Dissertation submitted in fulfilment of the requirements for the degree
Master of Science
Section Heading Page
1.2 Classes of catalysis 4
1.3 Carbon-carbon bond forming reactions 7
1.4 Palladium-catalysed carbon-carbon bond forming reactions 8
1.5 Carbonylation chemistry 15
systems 19
1.7 Summary 28
compounds
oxygen-containing unsaturated systems 45
2.3 Fundamental study on the effect of the oxygen
atom on methoxycarbonylation 58
carbohydrate analogues 70
2.4.1.1 Synthesis of the unsaturated ribose analogue 70
2.4.1.2 Synthesis of the unsaturated methylglucoside analogue
(benzyl protected) 72
glucose derivative 78
carbohydrate analogues 81
optimised conditions 85
2.5 Conclusion 88
2.6 References 89
Section Heading Page
3.1.2 Alkyne reactivity 94
3.1.4 Ibuprofen synthesis: Illustration of commercial application
of palladium-catalysed carbonylation 98
3.1.6 Overview on project objective: Conversion of alkynes into
saturated, branched esters through a carbonylation reaction
followed by a hydrogenation reaction in one pot 102
3.1.7 Hydrogenation of alkenes 103
3.1.8 Hydrogenation of organic substrates using metal-BINAP
complexes: A review on Noyoris contribution to
asymmetric hydrogenation 104
catalyst as well as Pd/Al(OTf)3/BINAP homogeneous catalyst
system 107
atropate using Pd/Al(OTf)3/BINAP catalyst system 108
3.4 One-pot methoxycarbonylation and hydrogenation of various
aromatic alkynes using Pd/Al(OTf)3/BINAP catalyst system 113
3.5 Asymmetric hydrogenation using a chiral ligand 117
3.6 Summary and general conclusion of the results obtained 122
3.7 References 123
4.2.1 Nuclear Magnetic Resonance (NMR) spectroscopy 131
4.2.2 Mass spectrometry (m/z) 131
4.2.3 Infrared (IR) spectroscopy 131
4.2.4 Melting points 131
4.3 Experimental methods 132
4.3.1 Synthesis of (2R,3S,4R)-2-(acetoxymethyl)-3,4-dihydro-2H-
4.3.5 Synthesis of cinnamyl acetate 136
4.3.6 Synthesis of (E)-(3-(benzyloxy)prop-1-enyl)benzene 137
4.3.7 A general procedure for the alkylation of alkynols with
iodohexane 138
4.3.9 Synthesis of tert-butyldimethyl(((2R,3R,4S,5R,6S)-
2H-pyran-2-yl) methanol 146
4.3.13 A general procedure for the tosylation of alkynols 147
4.3.14 A general procedure for the coupling of an alkynyl tosylate
and an alcohol 149
4.3.15 A general procedure for the carbonylation reaction using small
high pressure reactors 154
containing alkynes 154
Hydrogenation 166
hydrogenation in one pot 166
4.4 References 169
BASF Badische Anilin- und Soda-Fabrik (Baden Aniline and Soda Factory)
Bn benzyl
COSY correlation spectroscopy
DHP 3,4-dihydro-2H-pyran
eq equivalents
HMPT hexamethylphosphorous triamide
MP melting point
MSA methylsulfonic acid
TsOH toluenesulfonic acid
iv
Synopsis
Alkenes and alkynes have been used in prior work in methoxycarbonylation reactions,
affording both branched and linear ester products. Previously in the group, this reaction, i.e.
methoxycarbonylation, was shown to proceed successfully for simple alkenes and alkynes
using a novel Pd(OAc)2/Al(OTf)3/ligand catalyst system. The Al(OTf)3, which serves as the
co-catalyst, was found to afford superior results as compared to the Brønsted acids which are
conventionally used. The initial objective of the project was to demonstrate the
methoxycarbonylation reaction on unsaturated carbohydrate systems, where functionalised
glycal and pseudo-glycal derivatives were target substrates. Carbohydrates have numerous
applications and the ability to add functionality (an ester group in this case) in one quick and
easy step to compounds of such complexity would be of great benefit to the synthesis
chemist. Initial attempts of methoxycarbonylation on model compounds, as well as on the
glycals themselves, were unsuccessful despite several optimisation efforts. This set-back
birthed an endeavour to study the influence of the oxygen atom on the methoxycarbonylation
reaction of such substrates.
It was decided to investigate the influence of the O atom on the outcome of the Pd-catalysed
methoxycarbonylation reaction using oxygen-containing alkynes. Methoxycarbonylation was
carried out under various conditions on a series of alkynols, where the oxygen atom was at
varying positions from the triple bond. The free hydroxyl (OH) groups were also alkylated,
allowing both the alcohol and the ether analogues to be studied. Furthermore, the influence of
other functionalities in the alkynol substrates, e.g. aromatic group or additional oxygen
atoms, was briefly investigated.
The results of the study unequivocally showed that the O atom had a detrimental effect on the
outcome of the methoxycarbonylation reaction. The presence of the O atom caused a
significant decrease in the rate of the reaction and the closer the O atom was to the triple
bond, the more pronounced the effect. The product yield could be increased by increasing
either the catalyst loading or the reaction time. However, despite several optimisations,
methoxycarbonylation did not occur when the O atom was in the allylic position with respect
to the triple bond. It was also established that the „state of the oxygen atom was important:
poorer results were obtained when the O atom was in the free OH form as compared to the
v
ether state. The presence of more than one oxygen atom did not seem to affect the reaction,
where sufficient CH2 spacers existed between the alkyne and the O atoms. Additionally, the
presence of an aromatic group also played no deleterious role. It is proposed that the observed
phenomenon caused by the O atom is a result of an electronic effect where the O atom
coordinates to the Pd metal through its lone pair of electrons and by so doing inhibits/retards
the desired catalytic reaction required for methoxycarbonylation.
With the newly-found information about the Pd(OAc)2/Al(OTf)3/BINAP catalyst system and
the effect that the O atom has on methoxycarbonylation reactions, carbohydrate systems with
pendant alkyne chains were synthesised with the intention to demonstrate the possibility of
carrying out a catalytic reaction of this nature (methoxycarbonylation) on this complex class
of compounds. After a reasonable amount of optimisation work, ideal conditions (i.e. lowest
temperature, lowest catalyst loading, shortest time, highest yield) were obtained to facilitate
methoxycarbonylation of these carbohydrate substrates in high yields. To the best of our
knowledge, this is the first reported case where such a catalytic reaction was demonstrated on
this class of compounds.
(Pd(OAc)2/Al(OTf)3/BINAP) was found to effectively facilitate hydrogenation of methyl
atropate under an atmosphere of hydrogen. The possibility of carrying out a
methoxycarbonylation and a hydrogenation consecutively in one pot was explored. Optimum
conditions were obtained for this one pot – two step conversion using phenylacetylene. All
that was required between the two reactions was an exchange of the carbon monoxide (CO)
gas used for the methoxycarbonylation, with hydrogen gas which was essential for the
hydrogenation step. Several other aryl alkynes were used as substrate for the one pot – two
step conversion; positive results were obtained for most. This system allowed the formation
of aryl esters, which are valuable precursors in the pharmaceutical industry, from a pool of
aryl alkynes. Furthermore, the ability to form enantiomerically pure products by using a
chiral ligand was briefly probed.
vi
Acknowledgements
“Only as high as I reach can I grow, only as far as I seek can I go, only as deep
as I look can I see, only as much as I dream can I be.”
-Karen Ravn
I would like to express my deepest gratitude to the following special people who have helped
extend my reach and in their unique ways, were able to challenge my way of thinking, open
my eyes to the great wealth that knowledge brings and continuously encouraged me to dream
big dreams and to strive to reach them…
Prof D.B.G. Williams, my supervisor, for his tireless guidance through the project, the
knowledge he has imparted, the continuous motivation to think independently and the
passion he has instilled in me for chemistry.
Dr H.H. Kinfe, thank you for the constant support, assistance and encouragement.
My colleagues: Sandile, Tanya, Hendrik, Tyler, Adam, Alicia, Mosotho and Megan.
Thank you so much for sharing your experiences, knowledge and jokes and for the
motivation and encouragement during tough times… There was never a dull moment
in the lab!
My dear friends, a special mention to Edwin, thank you all for the love and support.
You kept my flame burning!
My mom and dad. Thank you for raising me, for all the sacrifices and for encouraging
me from an early age to learn, to dream and to work hard. To my little brother, Mosa
and the rest of the family, thank you for the love and support, you mean so much to
me!
My mentor, Petrus, thank you for the support, friendly advice, and interest in my
project and my progress.
Sasol, THRIP and the University of Johannesburg, thank you for the financial
assistance and interest in my studies.
Lastly, but most importantly, my Heavenly Father. Thank you for the gift of life, the
opportunity to explore the marvellous works of Your hand through my studies in the
field of science and for the special people you have strategically placed in my life to
direct, assist and support me through the beautiful journey you have set before me.
Ke ya leboha!
Literature review of palladium-catalysed reactions
1.1 Catalysis over the years
Catalysis is practiced on a large scale by Nature in the form of fermentation, digestion, and
many other forms of enzymatic processes. It was also first practiced by early societies, before
its impact was recognised, as demonstrated by the production of soap, cheese, wine and beer
(fermentation), sulfuric acid (oil of vitriol), and ether.
Jöns J. Berzelius, a Swedish chemist, recognised a common “force” that facilitated various
chemistries that were reported by others. In 1836, he provided an early definition of catalysis:
Reactions that are accelerated by substances that remain unchanged after the reaction. 1
Several scientists, such as Berzelius, Sir Humphrey Davy 2 and Wilhem Ostwald, investigated
and discovered many of the early fundamental concepts of catalysis in the 1800s. During this
time, even before these fundamental concepts of catalysis were defined, various materials
were used as catalysts 1 by others like Louis Jacques Thenard (who studied the decomposition
of NH3 in 1813), Johann Wolfgang Döbereiner (who, in 1810, demonstrated the Pt black-
mediated oxidation of alcohols), Ambrogio Fusinieri (in 1824 showed catalytic oxidation
over Pt) 3 , Michael Faraday
4 and Pierre Dulong.
5
It was found that a catalyst facilitated otherwise slow reactions to occur quicker. A catalyst
can also direct a reaction towards the formation of a specific product, as well as allow
reactions to be carried out at lower pressures and temperatures. Catalysts come in different
forms: they can be metals, oxides, sulfides, nitrides, carbides, salts or acids, among others. 6
Catalysis has played an important role in the expansion of the chemical industry. It has
allowed the development of new technologies which allow conversion of cheaper feedstocks
into more valuable chemicals.
The first man-made commercially catalysed process did not emerge until around 1750 and
was followed by further growth in the industry in the late 1800s. Initially, catalysts were used
2
for the efficient production of basic, inorganic chemicals such as sulfuric acid 7 , chlorine
8 ,
ammonia and nitric acid. Ammonia was an important component in agricultural fertilizers.
Other bulk inorganic chemicals were especially used for explosives in World War I. Later on
catalysts were used for food processing needs that emerged, such as the Ni based catalysts
that were used for hardening of fats in 1907.
In the early 20 th
century, methanol was synthesised at high pressure over a ZnO-chromia
catalyst (a method developed by BASF), marking the emergence of synthesis of organic
chemicals in large volumes. The Fischer-Tropsch technology was another excellent
development during this time, allowing the synthesis of fuels and other organic chemicals. 9
Coal was the primary feedstock for basic organic chemicals.
As time progressed, the transportation industry arose, also leading to the emergence of the
modern petrochemical industry. Catalysts were used to refine petroleum products into fuel
feedstocks via processes such as alkylation of olefins and isomerisation of paraffins with
AlCl3; catalytic cracking; naphtha reforming; Friedel-Crafts chemistry for cumene
production 10
; oxychlorination; zeolitic cracking and hydrocracking as well as dewaxing and
hydroprocessing. 11
Refining of petroleum led not only to fuel products but also generated chemicals that would
enhance the quality of life; these included polyethylene, acetic acid and propylene oxide.
Again, numerous catalysts were developed to produce these chemicals: ICU developed a
Cu/ZnO catalyst for methanol synthesis in the 1960s; acetaldehyde was synthesised from
ethylene and water by the Hoechst-Wacker process using an organopalladium catalyst; in
1980, Rh-catalysed acetic acid production from methanol was discovered; 12
propylene oxide
was formed from hydrogen peroxide and propylene in 2008 with TS-1 catalyst. These are
only a few examples of the catalysts developed.
While the commodity chemicals industry was maturing, more specialised chemicals were
starting to be produced on large scale, stimulating growth of the speciality chemicals
industry. Chemicals produced included agricultural pesticides, pharmaceuticals, water
treatment chemicals, new fibres, dyes and pigments as well as flavour and fragrance
chemicals. The formation of many of these chemicals was driven by the discovery of highly
selective catalysts. The first direct commercial synthesis of an optically active material over a
3
synthetic catalyst was discovered by William Knowles in 1974; it was a catalytic route to L-
dopa using Rh in conjunction with chiral phosphine ligands. 12
The growth in industrial activity resulted in a severe increase in pollution. A need arose to
control harmful emissions and waste that were released into the environment. This resulted in
the growth of environmental catalysis which is a huge segment of the current global catalyst
business. 13
Some of the commercialised events include: hydrodesulfurisation; auto emission
control catalysts for the reduction of CO, NOx and hydrocarbons emitted from vehicles; 14
selective catalytic reduction of NOx by NH3 for power plants; ozone emission control
catalysts; reduction of ozone emitting CFCs; 15
catalytic destruction of volatile organic
compounds; 16
diesel oxidation exhaust catalysts; catalytic decomposition of N2O using metal
oxides; 17
Pt-Rh-alkali NOx storage catalysts; diesel particulate catalysts and NOx removal in
FCC regenerator units. 18
In the late 1990s the discovery and development of zeolite molecular sieves brought about the
discovery of many novel and selective catalytic processes for the conversion of
hydrocarbons. Shape selective zeolites were used in innovative petrochemical and chemical
processes, allowing high selectivity to a wide variety of reactants and products. 19
Following the continual discovery of new catalysts and catalytic processes, concern arose
about the sustainability of petroleum based feedstocks. This led to the emergence of biomass
feedstocks. New catalysts arose for the conversion of biomass feedstock into more valuable
products. Such processes included, but were not limited to, the conversion of bioethanol to
ethyl acetate, starch to ethanol and corn to 1,3-propanediol. 20
Today over 90% of all industrial chemicals are produced with the aid of catalysts. 21
Apart
from the production of countless chemical products, catalysis has also made a significant
impact in providing means of waste control, pollutant removal and energy supply.
The remainder of this chapter will be dedicated to providing an overview of catalysis with a
distinct focus on homogeneous catalysis by palladium.
4
1.2 Classes of catalysis
Catalysts are generally classified into different types, based on the physical nature of the
catalyst: homogeneous, heterogeneous, organocatalysts and bio- (enzymatic) catalysts. The
latter two are the most recent additions to this family and have developed explosively, being
included in many commercial applications. In bio-catalysis, enzymes are used to produce
chemical products with high specificity. This class of catalysis will not be discussed in detail.
Homogeneous catalysts represent those catalysts which are soluble in the reaction medium,
most commonly in the liquid phase. 22
Contrarily, in heterogeneous catalysis, solids normally
catalyse reactions that are in the gaseous form or in solution. In this instance the reactions
usually occur on the surface of the catalyst unless the solid is porous in which case the
reaction may take place in the pores. 22
Also under heterogeneous catalysis, a liquid catalyst
may facilitate a reaction occurring in an immiscible liquid phase or one occurring with
gaseous reactants. One such example of a liquid catalyst in a gaseous reaction is the
polymerisation of ethylene catalysed by phosphoric acid. 23
This type of system is usually
referred to as two-phase rather than heterogeneous, giving a feeling of nuance and subtlety to
the descriptor.
The two types of catalysis (homogeneous and heterogeneous) have their unique features,
advantages and disadvantages. Below is a list of some of the main differences.
Table 1.1: A comparison of homogeneous and heterogeneous catalysis 22,24
Homogeneous Heterogeneous
oxide
and pressure)
Selectivity Can be tuned. Possibility of high
selectivity Usually poor
Catalyst stability Often decompose < 100 ºC Stable to high temperatures
5
continuous
Service life of catalyst Variable Long
Mode of use Dissolved in reaction medium Fixed bed or slurry
Diffusion problems High None
understanding Plausible Difficult
As a result of the ease of isolating the product from the catalyst, heterogeneous catalysis was
(and still is) widely employed in industry. However, since the success of Otto Roelens work
in 1938 on the hydroformylation process (a homogeneously catalysed process) for the
industrial synthesis of aldehydes or alcohols (oxo alcohols) from alkenes and CO/H2, 25
homogeneous catalysis by organometallic complexes gained significant interest for
application to many industrial processes.
Apart from Roelen, other scientists who carried out fundamental research which significantly
contributed in providing a basis for homogeneous catalysis include Nobel prize winners:
Fischer, Wilkinson, Ziegler, and Natta. Today, dozens of major industrial catalysed processes
are operating, based on their fundamental discoveries. 26
Below are a few examples of
applications of homogeneous catalysis in industry.
6
Table 1.2: Examples of applications of homogeneous catalysis in industry
Process Catalyst Company
[Rh(diene)(solvent)] + / DIPAMP
Although homogeneous catalysis is very diverse and can be highly stereoselective, its
application in industry has been limited due to the complexity, sensitivity and expense of the
catalyst system as well as challenges regarding isolation and recycling of the catalyst.
However, several significant developments for homogeneous catalysis have emerged since
the 1970s to date. 35
These include the development of “hybrid catalysts” and two-phase
processes which are evident in phase transfer catalysis, the use of ionic liquids (or more
precisely, nonaqueous ionic liquids (NAILS) 36
) 37
dioxide and water 38
and the immobilisation of the catalyst by
the use of dendrimers and polymer supports. 40
These improvements aim to combine the
7
practical advantages of homogenous and heterogeneous catalysis to allow for highly efficient,
greener and more economical processes in the chemical industry.
Other developments occurring in homogeneous catalysis include the on-going search for new
applications and the continual improvement of chemo- and stereoselectivity of existing
catalyst systems. The latter issue is seen particularly in the pharmaceutical and fine chemical
industries where the possibility of enhancing selectivity of homogeneously catalysed
processes is extensively investigated. The main driving force behind this type of work is that
not all isomers of optically active compounds are equally useful: often, only a specific isomer
is effective as a drug, insecticide or food additive. 41
Bond-forming transformations make up a large portion of organic synthesis, including
carbon-carbon bond forming reactions. Numerous stoichiometric routes exist for these
reactions; however, transition metal catalysed reactions play a significant and increasingly
dominant role. 42
The following section contains a more detailed description of carbon-carbon
bond formation reactions and the application of catalysis in these transformations.
1.3 Carbon-carbon bond forming reactions
Carbon-carbon bond formation is a fundamental theme of organic chemistry. 43
Several
methodologies exist to effect carbon-carbon bond formation. Many of these proceed via
ionic, polar, radical or pericyclic reaction mechanisms. 44
Such reactions include: carbanion
reactions and other addition reactions of alkenes, alkynes and aromatics.
Organometallic reagents play a pivotal role in carbon-carbon bond forming reactions. These
reagents include organolithium reagents, 45
organomagnesium reagents (Grignard reagents), 46
organocerium reagents 47
organotitanium reagents, 48
organocopper reagents, 49
organochromium reagents, 50
organozinc reagents, 51
organoboron reagents 52
and organosilicon
reagents. 53
The highly polarised carbon-metal bond offers a convenient site for reaction with
other organic molecules (Figure 1.1).
8
Figure 1.1: Polarised carbon-metal bond
The general reactivity of the organometallic reagent increases with an increase in the ionic
character of the carbon-metal bond. This ionic character is established by evaluating the
difference in electronegativity between the carbon atom and the metal centre; the larger the
difference, the more ionic the bond. 54
Table 1.3: Electronegativity (EN) values and ionic character 54
Element Li Mg Ti Al Zn Cu Si Sn B C
EN 0.97 1.23 1.32 1.47 1.66 1.75 1.74 1.72 2.01 2.5
% Ionicity 43 35 30 22 15 12 12 11 6
Transition metal-catalysed techniques have come to play a significant role in organic
chemistry, particularly in carbon-carbon bond formation reactions. 42
Transition metals have a
unique ability to activate various organic compounds and through this activation can catalyse
the formation of new bonds. Different ligands are coordinated to several transition metals
such as palladium, rhodium, cobalt or iridium to form complexes that can catalyse these
transformations.
Among all of these transition metals, palladium has probably been found to be most useful.
One event that fuelled research into the use of palladium in organic synthesis was the
discovery of the industrially important Wacker process, where ethylene is oxidised to
acetaldehyde by air in a palladium-catalysed reaction. 27
Since then, a significant number of
primarily palladium-catalysed, carbon-carbon bond forming reactions have been developed.
1.4 Palladium-catalysed carbon-carbon bond forming reactions
A large amount of effort has been expended on the study of palladium chemistry over the last
25-30 years. Palladium chemistry has become a very important part of organometallic and
coordination chemistry. Over 90 organic transformations are catalysed by palladium
catalysts. Most of these are carbon-carbon bond-forming reactions. Such transformations
-- C M++
include the Suzuki-Miyaura reaction, the Stille reaction, the Negishi reaction, the Kumada
reaction, the Hiyama reaction, the Sonogashira reaction, the Heck reaction, the Buchwald-
Hartwig reaction, the cyanation reaction and a range of carbonylation reactions. The diagram
below demonstrates a few of these important transformations which are also briefly explained
below.
Suzuki-Miyaura coupling 55
The Suzuki cross-coupling reaction (Scheme 1.1), reported by Suzuki and Miyaura in 1979,
is a palladium catalysed cross-coupling reaction between organoboron compounds and
organic halides or triflates. It provides a powerful and basic method for the formation of
carbon-carbon bonds. The advantages of this method include mild reaction conditions,
stereoselectivity and regeoselectivity, commercial availability of many boronic acids and the
low toxicity of boronic acids as compared to reagents used in other similar reactions (e.g.
organostannanes used in the Stille coupling reactions). Furthermore, the starting materials for
the Suzuki reaction are unaffected by water and tolerate a wide variety of functional groups
R X
R
O
OH(R')
carbonylation
R
10
which results in a diversity of products. The inorganic by-products are easily removed from
the reaction mixture, making the reaction suitable for industrial processes.
Scheme 1.1
The Stille cross coupling reaction is a Pd(0)-catalysed coupling reaction between an
organostannane and an organic electrophile to form a new carbon-carbon sigma bond. The
Stille reaction is a versatile alternative to the Suzuki reaction where the organoboron reagents
are replaced by organostannanes. Tin potentially bears four organic functional groups, and
the product formed depends greatly on the rate of transmetallation of each group. The relative
rate of transmetallation of various groups forms the following series: alkynyl > vinyl > aryl >
allyl ~ benzyl >> alkyl.
The Stille reaction (Scheme 1.2) is advantageous over the Suzuki reaction because it is run
under neutral conditions making it tolerant of a wider range of functional groups. The
precursor organotin compounds are not sensitive to moisture or oxygen unlike other reactive
organometallic compounds; they are also easily prepared, isolated and stored. The main
disadvantage, however, is the toxicity of and difficulty to remove tin by-products from the
reaction mixture.
Scheme 1.2
The Stille-Kelly coupling (Scheme 1.3) is the palladium-catalysed intramolecular biaryl
coupling of aryl halides or aryl triflates in the presence of distannanes. This reaction provides
some interesting products but is somewhat limited in scope.
R X +
Negishi coupling 58
In the Negishi coupling reaction (Scheme 1.4), an organozinc reagent is cross coupled with
an organohalide or its equivalent. A wide range of functional groups including ketones,
esters, amines and nitriles can be incorporated in the organohalide, improving the functional
group tolerance over organolithium and -magnesium reagents. The organozinc reagent can be
prepared in-situ, by several methodologies, including transmetallation of the corresponding
Grignard reagent or organolithium compound, or oxidative addition of activated Zn(0) to an
organohalide.
Kumada coupling 59
When an organohalide is cross-coupled to a Grignard reagent, the reaction is known as the
Kumada coupling reaction (Scheme 1.5). The reaction has limited tolerance to different
functional groups, but the high reactivity of the Grignard reagent allows viable reactions to
occur under mild conditions.
R X +
formation between organosilanes and aryl, alkenyl or alkyl halides or pseudohalides. The
reaction also requires an activating agent such as a fluoride ion or base. It has had limited
uptake in the wider community of chemists as a reaction tool.
Scheme 1.6
Sonogashira coupling 61
The Sonogashira reaction results in the formation of aryl- and alkenyl-alkynes. The alkyne
moiety is introduced via a copper salt which is generated in situ from a terminal alkyne and a
Cu(I) salt such as CuI or CuCN in the presence of an amine base. The reaction is usually
carried out at around room temperature, and the handling of the explosive copper acetylides
is avoided by the use of only a catalytic amount of the copper(I) salt, which is commercially
available. Recently, the reaction has been improved and has led to the development of
copper- and amine-free coupling protocols.
The best general palladium catalysts for the Sonogashira reaction (Scheme 1.7) are
Pd(PPh3)2Cl2 or Pd(PPh3)4. The solvents used in the reaction do not need to be excessively
dried but should be thoroughly deoxygenated in order to maintain optimum activity of the
palladium catalyst. The base can serve as a solvent, but usually a co-solvent is also used. The
coupling is stereospecific, retaining the stereochemical integrity of the substrates. The order
of reactivity of the aryl and vinyl halides is I ~ OTf > Br >> Cl, and as a result of the
difference in reactivity, selective coupling with iodides in the presence of bromides can be
achieved. A wide variety of functional groups are accommodated on the aromatic and vinyl
halide substrates. The Sonogashira reaction works well on both small and larger scale.
Scheme 1.7
R X +
Heck reaction 62
In the early 1970s, Heck and Mizoroki independently discovered that aryl-, benzyl- and
styryl- substituted olefins may be formed from the reaction of aryl, benzyl, and styryl halides
with olefins at high temperatures in the presence of a hindered amine base and a Pd(0)
catalyst (Scheme 1.8). Today, this palladium-catalysed arylation and alkenylation of olefins is
known as the Heck reaction and has become a popular catalytic carbon-carbon bond-forming
method in organic chemistry. The Heck reaction undergoes a slightly different mechanistic
pathway as compared to other palladium-catalysed coupling reactions (see Scheme 1.12
below). The olefin insertion step, following oxidative addition, is usually directed by steric
hindrance, the organometallic intermediate then undergoes β-hydride elimination under
thermodynamically controlled conditions, resulting preferentially in the formation of the E
product.
In 1995, Buchwald and Hartwig independently reported the palladium-catalysed coupling of
aryl halides with amine nucleophiles in the presence of stoichiometric amounts of base to
afford new C-N bonds (Scheme 1.9). This reaction has seen dramatic development and is
now quite widely used for the catalytic synthesis of amines.
Scheme 1.9
Cyanation reactions 64
The palladium catalysed cyanation of aromatic halides is an improved alternative to the
Rosemund-Von Braun reaction, which normally employs harsh reaction conditions and
requires tedious workup procedures. The cyanide nucleophile used in the reaction should be
kept at low concentrations during the reaction as it is a strong nucleophile and can lead to
catalyst poisoning. This is usually achieved by the use of Zn(CN)2 as the cyanide source: it is
R X R''
R
R'
Pd(0)
14
poorly soluble in dimethylformamide (DMF), a common solvent for the reaction. An
alternative, non-toxic source of cyanide is K4[Fe(CN)6], which can be used in combination
with the palladium catalyst to produce aryl nitriles from their corresponding halides. In
appropriate cases, C-H activation also takes place, giving good atom efficiency (Scheme
1.10).
Palladium-catalysed carbonylation reactions can be used in the synthesis of aldehydes, acids,
esters and amides from halides, olefins and alcohols in the presence of carbon monoxide, a
nucleophile and a base (Scheme 1.11). The specific outcome in terms of the functional group
generated of the reaction depends on the nucleophile. Carbonylation is superior to standard
organolithium and Grignard chemistry mainly because of the range of functional groups with
which the reaction is compatible.
Scheme 1.11
Generally, the palladium catalysed carbon-carbon bond forming reactions follow a similar
mechanism (Scheme 1.12). This involves an initial oxidative addition of the C-X system to a
Pd(0) species, yielding a Pd(II) intermediate. This is followed by a transmetallation step,
isomerisation of the organometallic complex such that the two eliminating groups occupy cis
positions with respect to each other, and finally reductive elimination of the product to
regenerate the active Pd(0) catalyst. 66
R X
R Nu
O Pd(0)
reactions
This project will focus on one of the palladium-catalysed carbon-carbon bond forming
reactions, specifically the carbonylation reaction. Because of this focus, more detail will be
given for this reaction than has been done for the various reactions, above.
1.5 Carbonylation chemistry
Carbonylation reactions involve the insertion of the C=O moiety, obtained directly from
carbon monoxide, with or without other groups, into various substrates such as alcohols,
alkenes, alkynes, halides and amines, nitro compounds or substituted aromatic analogues of
these. 67
These reactions are normally transition metal-catalysed; metal complexes of cobalt,
nickel, palladium, rhodium, ruthenium, iridium and platinum have been used to facilitate
carbonylation reactions. 68
Carbonylation reactions are quite diverse. They include, but are not
limited to, the synthesis of aldehydes (hydroformylation) 69
, carboxylic acids
(hydrocarboxylation) 70
.
The first well-established catalytic carbonylation reaction was discovered by Roelen over
eighty years ago while he was investigating the mechanism of the cobalt-catalysed Fischer-
PdII
L
XL
M-R'
M-X
Transmetallation
PdII
L
L
R'R
Isomerisation/Rearrangement
PdII
L
R'L
R
R-R'
L2Pd(0)
16
Tropsch reaction for the synthesis of hydrocarbons from carbon monoxide and hydrogen. He
discovered that the addition of ethene to the usual syngas mixture (carbon monoxide and
hydrogen) resulted in the formation of propanal in notable yields (Scheme 1.13). 25
Scheme 1.13
Following Roelens discovery, Reppe and co-workers extended the catalytic synthesis of
various unsaturated carbonyl compounds from alkenes and alkynes. One important discovery
was the use of Ni(CO)4 as a catalyst for the carbonylation of acetylene to acrylic acid. 72
Scheme 1.14
Reppes reactions, however, involved harsh operating conditions, required unstable catalysts
and in some cases corrosive co-catalysts, and generated toxic by-products and waste that
required extensive and tricky removal from the major product. 46
Modifications of Reppes process were brought about by Chiusoli et al. 73
These demonstrated
Thereafter, Wilkinson 74
Tsuji 76
made substantial contributions, involving the use of phosphines as ligands in
palladium- and rhodium-catalysed carbonylation reactions. They illustrated that
carbonylation reactions could be carried out under milder conditions using more stable and
effective catalysts.
the reactivity and versatile functionalities of the carbonyl group. 77
The inherent reactivity of
the carbonyl group, which enables nucleophilic attack at the carbon position and electrophilic
attack at the oxygen position, along with polarity effects on functional groups or
+ CO + H2
HCo(CO)4 H
O
17
neighbouring atoms allow the carbonyl group to be introduced into different sites in an
organic molecule, resulting in good product yields and high selectivity. 78
Several industrial processes that make use of carbonylation reactions for the large scale
synthesis of valuable chemicals have been established.
Table 1.4: Industrial applications of carbonylation reactions
No Process Catalyst Company
acids 33
acetic anhydride 79
acid 80
Ni(OCOC2H5)2 BASF
acid 81
phenyl acetic acid 82
ethanol to Ibuprofen 83
dimethyl carbonate 84
Pd(OAc)2/2-PyPPh2 Shell
diphenyl carbonate 86
Pd(II) ammonium salts/co-
acid 87
Co2(CO)8/ pyridine BASF
Although several types of substrates, as already mentioned (and evident in Table 1.4) above,
may be used for carbonylation, olefins in particular have been used extensively for numerous
carbonylation transformations (Figure 1.3).
Figure 1.3: Carbonylation of olefins 88
Palladium catalysts have been found to be effective for a variety of carbonylation reactions, a
number of which benefit from the fact that the reactions occur at lower temperatures and
pressures than with many other catalyst systems. 89
R +
R
R
O
R, R' = H, aryl, alkyl X, Y = polymer end groups cat = catalyst ox = oxidant
19
As already mentioned, the project focuses on palladium-catalysed methoxycarbonylation of
unsaturated systems. As was also mentioned, methoxycarbonylation is a class of
carbonylation reactions, whereby substrates (alkenes, alkynes, alcohols or halides) are
converted to methyl ester products in the presence of carbon monoxide, methanol and a
catalyst (usually palladium). The terms methoxycarbonylation and hydroesterification might
be used interchangeably: the former being a subset of the latter.
1.6 Palladium-catalysed methoxycarbonylation of unsaturated systems
In general, the palladium-catalysed methoxycarbonylation of unsaturated systems is the
palladium-catalysed addition of a carbonyl moiety to a double or triple bond, with reductive
elimination of the product through methanolysis, producing valuable carboxylic acid esters
(Scheme 1.15). 90
Scheme 1.15: Methoxycarbonylation of alkenes and alkynes
A substantial amount of research has been carried out in recent years for the formation of
branched esters from vinyl aromatics using the methoxycarbonylation reaction, since these
products serve as precursors to non-steroidal anti-inflammatory drugs such as Ibuprofen
(Figure 4) and Naproxen (Figure 5). 91
Figure 1.4: (S)-Ibuprofen Figure 1.5: (S)-Naproxen
COOH
CH3
CH3O
COOH
CH3
There are two postulated mechanisms for the hydroesterification reaction: the hydride
mechanism 92
. The scheme below is a representation of the
two mechanisms, each of which has supporting evidence.
Scheme 1.16: Proposed mechanisms for methoxycarbonylation of olefins
In the hydride mechanism, a Pd-H species is the starting point and the olefin is inserted into
the palladium hydride bond. This is followed by the insertion of carbon monoxide to generate
a palladium acyl intermediate, giving the final product upon nucleophillic attack of the
alcohol. 94
The carboalkoxy mechanism on the other hand involves the formation of a palladium acyloxy
species as a key initiating step by the attack of the alcohol onto the Pd-CO bond. This is
followed by the insertion of the alkene or alkyne into the palladium-CO bond to generate a
Pd-alkyl intermediate and protonolysis of the metal-alkyl bond which results in the formation
of the product and the regeneration of the active palladium species. 95
It was found in various
experiments that both the substrate and the reaction conditions determine which of the two
mechanisms occurs. 96
Knifton used a PdCl2(PPh3)2/SnCl2 catalyst system for hydroesterification of olefins. He
managed to isolate a hydrido palladium complex, HPd(PPh3)2(SnCl3), which gave a strong
indication of the hydride mechanism being the route followed for hydroesterification. 97
[Pd]-H
21
Noskov et al. performed extensive studies on the mechanism and kinetics of the
hydrocarboxylation of olefins using a PdCl2(PPh3)2 catalyst precursor. Through in situ IR
studies, they were able to detect a Pd-acyl complex, a key intermediate of the hydride
mechanism. 98
From a mixture of Pd(OAc)2 and TPPTS (triphenylphosphine trisulfonate) in aqueous
trifluoroacetic acid, Sheldon et al. were able to observe a water soluble Pd-H species,
[HPd(TPPTS)3] + using
1 H and
31 P NMR spectroscopy. In the presence of ethene and carbon
monoxide, the Pd-H complex formed Pd-alkyl and Pd-acyl intermediates. These
intermediates are known to be participants in the hydride route. These results thus confirmed
the occurrence of the hydride mechanism under the given conditions. 99
Seayad et al. synthesised the cationic palladium complex, Pd(OTs)2(PPh3)2 in situ from
Pd(OAc)2, PPh3 and TsOH in methanol. They then performed a detailed study on the
mechanism and kinetics of the hydroesterification of styrene. The authors proposed a
mechanism through a cationic hydrido palladium complex [HPd(CO)(PPh3)2] + (TsO
- ) which
was successfully isolated and identified. The formation of Pd-hydride and Pd-alkyl
complexes was confirmed by 1 H and
31 P NMR characterisation of these intermediates.
100
Cavinato and co-workers provided further (indirect) evidence in favour of the hydride
mechanism in 2004. They managed to synthesise trans-[Pd(COOCH3)(PPh3)2(TsO)], an
intermediate formed in the carbomethoxy mechanism. They then subjected this pre-formed
catalyst to methoxycarbonylation of ethene at room temperature. The catalyst was unable to
catalyse the reaction. This was an indication that the carboalkoxy mechanism was not the
mechanism of choice. 101
The authors determined that the same intermediate, trans-[Pd(COOCH3)(PPh3)2(TsO)],
served as a catalyst precursor for the hydroesterification of ethene at 100 °C, but was
recovered as trans-[Pd(COCH2CH3)(PPh3)2(TsO)] complex after the reaction, which was
found to be able to further catalyse the reaction. It was postulated that CO2 evolved from
trans-[Pd(COOCH3)(PPh3)2(TsO)] to generate a catalytically active species. In other work,
the trans-[Pd(COCH2CH3)(PPh3)2(TsO)] complex was also isolated from the
hydroesterification of ethene in MeOH using the catalyst precursor Pd(PPh3)2(TsO)2. 96
22
All of these results taken together indicated a greater preference for the hydride mechanism
during hydroesterification. It is, however, possible that both mechanisms occur
simultaneously since the formation of the palladium-methoxy species (crucial for the
carboalkoxy mechanism) is easily formed in methanol solvent. However, the hydride
mechanism is favoured, particularly in fast reactions.
1.6.2 The catalyst system for alkoxycarbonylation reactions
The palladium catalyst
A catalyst is a compound that can be used in very small quantities to reduce the activation
energy of a reaction and as a result increase the rate at which the particular reaction occurs, as
was defined earlier. Catalysts can generally be recycled and reused.
In the case of carbonylation reactions, particularly methoxycarbonylation reaction, palladium
has been extensively and successfully used as catalyst. The oxidation state of the active
catalyst is not well-established. However, the palladium precursor can possess an oxidation
state of 0 or +2 102
. It has been found that in the absence of a stabiliser, the palladium tends to
form a less active (or inactive) dinuclear species 103
or precipitate out of solution and form
palladium black, rendering the catalyst inactive 104
. Components such as the co-catalyst and
the ligand play a role in the stabilisation and activity of the palladium catalyst.
The acid co-catalyst: Brønsted vs Lewis acidity
In methoxycarbonylation reactions, the co-catalyst, also known as the promoter, has been
found to contribute to catalyst stabilisation as well as regeneration of the active catalyst
form. 105
. Traditionally, Brønsted acids
have been used as promoters for the methoxycarbonylation reaction. Substantial work has
been performed to try and determine the order of activity in the reaction when different
Brønsted acids are used. It was found that this order varies with respect to the substrate used:
For styrene, the activity decreases in the order p-TsOH (p-toluenesulfonic acid) > MSA
(methanesulfonic acid) > triflic acid (trifluoromethanesulfonic acid) > trifluoroacetic acid >
HCl (hydrochloric acid), 107
whereas for propene, the series differs slightly, being triflic acid >
H2SO4 (sulfuric acid) > p-TsOH > HCl and for propyne the activity series was found to be
MSA > p-TsOH > Ph-PO(OH)2 > CH3COOH > HCl.
23
Although the substrate plays a significant role in determining which promoter would allow
most reaction activity, a common feature also required for good activity seems to be strong
acidity (pKa<2) with weak co-ordinating strength. 108
Typical examples of anions that will
weakly co-ordinate to the metal catalyst include PF6 - , BF4
- , TsO
- , Cl
- , CF3SO3
name a few.
Activation of the palladium catalyst by the acid promoter is thought to proceed through the
following reactions: 105
Scheme 1.17: Activation of the palladium catalyst
Interestingly, it is evident from the reactions above that the promoter is involved in the
generation of the Pd-H intermediate, which further supports the hydride mechanism for
methoxycarbonylation. It can also be rationalised that the reaction shown in the first equation
of Scheme 1.17 increases the rate of the reaction due to the fact that it tends to retain the
palladium in the divalent state and also leads to an increase in the concentration of the
hydride complex which initiates the reaction. 109
A Lewis acid is defined as a compound that has the ability to accept an electron pair 110
. The
Lewis definition of acids and bases, unlike that of Brønsted, encapsulates all of the acid-base
pairs. Lewis named acids and bases which react with zero activation energy as primary acids
and bases, and those that require activation energy before their primary or acidic or basic
functions appear as secondary acids and base, thus describing all acid-base pairs. 110
In principle, all reactions that may be catalysed by a Brønsted acid could possibly be
catalysed by a Lewis acid, most likely at a different rate or degree of selectivity. It is
important to note, however, that Lewis acids have the potential to form Brønsted acids in the
Pd0 + HX HPdX
24
presence of water. Hence, if one wishes to show that a reaction is in fact catalysed by a Lewis
acid and not necessarily a Brønsted acid, water should be eliminated from the reaction
medium. 111
The scheme below indicates how a Lewis acid may convert into a complex Brønsted acid, or
a Lewis-assisted Brønsted acid, in the presence of water. 112
Scheme 1.18: Conversion of a Lewis acid to a Brønsted acid in the presence of water
Lewis acids catalyse a large variety of organic reactions 113
. These include electrophilic
degradation of perfluorinated compounds, 114
metathesis 115
(a modern synthetic route used successfully for the production of large
macromolecules by cyclisation of open-chain precursors that have various functional groups
on them) and other specific reactions such as the Beckman rearrangement reaction, 116
which
transforms oximes into amides, as well as the Diels-Alder reaction. The latter two specific
reactions were also found to take place under Brønsted acid catalysis; the use of a Lewis acid
afforded superior results, though.
Below are reaction schemes of some of the Lewis acid-catalysed reactions mentioned in the
preceding paragraph.
adduct hydrolysis
Scheme 1.20: Beckman reaction
Scheme 1.21: Diels-Alder reaction
Recently, it was found in these laboratories that the use of the Lewis acid Al(OTf)3, instead of
the traditional Brønsted acids, as promoter (co-catalyst) for the methoxycarbonylation of
alkenes and alkynes significantly improved the efficiency and reactivity of the Pd catalyst. 117
This was the first reported instance where a stable and recyclable Lewis acid co-catalyst was
utilised for a methoxycarbonylation reaction. Previously in the group, it had been shown that
Al(OTf)3 was an efficient catalyst in several other organic transformations such as ring-
opening of epoxides with alcohols and amines 118
as well as an atom efficient route for acetal
formation. 119
Quantitative work was also done, in our laboratories as well as in others, to demonstrate that
Al(OTf)3 did not form TfOH within the reaction. 120
It was shown with 1-pentene and styrene
as substrates that the activity of this catalytic system greatly out-performs that in which
Brønsted acids are used. It was also shown that the use of the Lewis acid instead of the
traditional Brønsted acid had little influence on the branched:linear ratio of the products
formed. An additional benefit of using Al(OTf)3 was the suppression of quaternisation of the
ligand PPh3 (a notable and nuisance side-reaction that occurs in Brønsted acid-catalysed
reactions), which results in an improved lifetime of the phosphine ligand. 117
N OH
The role of the ligand in the catalyst system
The ligand plays a critical role in catalyst stability (by preventing agglomeration of the
palladium which would otherwise lead to palladium black), 121
activity as well as selectivity of
hydroesterification reactions. The steric and electronic effects of the ligand as well as the
quantity of ligand used in a catalytic system, all significantly affect the outcome of the
reaction. Much work goes into the manipulation and modification of each of these aspects in
order to optimise a particular catalytic process.
Various ligands have been used in an attempt to improve or direct productivity of the
methoxycarbonylation reaction, mostly being phosphine systems. There is no single ligand
that is efficient for carbonylation chemistry of all substrates: different ligands have been
found to afford optimum results in the catalysis of the same reaction with different substrates
and vice versa.
and
theoretically. 123
Initially, it was found that monodentate phosphine ligands (Figure 1.4 and
Figure 1.5) favoured the hydroesterification of ethene to methyl propanoate, while bidentate
phosphine ligands (Figure 1.6 and Figure 1.7) lead to the formation of polyketones. 124
It was
later shown that the use of an appropriate choice of ligand could control the chemoselectivity
of the reaction, for example, methoxycarbonylation of ethene could be favoured over
polymerisation by using sterically hindered diphosphine (bidentate) ligands. 125
Recent
polymerisation when sterically bulky diphosphine ligands were used. Further probing of the
effect of monodentate and bidentate ligands also showed that trialkyl monodentate phosphine
ligands such as P(nBu)3, were more effective than aryl monodentate phosphines like PPh3 in
the methoxycarbonylation of olefins with [Pd(OAc)2L2/L] as catalyst. In the same manner,
alkyl diphosphine ligands with bulky end groups afforded the methoxycarbonylation product,
methyl propanoate, with 98% selectivity. 126
27
P
Figure 1.4: Example of a monodentate alkyl phosphine ligand (P(nBu)3)
Figure 1.5: Example of a monodentate aryl phosphine ligand (PPh3)
Figure 1.6: Example of a bidentate alkyl phosphine ligand (dtbpp)
Figure 1.7: Example of a bidentate aryl phosphine ligand (BINAP)
The example with ethene clearly indicates the importance of the ligand in the outcome of the
reaction. The course of the reaction can be completely altered and a particular reaction can be
optimised by manipulating only the ligand in a catalyst system and keeping all other
conditions constant. The effect of a particular ligand is also dependent on the substrate used,
i.e. alkyl diphosphine ligands might afford optimum results for the methoxycarbonylation of
ethene, but fail to give the same results for the carbonylation of a different substrate.
P
During development of the Pd/Al(OTf)3 catalyst system for methoxycarbonylation of
unsaturated systems, PPh3 was found to produce the best results for methoxycarbonylation of
alkenes such as styrene and pentene while BINAP, a bidentate ligand, was shown to give the
best results for the methoxycarbonylation of alkynes such as phenylacetylene.
The stereoselectivity in a reaction can be manipulated or introduced by the use of a chiral
ligand. For example, chiral BINAP has also been used in asymmetric catalytic reactions, such
as asymmetric hydrogenation and asymmetric carbonylation. 127
In these instances not only is
the reaction chemoselective, but stereoselectivity was also introduced. In this work, the
possibility of introducing stereoselectivity to a catalytic process that yields a racemic mixture
of products, will be explored briefly. The formation of chiral products will be pursued by
using a chiral ligand (i.e. chiral BINAP).
MeOH as solvent and reagent in methoxycarbonylation reactions
An alcohol, specifically methanol in this instance, is another essential component for the
methoxycarbonylation of unsaturated systems. The alcohol participates in the last step of the
reaction mechanism, a reductive elimination, whereby the final ester product is released and
the active catalyst specie is regenerated. reductive elimination. Different alcohols may be
used for hydroesterification reactions, e.g. ethanol may be used instead of methanol to afford
ethyl esters rather than methyl esters. However, the more complex the alcohol, the slower the
reaction and the higher the probability that complications may arise.
Although the alcohol is a reagent in the methoxycarbonylation reaction, it is also usually used
as the solvent as it allows good solubility of the catalyst, the substrate and the products.
Where the alcohol was found to be a poor solvent, co-solvents have been used. 128
The co-
solvent should, however, not affect the reaction. A good example of an unreactive co-solvent
used along with methanol in methoxycarbonylation reactions is dimethoxyethane. 128
1.7 Summary
Catalysis was practiced in nature long before man was aware of such a phenomenon.
Catalysis has grown tremendously since the early 1800s when it was first described. It played
a major role in the development of the chemical industry, greatly improving the quality of
life. Throughout the years we have seen significant growth in the number and the quality of
catalysts produced for various reactions.
29
A very large number of reactions are catalysed by transition metals such as iron, rhodium,
iridium, palladium and many others, either heterogeneously or homogeneously.
Heterogeneous catalysis has been the preferred route in industry especially because of the
ease in separation of the catalyst from the product. Heterogeneously catalysed reactions are,
however, not as wide in scope as those catalysed homogeneously. Homogeneous catalysis is
unfortunately plagued by the difficulty and sometimes the expense of separating the product
from the catalyst system. Consequently, this method has not been optimally utilised in
industry.
Over and above the continuing search for new catalysts and the improvement of existing
ones, much of the research currently taking place in homogeneous catalysis focuses on
finding easy and economical ways for catalyst regeneration: the use of solid supports,
dendrimers and the development of biphasic catalyst systems are examples of methods
currently being investigated to allow easy separation of homogeneous catalysts from products
(and reagents).
Biocatalysis/ enzymatic catalysis (where enzymes are used to catalyse highly chemoselective
and stereoselective chemical reactions) is a new branch in catalysis that is also growing at a
fast pace.
Amongst the various catalytic transformations, catalysts play a significant role in carbon-
carbon bond formation reactions. Carbonylation is an example of a metal-catalysed carbon-
carbon bond forming reaction, where a carbonyl group is introduced to an alkene, alkyne,
alcohol or halide. Various metals (palladium, rhodium, iridium, nickel, etc.) have been used
as catalysts for carbonylation reactions. Palladium is a popular choice because of its high
activity under mild conditions.
hydrocarboxylation and hydroesterification. In the latter transformation, substrates are
converted into ester products in the presence of carbon monoxide and an alcohol. When the
alcohol used is methanol, the reaction is referred to as the methoxycarbonylation reaction.
30
Different routes have been reported for the methoxycarbonylation of alcohols, halides and
unsaturated systems. A catalyst (normally palladium based), an acid co-catalyst (normally a
Brønsted acid), carbon monoxide and methanol are required for the reaction. In this work, it
is proposed to investigate the methoxycarbonylation of unsaturated systems, i.e. alkenes and
alkynes, using a method that was recently developed in our laboratories, whereby a the Lewis
acid co-catalyst Al(OTf)3 is used instead of the conventional Brønsted acid, along with the
usual palladium catalyst.
1.8 Current work
The project takes a deeper look into the application of a reasonably new catalytic system
specifically for the palladium-catalysed methoxycarbonylation of alkenes and alkynes in the
presence of a Lewis acid co-catalyst, Al(OTf)3. This catalyst system has been shown to
successfully facilitate methoxycarbonylation of simple unsaturated substrates such as styrene,
1-pentene and phenylacetylene. 117
methoxycarbonylation of unsaturated compounds that contain one or more oxygen
heteroatoms.
A large portion of useful organic compounds contain at least one heteroatom, and these
include sulfur, nitrogen, halide or oxygen atoms, the latter being most common. Numerous
stoichiometric routes exist for various chemical transformations of these compounds.
Although catalytic processes are atom efficient, direct and normally less hazardous, as
compared to the traditional, multi-step chemistry, they are seldom used for synthesis of
complex organic compounds due to the harsh reaction conditions that are usually required, as
well as the complex mixture of products that usually form. The possibility, therefore, of
introducing an ester group to complex, oxygen-containing compounds such as carbohydrates,
in a single catalytic step (i.e. by methoxycarbonylation) that is mild, selective and high
yielding, would be of great benefit to the synthetic chemist.
A study of the influence of the oxygen atom on methoxycarbonylation of unsaturated
compounds, using the above-mentioned catalyst system, is to be carried out and reaction
conditions are to be optimised for the successful methoxycarbonylation of unsaturated
carbohydrates. Specifically, the position of the O atom with respect to the alkyne will be
probed, as will the nature of the O atom (free OH, ether, etc.). This is to be the first reported
case of a catalytic transformation of this nature on such complex substrates.
31
Furthermore, the project explores the possibility of using the same catalyst system that has
been used for methoxycarbonylation of unsaturated systems, in a hydrogenation reaction.
This would in principle allow a two-step conversion in one pot: the first step would be the
methoxycarbonylation of an alkyne followed by a hydrogenation step, resulting in saturated
ester products. The conversion of aryl alkynes to form aromatic branched ester products is of
great interest, as most of these compounds have useful roles in synthesis, particularly in the
pharmaceutical industry. This is evident in the formation of the non-steroidal anti-
inflammatory drugs, ibuprofen and naproxen, where aromatic branched esters are used as
precursors.
Since the methoxycarbonylation reaction of alkynes is highly regioselective, providing the
branched product, the reaction lends itself to the formation of the branched 2-arylpropionate
by hydrogenation of the intermediate α,β-unsaturated ester. Specific aspects to be studied
include the hydrogenation of the α,β-unsaturated ester to its saturated analogue in the
presence of the catalyst system and reaction set-up used for the methoxycarbonylation
reaction (i.e. Pd(OAc)2/Al(OTf)3/BINAP/MeOH in the presence of molecular hydrogen).
Once conditions for that reaction have been established, a protocol to perform the
hydrogenation reaction post-methoxycarbonylation will be investigated. This is likely to
involve atmosphere exchange (H2 for CO), under conditions in which the catalyst is active
from the prior reaction. It is anticipated that the two-step reaction will require substantial
optimisation.
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Bosnich, B. In Asymmetric Catalysis; Martinus Nijhoff; Dordrecht, 1986, 19-28 (g)
Consiglio, G. Cheminform, 1994, 25, 17.
128. (a) Shaw, M. PhD, Thesis, University of Johannesburg, 2011 (b) Hughes, T. PhD,
Thesis, University of Johannesburg, 2012
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2.1 Introduction
Heteroatomic compounds constitute a large and important class of synthetic and natural
products. There are various stoichiometric procedures available to introduce heteroatoms
such as oxygen, nitrogen, sulfur and halides to hydrocarbon moieties, as well as to react these
heteroatomic compounds to form various other target molecules.
Carboxylic acids and t