-Coupling Reactions Of Organoboranes: An Easy Way

To Construct C[BOND]C Bonds (Nobel Lecture)’ Angewandte Chemie 50(30):

6722-6737.

[82] Meijere, A., Brase, S. and Oestreich, M. (2014) Metal Catalyzed Cross-Coupling

Reactions and More, 3 Volume Set Weinheim: Wiley-VCH

60

[83] Miyaura, N. and Suzuki, A. (1995) ’Palladium-Catalyzed Cross-Coupling Re-

actions of Organoboron Compounds’ Chemical Reviews 95: 2457-2483.

[84] Kurti, L. and Czako, B. (2005) Strategic Applications of Named Reactions in

Organic Synthesis Academic Press

[85] Liu, L., Zhang, Y. and Wang, Y. (2005) ’Phosphine-Free Palladium Acetate

Catalyzed Suzuki Reaction in Water’ Journal of the American Chemical Society

70(15): 6122-6125.

[86] Zhu, B. and Panek, J. S. (2000) ’Total Synthesis of Epothilone A’ Organic

Letters 2(17): 2575-2578.

[87] Han, F. S. (2013) ’Transition-metal-catalyzed Suzuki-Miyaura cross-coupling

reactions: a remarkable advance from palladium to nickel catalysts’ Chemical

Society Reviews 42(12): 5270-5298.

[88] Wu, L., Ling, J. and Wu, Z. Q. (2011) ’A Highly Active and Recyclable Catalyst:

Phosphine Dendrimer-Stabilized Nickel Nanoparticles for the Suzuki Coupling

Reaction’ Advanced Synthesis & Catalysis 353(9): 1452-1456.

[89] Gurung, S. K., Thapa, S., Kafle, A., Dickie, D. A. and Giri, R. (2014) ’Copper-

Catalyzed Suzuki-Miyaura Coupling of Arylboronate Esters: Transmetalation

with (PN)CuF and Identification of Intermediates’ Organic Letters 16(4): 1264-

1267.

[90] Han, J., Liu, Y. and Guo, R. (2009) ’Facile Synthesis of Highly Stable Gold

Nanoparticles and Their Unexpected Excellent Catalytic Activity for Suzuki-

Miyaura Cross-Coupling Reaction in Water’ Journal of the American Chemical

Society 131(6): 2060-2061.

[91] Nun, P., Martinez, J. and Lamaty, F. (2009) ’Solvent-Free Microwave-Assisted

Suzuki-Miyaura Coupling Catalyzed by PEPPSI-iPr’ Synlett (11): 1761-1764.

61

[92] Yanga, J., Lia, P. and Wang, L. (2011) ’Recyclable Catalysts for Suzuki-Miyaura

Cross-Coupling Reactions at Ambient Temperature Based on a Simple Mer-

rifield Resin Supported Phenanthroline-Palladium(II) Complex’ Synlett (8):

1295-1301.

[93] Wei, J. F., Jiao, J., Feng, J. J., Lv, J., Zhang, X. R., Shi, X. Y. and Chen,

Z. G. (2009) ’PdEDTA Held in an Ionic Liquid Brush as a Highly Efficient

and Reusable Catalyst for Suzuki Reactions in Water’ The Journal of Organic

Chemistry 74(16): 6283-6286.

[94] Okuro, K., Furuune, M., Miura, M. and Nomura, M. (1992) ’Copper-catalyzed

coupling reaction of aryl and vinyl halides with terminal alkynes’ Tetrahedron

Letters 33(37): 5363-5364.

[95] Yi, J., Lu, X., Sun, Y. Y., Xiao, B. and Liu, L. (2013) ’Nickel-Catalyzed Sono-

gashitra Reactions of Non-activated Secondary Alkyl Bromides and Iodides’

Angewandte Chemie International Edition 52: 12409-12413.

[96] Ganem, B. and Osby, J. O. (1986) ’Synthetically Useful Reactions with Metal

Boride and Aluminide Catalysts’ Chemical Reviews 86: 763-780.

[97] Cuthbertson, J., Graya, V. J. and Wilden, J. D. (2014) ’Observations on tran-

sition metal free biaryl coupling: potassium tert-butoxide alone promotes the

reaction without diamine or phenanthroline catalysts’ Chemical Communica-

tions 50(20): 2575-2578.

[98] Wu, Y., Choy, P. Y. and Kwong, F. Y. (2014) ’A Direct C-H Arylation of

Unactivated Arenes Promoted by Mixed Potassium Alkoxides’ Asian Journal

of Organic Chemistry 3: 1262-1265.

[99] Studer, A. and Curran, D. P. (2014) ’The electron is a catalyst’ Nature Chem-

istry 6: 765-773.

[100] Leadbeater, N. E. (2010) ’Cross coupling: When is free really free?’ Nature

Chemistry 2(12): 1007-1009.

62

[101] Hall, D. (2011) Boronic Acids: Preparation and Applications in Organic Syn-

thesis, Medicine and Materials, 2nd ed. Weinheim: Wiley-VCH

63

A Appendix

A.1 General methods and chemicals

All chemicals were purchased from commercial suppliers with the highest available

purity. Solvents for workup and flash column chromatography were of analytical grade

and used as supplied. Microwave reactions were carried out using Biotage Initiator

Classic reactor. All reactions were set up in Biotage Microwave Reaction Vials (if

not stated otherwise). Thin layer chromatography was carried out using pre-coated

Merck silica gel 60 F254 aluminium-backed plates (0.25 mm), and visualized by UV

light (δ = 254 nm). Flash column chromatography was carried out using Merck silica

gel 60 (0.040-0.063 mm). NMR spectroscopy was carried out using Bruker Ascend

400 spectrometer (400 MHz). Gas chromatography was carried out with Agilent

Technologies 6850A gas chromatograph and a 6850 automatic sampler.

A.2 Preparations of metal borides

A.2.1 Method A

Metal chloride hexa- or tetra hydrate (2.0 mmol) was dissolved in anhydrous

methanol (100 ml) in inert atmosphere. The solution was stirred and degassed.

Sodium borohydride (4.0 mmol, 2 eq.) was added, while instantaneous gas evolu-

tion was observed with the precipitation of the black powder. The suspension was

stirred, the gas evolution ceased in a few minutes. The suspension was filtered, washed

with prepurged water and acetone, and dried in vacuum.

A.2.2 Method B

Metal chloride hexa- or tetra hydrate (2.0 mmol) was dissolved in prepurged water

(100 ml) in inert atmosphere. The solution was stirred and degassed. Sodium boro-

hydride (4.0 mmol, 2 eq.) was added, while instantaneous gas evolution was observed

with the precipitation of the black powder. The suspension was stirred, the gas evo-

64

lution ceased in a few minutes. The suspension was filtered, washed with acetone and

methanol and dried in vacuum.

A.2.3 Preparation of nickel boride on filtering paper

Nickel chloride hexahydrate (0.2 mmol) was dissolved in methanol (0.5 ml) and

injected onto a 0.5 x 0.5 cm filtering paper, and the paper was dried on air. Sodium

borohydride (4.0 mmol, 2 eq.) was dissolved in methanol (0.5 ml) and injected on

the dried paper, while instantaneous gas evolution was observed and the surface of

the paper was covered with the black catalyst.

A.3 Sonogashira coupling

A.3.1 Characterisation of 4-methylbiphenyl

1H-NMR (400 MHz, CDCl3) δ (ppm): 7.53 (d, 2H), 7.51 (d, 2H), 7.44-7.42 (t, 2H),

7.34-7.33 (m, 3H), 2.37 (s, 3H).

A.3.2 Characterisation of 1,4-diphenylbutadiyne

1H-NMR (400 MHz, CDCl3) δ (ppm): 7.40-7.32 (m, 6H), 7.55-7.53 (m, 4H).

A.4 Glaser coupling

A.4.1 Solvent screening method

In solvent (1 ml), phenylacetylene (0.25 mmol) was dissolved in a microwave vial,

potassium tert-butoxide (0.5 mmol, 2.0 eq.) and pre-prepared nickel boride (3.75 mg,

0.03 mmol, 0.12 eq.) were added to the solution. After 24 hours of stirring at room

temperature, the mixtures were analyzed with TLC (eluent: hexane).

65

A.4.2 GC method

Table A.1: GC method for the Glaser coupling

Oven Ramp ◦C/min Next ◦C Hold min Run Time

Initial 80 0.00 0.00

Ramp 1 20.00 120 3.00 5.00

Ramp 2 40.00 250 8.00 16.25

Post Run 50 0.00 16.25

A.4.3 GC chromatograms of the reaction components

Phenylacetylene (Starting material)

66

1,4-diphenylbutadiyne (Product)

Anisole (standard)

67

A.4.4 GC calibration curve for 1,4-diphenylbutadiyne (product)

Table A.2: Calibration of 1,4-

diphenylbutadiyne (p) with anisole (a)

as standard

Entry np/na Concentration Ap/Aa

(-) (g/dm3) (-)

1 0.00 0.00 0.00

2 0.50 30.2 0.68

3 1.01 60.4 1.31

4 1.48 89.0 1.93

5 1.99 119.2 2.51

y = 0.7886x - 0.0177R² = 0.9993

0.00

0.50

1.00

1.50

2.00

0.00 0.50 1.00 1.50 2.00 2.50 3.00

np/n

a [-

]

Ap/Aa [-]

Figure A.1: 1,4-Diphenylbutadiyne calibration curve with anisole as standard

68

A.5 Suzuki-Miyaura coupling

A.5.1 Method for the catalytic investigations of metal borides

Metal boride (15 mg, 0.12 mmol, 0.12 eq.), phenylboronic acid (1.5 mmol, 1.5 eq.)

and potassium tert-butoxide (3.0 mmol, 3.0 eq.) were added to a microwave vial.

Ethanol (1 ml) was added and the phenylboronic acid dissolved. 3-Iodotoluene (1.0

mmol) was added with a Hamilton-syringe. An oil bath was heated to 110 ◦C. The

reaction was carried out for 24 hours. The reaction mixture then was analyzed with

TLC (eluent: hexane) and was filtered through celite than evaporated. Flash column

chromatography (eluent: hexane) was used to purify the product.

A.5.2 Characterisation of 3-methylbiphenyl

1H-NMR (400 MHz, CDCl3) δ (ppm): 7.69-7.67 (d, 2H), 7.54-7.48 (d, 2H), 7.44-7.40

(t, 2H), 7.26-7.25 (m, 3H), 2.51 (s, 3H).

A.5.3 GC method

Table A.3: GC method for the Suzuki-Miyaura coupling

Oven Ramp ◦C/min Next ◦C Hold min Run Time

Initial 100 5.00 5.00

Ramp 1 5.00 150 0.00 15.00

Ramp 2 10.00 220 5.00 27.00

Post Run 50 0.00 27.00

69

A.5.4 GC chromatograms of the reaction components

3-Iodotoluene (starting material)

3-Methylbiphenyl (product)

70

Dodecane (standard)

A.5.5 GC calibration curves

Table A.4: Calibration of the 3-iodotoluene

(s) and the 3-methylbiphenyl (p) with dode-

cane (d) as standard

Entry ns/nd np/nd As/Ad Ap/Ad

1 0.00 1.00 0.00 1.29

2 0.30 0.70 0.19 0.92

3 0.50 0.50 0.29 0.71

4 0.60 0.74

5 0.60 0.75

6 0.60 0.64

7 0.70 0.30 0.41 0.35

8 1.00 0.00 0.59 0.00

71

y = 1.7145x - 0.0072R² = 0.9990

0.00

0.20

0.40

0.60

0.80

1.00

1.20

0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70

ns/n

d [-

]

As/Ad [-]

Figure A.2: 3-iodotoluene calibration curve

y = 0.7649x + 0.0202R² = 0.99473

0

0.2

0.4

0.6

0.8

1

1.2

0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40

np/nd

Ap/Ad

Figure A.3: 3-methylbiphenyl calibration curve

72

A.5.6 Biphenyl GC calibration

Table A.5: Calibration of

the biphenyl (b) with do-

decane (d) as standard

Entry np/na Ab/Ad

1 0.005 0.0094

2 0.010 0.0171

3 0.015 0.0249

4 0.030 0.0465

5 0.040 0.0599

6 0.050 0.0734

73

y = 0.7036x - 0.0021R² = 0.9994

0

0.01

0.02

0.03

0.04

0.05

0.06

0 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08

nb/n

d [-

]

Ab/Ad [-]

Figure A.4: Biphenyl calibration curve

The coupling reaction of two equivalents of phenylboronic acid theoretically results

in one mol of biphenyl thus multiplying the calculated nb/nd values with 2 and divid-

ing the number by 1.5 (the initial ratio of the phenylboronic acid and the standard

is 1.5:1.0) gives the GC yield of the homocoupling side reaction .

A.5.7 Solvent screening method

Nickel boride (1.5 mg, 0.012 mmol, 0.12 eq.), phenylboronic acid (0.15 mmol, 1.5

eq.) and potassium tert-butoxide (0.30 mmol, 3.0 eq.) were added to a 2 ml sample

vial with plastic cap. Solvent (400 µl) was added and the phenylboronic acid dissolved.

3-Iodotoluene (0.10 mmol) was added with a Hamilton-syringe. A heating block was

heated to 110 ◦C. The reaction was carried out for 24 hours. The reaction mixture

was passed through a silica plug and analyzed with GC.

A.5.8 Preparation of the phenylboronic acod pinacol ester

To a solution of phenylboronic acid (1 mmol) in acetonitrile (4 ml) was added a

solution of FeCl3 (0.05 mmol, 0.05 eq.) in water (1 ml), imidazole (3 mmol, 3 eq.)

74

and pinacol (1 mmol, 1 eq.). The resulting cloudy orange mixture was stirred at room

temperature for 30 minutes. The reaction was then diluted with water (5 ml) and

extracted with diethyl ether (3 x 8 ml). The combined organic extracts were dried

(sodium sulphate) and concentrated in vacuum. The resulting oil was then purified

by flash column chromatography (eluent: hexane), affording the pure product. 1H-

NMR (400 MHz, CDCl3) δ (ppm): 7.80-7.78 (d, 2 H,), 7.45-7.42 (m, 1 H), 7.36-7.33

(m, 2 H), 1.32 (s, 12 H).

A.5.9 Method for microwave reactions

Nickel boride (1.5 mg, 0.012 mmol, 0.12 eq.) and potassium tert-butoxide (0.30

mmol, 3.0 eq.) were added to a microwave vial. Phenylboronic acid (0.15 mmol,

1.5 eq.) or phenylboronic acid pinacol ester (0.15 mmol, 1.5 eq.) was added to the

solvent (400 µl, ethanol or butanol). 3-Iodotoluene (0.10 mmol) and dodecane (0.10

mmol) was added with a Hamilton-syringe. The reaxtion mixture was passed through

a silica plug and analyzed with GC.

75