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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