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Development of sustainable catalytic methods for
the chemical utilisation of carbon dioxide and for
the valorisation of cashew nut shell liquid
Dissertation at Fakultät für Chemie und Biochemie
Ruhr-Universität Bochum
Submitted by
Valentina Bragoni
Born in Rome, Italy
Supervisor
Prof Dr Lukas J. Gooßen
Bochum, 2020
I
To my beloved family
II
III
You cannot get through a single day without having an impact on the
world around you.
What you do makes a difference, and you have to decide
what kind of difference you want to make.
Jane Goodall
IV
V
The present work was carried out at Ruhr-Universität Bochum between July 2016 and February
2020 in the research group of Prof Dr Lukas J. Gooßen
Evaluation Committee
Chair:
Evaluator: Prof Dr Lukas J. Gooßen
Evaluator: Prof Dr Kristina Tschulik
Evaluator: Prof Dr Viktoria H. Däschlein-Gessner
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VII
Official Declaration
Hereby I declare that I have not submitted this thesis in this or any similar form to any other
examination at the Ruhr-Universität Bochum or any other Institution. I officially ensure that
this work has been written entirely by myself. I herewith officially ensure that I have not used
any sources other than those cited and/or acknowledged, and any parts of the text which
constitute quotes in original wording or in its essence have been explicitly referred by me by
using official marking and proper quotation. This is also valid for used drafts, pictures and
similar formats. For cooperation projects, the contribution of each author has been clearly
stated.
Bochum,
Valentina Bragoni
VIII
IX
Acknowledgements
I wish to express my gratitude to Professor Gooßen for accepting me in his research group and
for his trust and support. I am also truly thankful to Dr Käthe Gooßen for her help in finalising
my manuscripts and Dr Wolf M. Pankau for reviewing this work.
I would like to thank Professor Tschulik and Professor Däschlein-Gessner for agreeing to be
part of the examination committee of my dissertation.
I thank our secretaries Stefanie, Sylwia and Damla for their constant help. I thank Christoph
Oppel for providing some of the unforgettable funniest situations, even when he was not aware
of it. I also thank Florian Kaschuba for his many jokes and Michael Wüstefeld for his
quenchless calm that makes me laugh.
I thank my project partners for their contributions and the constructive cooperation in the
projects. I would also like to thank all current and former members of the Gooßen group that I
have met for their support. Special thanks go to Timo, Dagmar, Stefania, Manu, Florian, Giulia
and Nardana for proofreading this work and Thilo for his constant support.
I thank Valerio, Valentina, Chiara, Andrea, Porthus, with whom I have been friend for almost
15 years. I thank Danilo, Laura and the other friends from salsa, for welcoming me like a second
family whenever I go back to Rome.
With all my heart I thank my family: my parents Mimma and Riccardo, for their constant
support and endless love, and my brother Daniele, whom I rarely see, but I love a lot. I want to
thank my lovely grandma Gabriella who cries every time I leave from Rome to come back to
Bochum, and makes me cry with her. I thank my aunts Maura and Fiorenza for their regular
family updates. A special thought goes to my grandma Angela, who keeps watch over me from
a special place.
X
Abbreviations
ABS branched alkyl benzene sulfonates m meta
Ac acetyl group Me methyl group
Ar aryl group MEA monoethanolamine
BenzP* 1,2-bis(tert-butylmethylphosphino) benzene MeCN acetonitrile
BDO 1,4-butanediol MES methyl ester sulfonate
bp boiling point mes mesityl group
BPhen 4,7-diphenyl-1,10-phenanthroline m.p. melting point
CCS carbon capture and storage MS mass spectrometry
CCU carbon capture and utilisation MTDB 7-methyl-1,5,7-triazabicyclo[4.4.0]-dec-5-
ene
CM cross-metathesis MTBE methyl tert-butyl ether
cmc critical micellar concentration NHC N-heterocyclic carbene
CNSL cashew nut shell liquid NMP N-methyl-2-pyrrolidone
Cy cyclohexyl group NMR nuclear magnetic resonance
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene NP nonylphenol
DCM dichloromethane NPEs nonylphenol ethoxylates
DMAc dimethylacetamide o ortho
DMF dimethylformamide p para
DMS dimethylsuccinate PC propylene carbonate
DMSO dimethylsulfoxide PMMA polymethylmethacrylate
Et ethyl group poly-PPh3 polymer-bound triphenylphosphine
FAE fatty alcohol ethoxylates rt room temperature
FAME fatty acid methyl ester RWGS reverse water-gas shift reaction
GC gas chromatography SDS sodium dodecyl sulfate
HG Hoveyda-Grubbs SHOP Shell higher olefin process
Ic tyrosinase activity THF tetrahydrofuran
IPr 1,3-di-iso-propyl-4,5-dimethylimidazol-2-
ylidene TMEDA N,N,N’,N’- tetramethylethylenediamine
iPr isopropyl group TMP 2,2,6,6-tetramethylpiperidine
IR infrared radiation TPS tetrapropylene benzene sulfonate
LAS/LABs linear alkyl benzene sulfonates vs versus
XI
Publications
V. Bragoni, M. Dyga, T. van Lingen, B. Exner, L. J. Gooßen, Pressure-induced acidity switch
opens up a salt-free, catalytic access to C4 base chemicals from CO2 and acetylene. manuscript
in preparation
J. Pollini, V. Bragoni, L. J. Gooßen, Beilstein J. Org. Chem. 2018, 14, 2737: Synthesis of a
tyrosinase inhibitor by consecutive ethenolysis and cross-metathesis of crude cashew nutshell
liquid.
V. Bragoni, R. K. Rit, R. Kirchmann, A. S. Trita, L. J. Gooßen, Green Chem. 2018, 20, 11288:
Synthesis of bio-based surfactants from cashew nutshell liquid in water.
C. Matheis, T. Krause, V. Bragoni, L. J. Gooßen, Chem. Eur. J. 2016, 22, 12270:
Trifluoromethylthiolation and Trifluoromethylselenolation of α-Diazo Esters Catalyzed by
Copper.
L. Huang, A. Biafora, G. Zhang, V. Bragoni, L. J. Goossen, Angew. Chem. Int. Ed. 2016, 55,
6933: Regioselective C−H Hydroarylation of Internal Alkynes with Arenecarboxylates:
Carboxylates as Deciduous Directing Groups.
XII
Poster Presentations
10th Workshop on Fats and Oils as Renewable Feedstock for the Chemical Industry. Karlsruhe,
Germany. March 2019. Best Poster Award: “Synthesis of bio-based surfactants from cashew
nut shell liquid in water”.
9th World Congress on Green Chemistry and Technology, Amsterdam, Netherlands. September
2018. Chair of the conference. Best Poster Award: “Synthesis of bio-based surfactants from
cashew nut shell liquid in water”.
3rd International Green Catalysis Symposium, Rennes, France. March 2017. “Chemical
Valorisation of Cashew Nut Shell Liquid by Olefin-Metathesis”.
Oral Presentations
10th Workshop on Fats and Oils as Renewable Feedstock for the Chemical Industry. Karlsruhe,
Germany. March 2019. “Sustainable synthesis of surfactants and biological active compounds
from cashew nut shell liquid”.
9th Young Chemists´ Symposium RUHR, Bochum, Germany. October 2018. “Synthesis of bio-
based surfactants from cashew nut shell liquid in water”.
XIII
Table of contents
Official Declaration ............................................................................................................. VII
Acknowledgements .............................................................................................................. IX
Abbreviations......................................................................................................................... X
Publications .......................................................................................................................... XI
Poster Presentations ............................................................................................................. XII
Oral Presentations ................................................................................................................ XII
Table of contents ............................................................................................................... XIII
1 Abstract .............................................................................................................................. 1
2 Structure of the thesis ......................................................................................................... 3
3 Introduction ........................................................................................................................ 4
3.1 Chemistry as a tool against environmental degradation .............................................. 4
3.2 Renewable resources ................................................................................................... 6
3.2.1 Renewable resources in chemical syntheses ........................................................ 7
3.2.2 Cashew nut shell liquid ........................................................................................ 9
3.2.3 Carbon dioxide ................................................................................................... 11
4 Compounds and chemical procedures relevant to this work ............................................ 20
4.1 Surfactants ................................................................................................................. 20
4.1.1 Classification ...................................................................................................... 22
4.1.2 Dermatological, toxicological and environmental aspects ................................. 30
4.2 Tyrosinase inhibitors ................................................................................................. 33
4.3 Alkynes ...................................................................................................................... 34
4.3.1 Physical and chemical properties ....................................................................... 36
4.3.2 Typical reactivity ................................................................................................ 37
4.4 C4 platform chemicals ............................................................................................... 42
4.4.1 1,4-butanediol, BDO .......................................................................................... 42
XIV
4.5 Catalysis in sustainable synthesis .............................................................................. 44
4.5.1 Hydrogenation .................................................................................................... 45
4.5.2 Reductive amination ........................................................................................... 47
4.5.3 Olefin metathesis ................................................................................................ 48
4.5.4 Carboxylation reactions for C–C bond formation .............................................. 52
4.5.5 Reductive carboxylation of alkynes and alkenes ............................................... 54
4.5.6 CO2 as CO substitution for carbonylation reactions .......................................... 56
4.5.7 Carboxylation of C–H bonds .............................................................................. 58
5 Research objectives .......................................................................................................... 66
6 Results and discussion ...................................................................................................... 67
6.1 Synthesis of bio-based surfactants from cashew nut shell liquid .............................. 67
6.1.1 Reductive amination of phenols ......................................................................... 68
6.1.2 Reductive amination of cardanol ........................................................................ 70
6.2 Synthesis of a tyrosinase inhibitor from cashew nut shell liquid .............................. 81
6.2.1 Ethenolysis and cross-metathesis of cashew nut shell liquid ............................. 82
6.3 Catalytic, waste-free alkoxycarboxylation of terminal alkynes ................................ 97
6.3.1 Carboxylation of aromatic alkynes .................................................................... 97
6.3.2 Carboxylation of aliphatic alkynes ................................................................... 100
6.3.3 Own work ......................................................................................................... 103
7 Conclusion and outlook .................................................................................................. 125
8 Experimental section ...................................................................................................... 129
8.1 General methods ...................................................................................................... 129
8.1.1 Chemicals and solvents .................................................................................... 129
8.1.2 Reactions set-up: equipment and procedure ..................................................... 129
8.1.3 Analytical methods ........................................................................................... 132
8.2 Synthesis of surfactants from cashew nut shell liquid ............................................. 134
XV
8.2.1 Chemicals ......................................................................................................... 134
8.2.2 Synthetic procedures ........................................................................................ 134
8.2.3 Synthesis and characterisation of products ...................................................... 137
8.3 Synthesis of a tyrosinase inhibitor from cashew nut shell liquid ............................ 146
8.3.1 Chemicals ......................................................................................................... 146
8.3.2 Preparation of CNSL ........................................................................................ 147
8.3.3 Synthesis and characterisation of products ...................................................... 148
8.4 Catalytic, waste-free alkoxycarboxylation of terminal alkynes .............................. 150
8.4.1 GP: General procedure for the alkoxycarbonylation/hydrogenation of terminal
alkynes with K3PO4 as base ........................................................................................... 150
8.4.2 Procedure for the alkoxycarboxylation of 1-heptyne with Cs2CO3 as base and
recovery of the base ........................................................................................................ 151
8.4.3 Synthesis and characterisation of the corresponding products ......................... 152
8.4.4 Synthesis of dimethyl succinate (3rd) .............................................................. 162
8.4.5 Synthesis and distillation of dipropyl succinate ............................................... 164
8.4.6 Calculation of the amount of acetylene ............................................................ 165
9 References ...................................................................................................................... 166
XVI
Abstract
1
1 Abstract
In this thesis, new strategies for the synthesis of fine chemicals starting from two waste by-
products, cashew nut shell liquid (CNSL) and carbon dioxide (CO2), are presented.
CNSL, an oil extracted from the shells of cashew nuts, is an inedible by-product of the cashew
nut processing. An eco-friendly and waste minimised synthesis of amine-based surfactants from
technical CNSL was developed (Scheme 1a). First, reductive amination of the crude CNSL
mixture was accomplished in water as the sole solvent. The resulting cyclohexylamine
derivatives were converted into surfactant molecules. In addition, a three-step synthesis of a
tyrosinase inhibitor, ginkgolic acid (13:0), was developed starting from crude CNSL. The
process proceeded through an ethenolysis of the crude CNSL mixture, cross-metathesis of the
intermediate with 1-hexene, followed by a one-pot hydrogenation step (Scheme 1b).
Anacardic acid
Cardol
CNSL
N-oxides
R =
betaines quats
ginkgolic acid (13:0)
tyrosinase inhibitor
1) [Ru], ethenolysis
2) [Ru], cross-metathesis
3) hydrogenation
a
b
1) reductive amination
2) derivatisation
Scheme 1. Synthesis of a) surfactants and b) a tyrosinase inhibitor from CNSL.
CO2, one of the most abundant and alarming greenhouse gases present in the atmosphere, was
employed as C1-building block in a zero-waste alkoxycarboxylation of aliphatic alkynes. The
reaction consisted of a catalytic C–H carboxylation of alkynes, followed by hydrogenation of
the triple bond. Subsequently, high CO2 pressure enables an acidity switch of the reaction
medium, permitting the esterification of the resulting carboxylates with alcohols, upon thermal
regeneration of the inorganic base caesium carbonate (Cs2CO3) (Scheme 2). The process opens
up a sustainable access to the C4 platform chemical 1,4-butanediol from acetylene (C2) and
carbon dioxide, where two of carbon moieties come from the waste by-product CO2.
Abstract
2
CuBr, CO2 PdAl2O3, H2
carboxylation
CO2
hydrogenation esterification
NMP, 60 °C, 12 h R'OH, rt, 3 h 200 °C, 20 h
2 x CsHCO3
Cs2CO3
2 equiv
T
CO2 + H2O
recycling of the base
Scheme 2. Salt-free alkoxycarboxylation of terminal alkynes.
Structure of the thesis
3
2 Structure of the thesis
The present thesis is written in a publication-based format. It contains two original and
published manuscripts. Sources cited in the original publications are also part of the
corresponding projects. A statement of each author’s contribution is listed in front of the
corresponding publication.
The introduction is dedicated to a general overview of the current world’s major concerns, e.g.
global warming and depletion of fossil resources, with particular attention given to the main
cause of global warming: the greenhouse effect. Two possible solutions are introduced and
explained: the chemical exploitation of inedible renewable resources as possible alternatives to
fossil fuels, and the re-utilisation of carbon dioxide as starting material and its incorporation
into valuable chemicals. The last part of the introduction is reserved for the description of
substrates, products and chemical processes relevant for the projects presented in “results and
discussion”.
After the introduction, the research objectives of the PhD work are defined, with pinpointing
the remaining challenges.
The “result and discussion” chapter refers to each project. The first two projects address the
valorisation of a renewable resource, cashew nut shell liquid, as starting material to build
surfactants as well as a biologically active compound. A reprint of each manuscript is attached
at the end of the corresponding project. For each project, the chronological approach and
challenges encountered, as well as any unpublished results, are presented. The third and last
project presented herein, regards the use of carbon dioxide in chemical transformation. The
state of the art and the details of the project are discussed.
Finally, a general conclusion summarises the main results of each project. In the experimental
section, details on the analytical methods, general procedures and full characterisation of the
compounds are given, and if already published, they have been adapted from the corresponding
supporting information. References are shown at the end of this dissertation.
Introduction
4
3 Introduction
The 21st century deals with tough challenges for human society: environmental degradation,
global warming and depletion of fossil resources. It is a chemist’ duty to help face these
challenges, by developing new and more sustainable chemical processes.
Since the Industrial Revolution, fossil fuels have a dominant role in global energy, and are the
major cause of air pollution as well as the major emitters of carbon dioxide (CO2) and other
greenhouse gases (methane CH4, nitrogen oxides NOx, ozone O3, chlorofluorocarbons CFCs,
hydrofluorocarbons HCFCs).1 Fossil resources (coal, oil, gas) are formed by a process of
anaerobic decomposition of organic substances that takes place over hundreds of millions of
years and are undoubtedly expiring without any possibility of a fast restoring, thus the
designation of non-renewable resources. The release of greenhouse gases into the atmosphere
by burning of fossil fuels and deforestation are the major causes of the increase of the Earth´s
average temperature (global warming) and of the depletion of the ozone layer, allowing the
entrance of harmful radiations to earth.2–4 Global warming is a serious environmental concern
followed by several alarming side effects:5,6 reduction of snow, ice and glaciers with consequent
rise of sea levels and reduction of the surface of the continents.7 It is linked to diffuse climate
changes such us regional changing in precipitations and storms and expansion of the deserts,
changes in timing of seasonal events (e.g. flowering and germinating of plants) with connected
effects in agriculture productivity.7,8 Rising of the atmospheric carbon dioxide concentration is
connected to a greater CO2-uptake from the oceans, which has caused a general acidification of
the water.9,10 Ongoing ocean acidification can lead to fatal consequences for the aquatic
environment and the food chains linked to it. Combustion of fossil fuels releases sulphuric,
carbonic and nitric acids that generate the acid rain that falls back to Earth, impacting on built
architecture and natural areas, and affecting flora and fauna.11,12
3.1 Chemistry as a tool against environmental degradation
To contrast environmental degradation a transition from the current linear economy to a circular
economy is demanded (Figure 1).13–15 Linear economy is strongly dependent on a vast income
of natural resources including large amounts of non-renewables, and is based on a 'take-make-
consume-throw away' approach, meaning that any waste generated by the manufacturing of a
Introduction
5
product from raw materials, packaging included, is thrown away. The philosophy of circular
economy is based on the recycling of materials, on the exploitation of more renewable
resources, and on preventing the formation of waste, by employing more efficient synthetic
processes.
Figure 1. Linear economy vs circular economy.
Green or sustainable chemistry can contribute to reach the circular economy’s philosophy.
Green chemistry is an area of chemistry focused on the development of more sustainable
processes that minimise the use and production of hazardous substances and that promote the
use of renewable sources to reduce our dependence on petrochemicals.16–19 Its twelve principles
(Figure 2), developed by Paul Anastas and John Warner in 1998, outline the concept of making
a greener chemical, process or product.17 The principles address the whole life cycle of
chemicals: from raw materials to production and disposal. Nowadays these twelve principles
are internationally recognised by the scientific community as guidelines to a more sustainable
chemistry. They are not meant to be twelve independent goals, but they all have to be followed,
whenever possible, in the development of a sustainable chemical process.
Various metrics have been implemented in order to quantify the sustainability of a chemical
process, both in laboratory and on industrial scale. Two of them are atom economy and
environmental factor (E-factor). Atom economy, introduced by Trost in 1991,20 is defined as
the molecular weight ratio of the desired product to the sum of the starting materials. It is a
theoretical calculation of the quantity of the reactants remained in the final product, thus
estimating the amount of waste that is generated. The drawback of this metric is that it does not
take into consideration inorganic reagents, solvents or the stoichiometry of the reagents. The E-
factor is defined as the mass ratio of waste to the desired product.21 It represents the realistic
Introduction
6
amount of waste that is generated in a chemical reaction since it includes solvents, inorganic
reagents and by-products. It is among the most commonly used green chemistry metrics in the
evaluation of the “environmental acceptability” of a manufacturing process.18,22–24
Figure 2. The twelve principles of green chemistry.
3.2 Renewable resources
A valuable solution for reducing gas emissions, as well as contrasting the depletion of fossil
fuels, is to incorporate renewable resources in the energetic portfolio of each country.
Renewables include water, sun, wind, biomass, biogas, and are considered unlimited due to
their high, regular regeneration rate.25 However, not all of them are always and wherever
efficient, but it is important to carefully evaluate which of them can be locally exploited.
Specific wind profiles and potentials are essential for a proper profiteering of the corresponding
renewable energy.26 Countries with plenty of solar irradiations can benefit from the solar
energy.27 The use of biomass has to be considered favourable when those are not in competition
with land use for agricultural production.28,29
Worldwide, the use of renewables as energetic supplies is becoming more and more
diffused.30,31 Germany, France, and the Netherlands are the European leaders in the biofuel
production from biomass.32 In 2016, Germany managed to produce a third (~30%) of the
electricity exploiting renewable sources,33 with only photovoltaic producing ca. 6% of it.34
Renewable energy emits less carbon dioxide than fossil fuels. In fact, renewables like solar,
water or wind power, apart from the construction works and maintenance requirements, do not
Introduction
7
emit CO2. Biomass are mostly plant-based materials and are formed by fixation of the solar
energy, atmospheric CO2 and water.35 When biomass is used as energy supply and thus burned,
the energy stored in it, together with water and CO2 is released in the same quantities needed
for the fixation. Therefore, the net amount of atmospheric CO2 does not increase when energy
is obtained from biomass. However, the composition of biomass is different from the fossil
content. Biomass usually has higher oxygen and less carbon content.36–40 The difference in
carbon and oxygen content translates into a lower calorific power of biomass compared to the
same weight of fossil fuels. On the other side, biomass has a higher content of volatiles that
assures a higher flame stability. To fully benefit of both energy sources, a co-combustion of
fossil fuels and biomass is highly desirable and often used in energy production.41–43
Another promising solution to increase sustainability and to reduce the environmental impact
of the chemical industry is to implement renewable resources into chemical value chain, as
replacement or co-raw material of fossil fuels.
In this work, chemical valorisation of renewables will strictly refer to the production of
chemicals from cashew nut shell liquid and from carbon dioxide.
3.2.1 Renewable resources in chemical syntheses
3.2.1.1 Biomass
Biomass used for chemical production include mostly wood or forest residues, food processing
(corncobs), waste from food crops (lignocellulose, starch), vegetable oils (Figure 3).44–46
Figure 3. Main biomass components.44
Introduction
8
Cellulose is the most abundant biopolymer on earth,29,47 and paper production is nowadays one
of the benchmark manufacturing for the valorisation of lignocellulosic biomass. Besides paper
manufacturing, many strategies have been developed in the last years that permit the conversion
of biomass into platform chemicals.48 Carbohydrates and triglycerides derived from sugar beet
and oilseed plants can be used to make biodegradable and/or recyclable plastics.49 In Europe,
great attention is given to the production of biodiesel from rapeseed oil, as well as
oleochemicals from triglycerides and platform chemicals or bioethanol from corn.28,45,46 One of
the most important transformations of vegetable oils, is the transesterification of palm or
rapeseed oil to fatty acid methyl ester (FAME), the so-called “biodiesel first generation”.50 If
instead, the oils are hydrogenated, a product much more similar to conventional diesel is
obtained: “biodiesel second generation”.
However, exploiting biomass in biorefinery is not a carbon-neutral process. Other factors have
to be counted in the total emissions of greenhouse gases: the fuel needed for agricultural
machinery, fertilisers, and natural areas converted into agricultural land that may imply
deforestation. Additionally, the functionalisation of biomass into the targeted product may
require some modification steps ahead, to remove or add functionalities or break the compound
into an easier molecule. Thus, it is important to prioritise renewables that already have
functional groups for the production of fine chemicals. Moreover, ethical issues raise when food
plants are not used for non-nutrition purposes. In this case, agricultural waste and non-food
resources have to be preferred.
3.2.1.2 Vegetable oils
Vegetable oils are extracted from seeds or other parts of fruits and named after their source of
origin. They are mainly used for culinary purposes, but over the years, they became a viable
alternative to petroleum-based compounds for fine chemical industry and material production.
Thanks to their good biodegradability, low toxicity, abundant availability, and relatively low
cost,51–54 they are employed in the manufacturing of lubricants, surfactants, soaps, polymers,
resins, coatings.52,55–59 Their global production in 2018 was about 200 Mtons.60
Naturally occurring vegetable oils contain mainly triglycerides (triesters of glycerol and long-
chain fatty acids), differing in the length of the aliphatic chain and in the position and number
of double bonds (Figure 4).51–54 The major structural component of triglycerides are fatty acids,
which account for 95% of the total weight.54 Triglycerides contain several active sites: double
Introduction
9
bonds and ester groups, offering a wide range of possible modifications. Classical
transformations are the hydrolysis to free fatty acids and glycerol, and the transesterification to
FAMEs.61
oleic acidC18H34O2
linoleic acidC18H32O2
linolenic acidC18H30O2
palmitic acidC16H32O2
7
7
7
7
Figure 4. Vegetable oil62 (left) and some examples of fatty acids (right).
Fatty acids are amphiphilic organic molecules containing a hydrophilic head and a hydrophobic
chain. They place themselves at the interface between two different phases, with the heads
pointing towards the more polar phase and the chains pointing towards the less polar. Thus, one
of the major applications of vegetable oils is in the soap manufactory where they are used as
detergents, emulsifiers, foaming agents.56,61 Fatty acids are also used in the production of
coatings, adhesives and additives for paints, because the unsaturated oils can polymerise when
exposed to the oxygen in air.54 Another wide application of fatty acids is the synthesis of
vegetable oil-based polymers and plastics.52,53,63,64,51. Polymers are prepared via
functionalisation of the fatty acids, e.g. epoxidation, ozonolysis, hydroformylation, ring-
opening metathesis, hydrogenation and reduction reactions.54,65,66 Biodiesel, an alternative
biofuel to petroleum-based diesel, is prepared from vegetable oils by pyrolysis, catalytic
cracking, transesterification (see 3.2.1.1).67–69
3.2.2 Cashew nut shell liquid
Cashew nut shell liquid (CNSL) is an inedible waste product of the cashew nut industry.70,71 It
is a dark, viscous oil, which is extracted from the shells of the cashew nuts, and its approximate
annual production is about 1 Mtons.70,71 Cashew nuts grow outside the cashew apple, which is
an edible fruit, and being the oil extracted from the shells of the nuts, does not compete with
food production in contrast with other food crop-based biofeedstock (Figure 5). Cashew nuts
Introduction
10
belong to the family of Anacardiaceae native in Brazil, and are today spread over different
regions of the world such as Tanzania, India, Brazil, Nigeria, Mozambique, Kenya, Vietnam
and other countries in Southeast Asia.70,72
Figure 5. Cashew apple73 and nut74.
CNSL is a mixture of phenolic compounds with unsaturated aromatic chains. The main
compounds in the mixture are anacardic acid, cardol and cardanol, each bearing 15-carbon side
chains with different degrees of unsaturation in meta position to the hydroxyl group (Figure 6).
The exact composition of the oil depends on its extraction method and on the home country of
the nuts. Crude (or natural) CNSL, obtained by solvent extraction, contains 60-70% anacardic
acid, 15-20% cardol and 10-12% cardanol.70,75,76 Technical (or commercial) CNSL is obtained
by thermal treatments such as roasting of the nuts at temperatures between 300 °C and 700 °C,
or by passing them through a hot CNSL bath (180 °C).71,77 This results in the decarboxylation
of anacardic acids leading to a mixture consisting mainly in cardanols (60-70%), cardols (15-
20%) and polymerisation by-products (5-10%).70,71,76
anacardic acid cardanol cardol
R=
Figure 6. Cashew nut shell liquid and components.
Introduction
11
Anacardic acid has shown several biological activities during the past years, such as inhibitor
of prostaglandin synthase,78 tyrosinase79 and lipoxygenase.80 It is known to exhibit
antitumor,81,82 and antimicrobial activities.83,84 However, only a limited number of
derivatisations of anacardic acid have been realised by now, including the synthesis of
hydrazones85 or lactones,86–88 sulfonamides,89 and kairomones.90 The main reason for this, is
that an isolation and purification of anacardic acid from the crude CNSL mixture, that avoids
its decomposition or decarboxylation, is laborious and relies on long wasteful processes such
as column chromatography or fractionate precipitation.75,79,81,84,91
Cardanol, on the contrary, has been greatly exploited for the generation of different functional
materials. It has found several applications as modifiers for epoxy resins or flame-retardant,92,93
rubber plasticiser,94 in the synthesis of aromatic amines and several polymers55,70,77,95–97 and in
the synthesis of surfactants.70,95,98–103
Cardol is the least studied and derivatised CNSL component. It has been used as coating
material104–106 or in the synthesis of polymer precursors.107 Some studies have been made
regarding its antileukemic108 and antioxidant properties.109
3.2.3 Carbon dioxide
Carbon dioxide is a non-toxic gas that occurs naturally in Earth’s atmosphere as a trace gas. Its
current atmospheric concentration is about 410 ppm,110 generated both from natural and human
sources (Figure 7).
Carbon dioxide is released naturally by volcanoes, geysers, oceans, soil and carbonate rocks. It
is present in groundwater, rivers, glaciers, deposits of natural gas and petroleum. Atmospheric
CO2 is essential for the photosynthesis of the plants that use it in combination with water, to
produce carbohydrates and oxygen. CO2 is produced by all aerobic organisms including animals
and humans with the respiration.
Anthropogenic emissions of CO2, mainly deriving from combustion of coal and other fossil
fuels, along with deforestation, have increased its level by about 45% since the Industrial
Revolution. The pre-industrial level of atmospheric carbon dioxide was, indeed, 280 ppm.111
About half of the CO2 released from human activities is not absorbed by the vegetation and the
oceans, thus, remaining in the atmosphere.
Introduction
12
Figure 7. Movement of carbon between land, atmosphere, and ocean in billions of tons per year.
Natural fluxes (yellow), human contributions (red), stored carbon (white).112
CO2 is one of the most alarming greenhouse gases due to its long atmospheric lifetime
(hundreds of years), its atmospheric concentration and its rate of increase. According to the
International Energy Agency (IEA), if the existing energy policies will be maintained, while
not undertaking drastic changes in energy usage and human habits, by 2040 the global
emissions of CO2 will increase by an additional 10% of the current value.113
Promising technologies for significantly reducing the emissions of CO2 are the carbon capture
and storage (CCS) and the carbon capture and utilisation (CCU). These technologies can
capture up to 90% of the carbon dioxide produced in power plants, preventing its release in the
atmosphere.114–117 A CCS project include capturing of the CO2 by separating it from the other
exhaust gases, its transport, and its geological storage in appropriate storing sites, deep below
the seabed. A CCU project aims at recycling carbon dioxide, after its capture, as a carbon source
for chemical production and useful goods.116,118–121 This last technique appears as a more
promising strategy to reduce the atmospheric concentration of CO2 as well as our dependence
from petrochemicals.116,118 Carbon dioxide can be captured from the exhaust gases using
Introduction
13
commercially available technologies.115 The most common capture method is the separation of
CO2 from the exhaust gases flows post-combustion, by chemical absorption of the exhaust gas
in washing solutions, e.g. monoethanolamine (MEA), ammonium hydroxide, and sodium
carbonate. Between them, washing with carbonate solution is the more convenient process in
term of energy losses and solvent regeneration. The most common storage method (in CCS
technology), is the geological storage into underground geological rocks, usually “saline
aquifers” (brine-containing porous rocks) or depleted natural gas and petroleum reservoirs.
Physical reutilisation of CO2 (in CCU technology) include its application in urea production
and in beverage industry,119,122 as inert gas in welding and fire extinguishers, as pressurising
gas in air guns,123,124 and in building materials, as an ingredient in concrete production.118
Chemical utilisation of carbon dioxide as C1-building block includes its incorporation into
products and materials either permanently, or at least for longer periods (see 3.2.3.2).116
Over 80% of the carbon dioxide recovered in Europe by the gas industry is obtained from the
waste gases of chemical processes,125 including fertiliser production, manufacture of industrial
materials such as cement, iron and steel, pulp and paper. Most of the recovered carbon dioxide
derives from the production of ammonia, steam methane reformers and ethylene oxide due to
the high carbon dioxide concentration (98%).
3.2.3.1 Chemical and physical properties of carbon dioxide
Carbon dioxide is a colourless, odourless (at low concentrations), and non-toxic gas with a
higher density than air.126 It has a sublimation point of 78.5 °C and a melting point of 56.6 °C
(triple point at 5.17 bar). Its critical point (T, P) is at 31 °C and 73.8 bar above which it is called
supercritical CO2 (sCO2) and adopts properties midway between a gas and a liquid.127 It behaves
as a supercritical fluid expanding to fill its container as a gas, but with a density like that of a
liquid. Carbon dioxide consists of a sp-hybridized carbon atom covalently double bonded to
two oxygen atoms, resulting in a linear molecular geometry (Figure 8).
116.3 pm
Figure 8. Geometry and bond length of the C–O bond in carbon dioxide.
Carbon dioxide presents two different reaction sites: the carbon is an electrophile, while the
oxygen atoms are nucleophiles. The two bonds are polar, but since it is centrosymmetric, the
Introduction
14
molecule has no net electric dipole. The C–O bonds have a length of 116.3 pm and a dissociation
energy of 532 kJ mol1. These properties make carbon dioxide the thermodynamically most
stable of all binary, neutral carbon compounds (Figure 9) and cause its inertness.128 The unique
properties of CO2, non-toxic, renewable and available in large quantities through techniques
like carbon capture and utilisation (CCU), make it a desirable raw material for qualified
chemical transformations. However, the high inertness and thermodynamic stability
(Gf° = 394.4 kJ mol1) cause a high demand of energy for its chemical conversion according
to the step from the oxidation state of carbon, +4 in CO2, to the value in the target molecule.
Figure 9. Free energy of formation of C1 species versus the oxidation state of carbon.122
Figure 9 shows that every transformation that leads to a reduction of the O/C ratio or to an
increase of the H/C ratio needs energy. As a consequence, chemical fixation of CO2 requires a
significant external energy input by means of temperature, radiation or pressure or by
employing high energy substrates, such as strained heterocycles, hydrogen, unsaturated
compounds or organometallic compounds (Figure 10).119,122,128,129
Introduction
15
non catalysed reaction
catalysed
reaction
Energy[kJ mol-1]
0
-394
high-energy
starting material
low energy
product
e.g.
hydrogen
alkenes
alkynes
epoxide
amines
CO2
e.g.
caboxylic acids
esters
carbonates
lactones
carbamates
Figure 10. Schematic illustration of the energy balance for chemical fixation of CO2 with energy-rich
reactants130
In principle, chemical transformations of carbon dioxide can be classified into two different
categories:122,128,130
1. Low energy processes, characterised by the carbon maintaining its oxidation state of +4,
with insertion of the whole CO2 motif (carboxylation reactions) in the synthesis of
carbamates RR'NCOOR'', carbonates (RO)2CO, urea (NH2)2CO, inorganic carbonates
CO32 or polymeric materials such as polycarbonates and polyurethanes. Moreover, the
formation of carboxylates RCOO (acids, esters, lactones), can be added to this category
even though the C–atom changes his oxidation state to +3. The energy needed for these
reactions is given by electron-rich co-reagents such as HO, amines RR'NH, carbanions
RR'R''C, olefins or alkynes.
2. High energy reactions that result in a reduction of the oxidation state of the carbon to
+2 or lower. In this category, syntheses of formic acid HCOOH, carbon monoxide CO,
formaldehyde H2CO, methanol CH3OH or methane CH4 are included. The external
energy needed to lift the carbon dioxide out of its thermodynamic sink can be given in
form of electrons (electrochemical reduction), hydrogen (hydrogenation), metals of the
main group 1 or 2, radiation or heat (photochemical or thermal reduction).
In order to assure sustainability in the chemical fixation of carbon dioxide, also the amount and
the retention-time of CO2 in the product, have to be evaluated.119,131 The mass of CO2 fixed in
Introduction
16
the product is calculated from the quantity of the product and the stoichiometry of the reaction.
The duration of CO2-retention in the product depends on the stability of the product and on its
applications. If, for example, CO2 is bound into urea used as a fertiliser, large amounts of CO2
are released by decomposition in the ground very quickly after application. On the other hand,
CO2 fixed in polymers and resins remains in the product for years or decades.
3.2.3.2 Industrial processes thate use CO2 as C1-building block
Despite its thermodynamic hurdles, carbon dioxide has been used since the 19th century in many
industrial syntheses.132–136 Some of the most important industrial applications of CO2 are
summarised in Scheme 3.
CO2
or
a
b
d
c
NH3MeOH or CH4H
2
NaOPh: ortho
KOPh: para
PhO-
SolventsPolymers
FertilisersFuel
Solvent
Salicylic acidMonomers
Preservative
Scheme 3. Industrial processes for the use of carbon dioxide as C1-building block. A: urea synthesis
after Bosch and Meiser. B: synthesis of (poly) propylene carbonate. C: synthesis of salicylic acid after
Kolbe and Schmitt. D: reduction with hydrogen.
By far, the most important and quantitatively large use of CO2 is in the synthesis of urea by
thermal reaction with ammonia (Scheme 3a). In 2016, the world’s total urea production was
approximately 90 million tons,137 and is estimated to grow with a rate of 5-7%/year in the next
twenty years due to the growing world population and the associated increasing demand for
synthetic fertilisers.122 The chemical conversion of the two gaseous reactants takes place at 180-
210 °C and 130-300 bar in a two steps process (Scheme 4).132,138,139 Under these conditions
ammonium carbamate is initially formed and produces urea in a following dehydration step.
2 NH3 CO2 H2NCOONH4 NH2CONH2 H2O
Scheme 4. Synthesis of urea from ammonia and carbon dioxide.
Introduction
17
Urea, with a nitrogen content of 46%, represents the most important nitrogen-based fertiliser
essential for the food supply of humanity. Nevertheless, the CO2 fixation time is relatively short
when urea is used as fertiliser, since CO2 is released again after application.
Another important industrial application of CO2 is the carboxylation of epoxides with an
estimated production of 150 kt/y (Scheme 3b).140 Depending on the catalyst used and the
reaction conditions, cyclic carbonates or polycarbonates can be formed.119,122,130,141–143 The
synthesis of cyclic carbonates is typically catalysed by halide salts such as Et4NBr or KI.143–146
They find several applications as solvents in the synthesis of heterocycles, in lithium batteries,
and as building blocks for polymers.119,122,130,142,143 For the preparation of alternating
polyalkylenes cobalt, chromium- or aluminium-salen complexes, Lewis acidic compounds and
zinc salts are suitable.119,141,142 Polycarbonates are applied in car manufacturing, buildings, CDs,
specialty optical, and as pore-forming agents in the ceramic industry.119,122
Further industrial processes for the use of CO2 are the Kolbe-Schmitt reaction for the
preparation of salicylic acids from phenolates (70 kt/y),140 and the production of methane and
methanol via hydrogenative reduction (20 Mt/a) (Scheme 3c and Scheme 3d). Salicylic acid is
a precursor to the pharmaceutical agent acetylsalicylic acid, better known as Aspirin©. With a
production volume between 40 to 50 kt/y,147,148 acetylsalicylic acid is one of the most widely
used active ingredients in the world and can act as an analgesic, anti-inflammatory, antipyretic,
and can be found on list of essential medicines from the World Health Organization (WHO).149
Salicylic acid synthesis relies on the well-known Kolbe-Schmitt synthesis since the mid of the
19th century, in which sodium phenolate is converted at 130-140 °C and 100 bar of CO2
pressure.150 The ortho-selectivity of salicylic acid is given by the chelate effect of sodium
anions. In contrast, by using potassium phenolate, the ratio is shifted towards the para-
hydroxybenzoic acid.151,152 However, the CO2 fixation is not long-term, since it is released
directly after application.
Production of methanol from CO2 is another important industrial application. The typical
feedstock used in the production of methanol is natural gas. In a typical plant, natural gas is
mixed with steam to produce the so-called “syngas” (reaction 1, Scheme 5), a mixture of
hydrogen and carbon monoxide, which is then pressurised and catalytically converted to
methanol, finally distilled to remove water and yield pure methanol (reaction 2, Scheme 5).
Introduction
18
CH4 H2O CO 3 H2 (1)
(2)CO 2 H2 CH3OH H2O
Scheme 5. Production of methanol from natural gas and steam (steam reforming).
Potentially, methanol can also be made from renewable resources such as biomass and CO2,
and using renewable energy.153 If CO2 is reduced to methanol with H2, (reaction 3, Scheme 6),
the reaction requires an extra amount of hydrogen compared to the transformation starting from
CO and is accompanied by a side reaction, the reverse water-gas-shift reaction (reaction 4,
Scheme 6).130
CO2 3 H2 CH3OH H2O (3)
(4)CO2H2 CO H2O
Scheme 6. Production of methanol from CO2 (3) and side reaction (4).
The key factor is the availability of hydrogen. Nowadays, the majority of hydrogen is produced
from fossil fuels by steam reforming (reaction 1, Scheme 5), whereas only a small amount is
produced by water electrolysis, a much greener solution in case renewable electricity is used,
but yet more expensive.154,155 Currently, the methanol production from CO2/H2 is technically
competitive with the industrial production from syngas, but not economically convenient.
Therefore, the preferred method to overcome these issues and producing methanol is adding
CO2 (up to 30% of total C) to the syngas mixture to enhance the rate of reaction and balance
the hydrogen/carbon ratio to the desired stoichiometry.119,128 Methanol is employed in various
applications.156 To name a few, it is used as fuel itself or derivatised, e.g. dimethyl ether, in the
production of methyl tert-butyl ether (MTBE), in the transesterification of vegetable oils to
yield FAMEs, for the production of formaldehyde or acetic acid, in the production of
(poly)methylmethacrylate (PMMA) and as solvent. For fuel applications, there is no long-term
CO2 fixation, as CO2 is liberated during the combustion. Nevertheless, long-term CO2 fixation
arises in other applications such as formaldehyde, PMMA, and polymers obtained from acetic
acid.
Particularly interesting are reductive hydrogenations of carbon dioxide, which provide
potentially valuable solutions for two different problems: the recycling of CO2 and the storage
of H2 as chemical energy for electricity generated in excess from renewable sources. Production
Introduction
19
and consumption of electricity indeed, have to be constantly balanced. While energy from coal,
gas or nuclear power plants is regularly generated and constantly available, the energy
production from wind or solar power plants varies both locally and temporally. In order to
harmonise these peaks and valleys, it is very important to develop an efficient form of storage
for electrical energy, which is easily available when the request increases. Mechanical storage
or storage in batteries fail when they need to supply high demands.122,157 Therefore, converting
CO2 and H2 into energy-rich compounds is currently the preferred storage method. If the
hydrogen would be electrolytically generated in events of excess of electricity, this strategy
would also result very cheap and competitive.
Introduction
20
4 Compounds and chemical procedures relevant to this work
In the present chapter, an introduction to substrates and products of relevance for the projects
described in “results and discussion” is given (4.1, 4.2, 4.3).
The last part of this chapter (4.5) describes the synthetic procedures adopted in the projects
presented in “results and discussion”.
4.1 Surfactants
Surfactants are amphiphilic organic molecules that lower the surface tension between two
different phases, liquid/ liquid, liquid/gas, liquid/solid, etc.56,158 They consist of a hydrophobic
part, the tail, usually a straight or branched hydrocarbon chain, and a hydrophilic part, the head,
a polar or ionic portion (Figure 11). Thus, a surfactant contains, both, a water-soluble and a
water-insoluble component, and it can diffuse in water and adsorb at the interface with air or
with oil (in the case of a water/oil mixture). The tendency to accumulate and adsorb at interfaces
is a fundamental property of surfactants. The stronger the tendency, the better the surfactant.
Due to this property, surfactants are commonly used as detergents, emulsifiers, dispersants,
wetting and foaming agents allowing hydrophobic compounds to mix with or “dissolve” in
water and being washed away.
hydrophilic head
hydrophobic tail
Figure 11. Structure of a surfactant molecule.
When the concentration of the surfactants in solution is low, the majority of the monomers
accumulates at the interface in a single layer with the heads facing the water phase, while a few
other monomers are randomly dispersed in solution. At a certain concentration, the monomers
start to aggregate to form structures called micelles (Figure 12). The concentration at which
micelles start to form is called critical micellar concentration (cmc), and is an intrinsic property
of each surfactant, depending on the length and shape of the chain, as well as on the size of the
head, varying from surfactant to surfactant. Below the cmc the surface tension of the liquid
decreases with increasing surfactant concentration because the number of surfactants at the
interface increases. Above the cmc, the surface tension of the solution is constant because the
Introduction
21
interfacial surfactant concentration does not change any more. The driving force behind the
aggregation is the tendency of the hydrophobic chains to minimise their contact with the water
aggregating in shapes where the chains are hidden from the water, pointing toward the inside
of the micelle, while the heads are directed towards the solvent, thus reducing the free energy
of the system.
Water
Air
micelle
single layer at the interface liq-gas
monomer
Figure 12. Behaviour of the surfactants in water: single layer of monomers at the interface, dispersed
monomers in solution and formation of micelles.
Historically, the first detergent-like compounds were made starting from natural fats. Evidence
of soap making showed that already ancient Babylonians (2800 BC) used ashes, boiled fats,
and soda from plants to wash their body and clothes.159 Other records show that also ancient
Egyptians and Romans used soaps in their tradition.160 Nowadays, surfactants are mostly
synthetically made from petroleum derivatives such as ethylene, and from natural raw materials
such as sugar and vegetable oils. The global surfactants market in 2017 accounted for about
$44 billions.161
The industrial development of many surfactants started in the mid-1800s with the prospering
of the textile industry, which needed surface-active substances, dispersants, and softeners in the
processes involved in the manufacturing of raw cotton and wool.56 Until the 1930, oils and fats
were almost exclusively the raw materials for surfactants synthesis. The first coal-based
surfactant, diisopropylnaphthalene sulfonate, was synthesised by Gunther at BASF in 1917.
Starting from the 1930s, with the exploitation of coal and petroleum as raw materials, the
surfactant industry split from the textile and developed as an independent business synthesising
new, special types of surfactants. Long-chain alkenes and alkanes obtained from Fischer-
Introduction
22
Tropsch processes were used in Germany for production of surfactants. With the spreading of
petroleum refining, also low molecular mass olefins became available as starting materials.
Ethylene found applications for the synthesis of ethylene oxide, the basic building block of non-
ionic surfactants and propylene was used as starting material for hydrophobic groups. Propylene
trimer and tetramer were respectively employed in the synthesis of isononylphenol, the starting
material for non-ionic surfactants, and in the synthesis of branched-chain dodecyl benzene, the
starting material for alkyl benzene sulfonates.
In 1930, Schöller and Wittwer at the I.G. Farben in Ludwigshafen developed the ethoxylation
process, in which ethylene oxide adds to a substrate.162 This reaction settled the basis for the
synthesis of a new class of compounds, the nonionic surfactants ethoxylates. Later, Schrauth
accomplished the high-pressure catalytic hydrogenation of fatty acids to fatty alcohols, while
Bertsch obtained primary alkyl sulfates by sulfating fatty alcohols, which appeared on the
market already in 1932 as soap-free detergent.163–165 In 1927 the first cationic surfactant, N-
acylaminoethyltrialkyl ammonium salt, was obtained,56 and a few years later their disinfectant
properties were discovered.166,167 Since then a series of cationic surfactants were developed:
alkyldimethylbenzyl ammonium salts, betaines (Du Pont), ampholytes (Th. Goldschmidt).
From 1960 the strong demand for biodegradability of surfactants determined major changes in
the surfactants industry (see 4.1.2).
4.1.1 Classification
Nowadays, surfactants are generally classified based on their polar heads. If the head is
negatively or positively charged the surfactant is called anionic or cationic. If the head has no
charge, the surfactant is called non-ionic, whereas if it contains both a positive and a negative
group is called zwitterionic. Anionics are the most widespread among all the types of
surfactants, mainly for historical reasons, but in the last two decades, due to lower toxicity and
better biodegradation, the market of non-ionic surfactants saw an exponential growth. Today,
the two classes of anionic and non-ionic surfactants represent circa the 90% of all the surfactant
market.161
4.1.1.1 Anionic surfactants
Anionic surfactants are currently the most important group with a global market share of
49%.168 They are the most widely used class of surfactants in industrial applications due to their
Introduction
23
relatively low cost of manufacture and are mainly used in cleaning products such as household
detergents.169 They are often skin irritants, therefore, government regulations limits their use in
personal care products.170 Better detergency is obtained with a linear alkyl chain of 12-16
carbon atoms, rather than a branched one. This linear chain, also assures a better
biodegradability.56,158 The most common hydrophilic groups are carboxylates, sulfates,
sulfonates and phosphates. In water the anionic groups can react with the positively charged
water hardness ions (calcium and magnesium) and be deactivated. Thus, when this kind of
surfactants is used as detergent, other ingredients may be added to prevent partial deactivation.
The most used counter ions are sodium and potassium to assure water solubility, or calcium and
magnesium to promote oil solubility. When both oil and water solubility have to be assured,
amine/alkanol amine salts are used as counter ions.171 Figure 13 shows some structures of the
most common surfactant types.
alkyl sulfate and alkyl ether sulfate
alkyl phosphate and alkyl ether phosphate
alkyl ether carboxylate
dialkyl sulfosuccinate linear alkyl benzene sulfonate
carboxylate
Figure 13. Some representative structure of anionic surfactants.
The most common type of anionic surfactant are the carboxylates, the so-called soaps, obtained
by saponification of natural oils and fats. Beef tallow, palm oil, coconut oil, palm kernel oil are
the most used naturally occurring raw materials, and to less extent, olive oil, peanut oil and lard.
Triglycerides are the main component (~ 91%) in tallow, palm/palm kernel/coconut oil and are
the more important starting material for the manufacturing of soaps, because they can be easily
transported and stored without any quality losses. Quality, transport and storage are important
factors in the soap industry, as well as the recovery of the main by-product of the saponification
Introduction
24
of the triglycerides, glycerol. Classical saponification of triglycerides produces three molecules
of soaps and one molecule of glycerol (Scheme 7).
3 NaOH
R1CO2Na
R2CO2Na
R3CO2Na
natural oil or fat soap glycerol
R = fatty acid alkyl group
Scheme 7. Saponification of triglycerides.
Alkyl benzene sulfonates have been the first synthetic detergents introduced in the 1930s as
replacement for the limited animal fats and are today the second most produced anionic
surfactants after soaps. They are made by sulfonation of alkyl benzenes with sulfur trioxide
(SO3), sulfuric acid (H2SO4), or chlorosulfuric acid (ClSO3H). The first step is the sulfonation
of alkyl benzene with a sulfonating agent to give pyrosulfonic acid, which spontaneously reacts
to give sulfonic acid (Scheme 8). The sulfonic acid is then neutralised with caustic soda, to give
the alkyl benzene sulfonate salt. Due to the bulky alkyl substituents, the sulfonation happens
almost exclusively in para position. Alkyl benzenes are usually obtained by alkylation of
benzene with alkenes or alkyl chlorides, using HF or AlCl3 as catalysts. Sulfonates may be
found in numerous personal-care and household-care products, e.g. soaps, shampoos, laundry
detergent, liquid dishwashing etc. Traditionally, alkyl benzene sulfonates were highly branched
and non-biodegradable (ABS), but following environmental concerns, they have been replaced
by biodegradable linear chain alkyl benzene sulfonates (LABS or LAS). Other sulfonate
surfactants are -olefin sulfonates, paraffin sulfonates, alkyl naphthalene sulfonates.
2 SO3
2NaOH
Scheme 8. Sulfonation of alkyl benzenes to produce alkyl benzenes sulfonates.
Sulfates are the largest class of synthetic anionic surfactants widely used in detergent
formulations. These are salts of acidic sulphuric acid esters, where the sulphur is bonded via an
oxygen atom to the hydrophobic residue. The labile ester bond splits easily at low pH where
the hydrolysis is autocatalytic. Due to their chemical instability, they are nowadays substituted
Introduction
25
by sulfonates in many applications. Raw materials are both linear and branched alcohols with
typically 8 to 16 carbons, or when alcohol ethoxylates are used as intermediates, they are
usually fatty alcohols with two or three oxyethylene units. The most common sulphated
surfactant is sodium dodecyl sulfate (SDS), obtained by neutralisation of the dodecylmonoester
of sulphuric acid with soda. The natural raw material is the dodecyl alcohol (coconut oil).
Sulfates have very good foaming properties and have a low toxicity to skin and eye, thus being
a popular ingredient in hand- and dishwashing formulations and shampoos.
Phosphate-containing anionic surfactants are usually prepared by reacting alcohols or
ethoxylates with phosphorus pentoxide, followed by neutralisation. The reaction leads to a
mixture of monoalkyl and dialkyl esters of phosphoric acid. All commercial phosphate
surfactants contain both mono- and diesters in different ratios, depending on the amount of the
reactants and the amount of water present in the reaction mixture, which generates differences
in the physicochemical properties. Phosphate surfactants have anti-corrosion and bactericidal
properties, they are easily soluble in hard water and have good wetting and dispersing
properties, thus they are widely employed in metal-working industry, as acid-adjusted cleansing
agents, e.g. for vehicles or swimming baths.
4.1.1.2 Non-ionic surfactants
Non-ionic surfactants have oxygen-containing hydrophilic groups, covalently bonded to
hydrophobic structures. The hydrogen bonds between the oxygen atoms of the chain and the
water determine the solubility of non-ionic surfactants in water. The degree of hydration and
thus, the solubility of the surfactants in water decreases by increasing the temperature. Non-
ionic surfactants are less sensitive to the hardness of water compared to anionic surfactants, and
foam less strongly; they have better cleaning properties and less toxicity, environmental
compatibility and ability to be used in food processing. The cmc of non-ionic surfactants is
circa two orders of magnitude lower than the corresponding anionic analogues of the same
length chain. Thanks to these properties, non-ionic surfactants applications, e.g. in household
detergents, personal-care products, food processing, grew exponentially during the last years,
affecting the surfactants market that is nowadays dominated by both anionic and non-ionic
surfactants.168,172 Figure 14 shows the structures of a few representative non-ionic surfactants.
Introduction
26
fatty alcohol ethoxylate
fatty acid/amide ethoxylate
fatty amine ethoxylate
alkyl glucoside
N-oxide nalkyl phenol ethoxylate
Figure 14. Some representative structure of non-ionic surfactants.
In the vast majority of non-ionic surfactants, the polar group is a polyether consisting of
oxyethylene units, obtained by ethoxylation of a fatty carbon chain under alkaline conditions.
The starting materials are usually fatty alcohols, alkyl phenols, fatty acids or fatty amines, linear
or branched, with a C12-C18 chain. Fatty alcohol ethoxylates (FAEO) dominate this class of
compounds. They are used in liquid and powder detergents, as stabilisers of oil-water
emulsions, and in several industrial applications. Alkyl phenol ethoxylates are another widely
used type of ethoxylate, the most common ones deriving from nonylphenols. Despite being
cheap, these surfactants suffer from biodegradability and potential toxicity (the by-product of
degradation is nonylphenol, which has considerable toxicity, see 4.1.2). Fatty acid esters of
sorbitan (Spans) and their ethoxylated derivatives (Tweens) are other commonly used non-ionic
surfactants. Alkyl glucoside surfactants have been synthesised by reaction of fatty alcohols with
glucose.
Amine oxide, or N-oxides of tertiary amines, are compounds where an oxygen atom is datively,
rather than covalently, bonded to a nitrogen atom and are obtained by reaction of tertiary amines
with hydrogen peroxide (Scheme 9).173 Amine oxides are can be classified as non-ionic,
zwitterionic, and cationic: in neutral aqueous solution they are regarded as non-ionic, but when
protonated in an acidic environment, they are classified as cationic. Sometimes N-oxides are
written as N+O, thus the classification as zwitterionic.
Introduction
27
Scheme 9. Synthesis of N-oxides by reaction of a tertiary amine with hydrogen peroxide.
N-oxides are insensitive to water hardness, they have good foaming properties, are mild to the
skin and thus are employed in dishwasher detergents, shampoos, conditioners, soaps. Amine
oxides are not known to be carcinogenic or toxic to the reproductive system. Moreover, they
have a very low bioaccumulation potential in aquatic species. Increasing demand for mild
surfactants, especially in personal care and home-cleaning products, is driving the market of N-
oxides.174 Moreover, products containing amine oxides offer higher performances in hard water
and high temperatures.
4.1.1.3 Cationic surfactants
Cationic surfactants are generally nitrogen-based compounds with the nitrogen atom carrying
the positive charge (Figure 15). Amine and quaternary ammonium salts (quats) are the most
common cationic surfactants, while phosphonium and sulfonium salts also exists, but are much
less industrially relevant. Amines can act as cationic surfactants only in their protonate state,
thus are ineffective at high pH. Instead, quaternary ammonium compounds are not pH sensitive.
Ethoxylated amines (Figure 14) possess properties belonging to both cationic and non-ionic
surfactants: the longer is the polyoxyethylene chain, the more non-ionic the character of the
compound.
Cationic surfactants are generally compatible with most inorganic ions and hard water, stable
to pH changes (both acidic and basic). They are incompatible with most of the anionic
surfactants, but they are compatible with non-ionics. The cmc of the cationic surfactants is close
to the one of anionics with similar alky chain length. Cationic surfactants tend to adsorb at
negatively charged surfaces, and thus, they are mainly used as anticorrosive agents for steel,
dispersants for inorganic pigments, antistatic agents for plastics, fertilisers and bactericides.158
Introduction
28
fatty amine salt
alkyl quat
dialkyl quat
ester quat
Figure 15. Structures of typical cationic surfactants.
The most common cationic surfactants are the alkyl quats with only one long alkyl group, such
dodecyl trimethyl ammonium chloride. Non-ester quaternary ammonium salts are usually
prepared via reaction of a tertiary amine with a suitable alkyl halide, usually methyl chloride,
or bromide, or, very commonly, also benzyl chloride. A widely used cationic surfactant is alkyl
dimethyl benzyl ammonium chloride. The choice of the alkylating reagent determines the
surfactant´s counter ion (Scheme 10a). The tertiary amine is usually prepared from a fatty acid.
It reacts with ammonia at high temperatures yielding the corresponding nitrile, via an amide
intermediate that is subsequently hydrogenated to the primary amine (Scheme 10b). The
secondary amine can be produced directly from primary amine and nitrile in a one-pot route
that proceeds through the intermediate imine, where ammonia is continuously removed from
the mixture in order to promote the secondary amine formation (Scheme 10c). Primary and
secondary amines can be methylated to tertiary amine, e.g. by reaction with formaldehyde under
reducing conditions (Scheme 10d).
Introduction
29
H2
2 H2
- H2O
H2
a
b
c
d
Scheme 10. Synthesis of the alkyl quats and tertiary amines.
The dialkyl quats are less soluble in water than the monoalkyl and more soluble in hydrocarbon
solvents, still only dispersible in water. The ester quat represents a more biodegradable
alternative to the dialkyl since the ester groups can be cleaved in water, which leads to a more
rapid breakdown of the compounds. Ester quats are usually prepared by esterification of a fatty
acid with amino alcohol, followed by N-alkylation (Scheme 11).
H2O
(CH3)2SO4
2
Scheme 11. Synthesis of dialkyl esters.
4.1.1.4 Zwitterionic surfactants
Zwitterionic surfactants contain both a positively and negatively charged group as hydrophilic
group, with the positive charge almost exclusively deriving from an ammonium moiety, while
the most common negative part is by far a carboxylate group. The main characteristic of the
zwitterionic surfactants is their change of charge depending on the pH of the solution. In acidic
solutions, they acquire a proton, becoming positively charged and assuming characteristics
similar to cationic surfactants. In basic solutions, they become negatively charged, assuming
characteristics similar to anionic surfactants. At a specific pH, the isoelectric point, they
maintain the charge separation and their properties resemble the ones of non-ionic surfactants.
The change in pH affects some of their surfactant properties such as wetting, detergency and
foaming, thus their applications.
Introduction
30
The most common surfactants of this category are the N-alkyl betaines, derivatives of
trimethylglycine. Betaines are insensitive to water hardness, have excellent compatibility with
other surfactants, forming mixed micelles. They have exceptional dermatological properties
and low eye irritation, thus are frequently used in personal-care products (shampoo, cosmetics).
N-alkyl betaines are usually prepared by reaction of a long-chain tertiary amine with sodium
chloroacetate, and sodium hydroxide (Scheme 12a). A betaine derivative, amidobetaine, is also
a zwitterionic surfactant. Its synthesis, analogously to the one of the betaine, starts from an
amidoamine (Scheme 12b).
RN(CH3)2
RCONH(CH2)3N(CH3)2
ClCH2COOH
ClCH2COOH
NaOH
NaOH
a
b
Scheme 12. Synthesis of betaines and amidobetaines.
4.1.2 Dermatological, toxicological and environmental aspects
Surfactants are in contact with many human activities, from agricultural to commerce, to home,
as cleaning and deterging products. Many of them enter in contact with human skin, via
shampoos, soaps, personal care products and some of them could be ingested, even if only as
residues from dishwashing. Thus, their effect on living organism has to be investigated before
introducing a new surfactant in the market. Moreover, surfactants are discharged after their use
into the sewers, and eventually end in rivers and seas affecting the aquatic environment and
life. Thus, also their biodegradability and toxicity are of vital importance and concern and have
to be evaluated for every surfactant.
Furthermore, many dermatological problems can be connected with the use of surfactants, due
to exposure of unprotected skin to surfactant solutions.56 Many dermatological studies have
been made that connect the skin irritation with the chain length of surfactants. A study on alkyl
glucosides, compared chain lengths from C-8 to C-16 showing that the maximum irritation to
the skin was obtained with the C-12 surfactant. Incorporation of oligoglycol residues between
the head and the chain (e.g. fatty acid alcohol ether sulfates, fatty alcohol carboxylates) reduces
the skin irritation activity. The presence of aromatic rings in the hydrophilic head increases the
Introduction
31
irritation effect, whereas, nitrogen-containing surfactants irritate the skin less. In this context,
betaines and amine oxides are extremely low irritating to the skin, and can be used as co-
surfactants to reduce the irritant action of anionic compounds.
Three factors are extremely important when evaluating the environmental impact of a
surfactant: aquatic toxicity, biodegradability and bioaccumulation.56 Aquatic toxicity is
measured on fish, daphnia, and algae, as LC50 (for fish) and EC50 (for daphnia and algae) values.
LC and EC stand for lethal and effective concentrations respectively. Biodegradation is the
aerobic degradation carried out by bacteria in nature, through a series of enzymatic reactions
that ultimately degrade the surfactant to carbon dioxide, water and oxides of other elements.
The rate of biodegradation can vary from 1-2 h (fatty acids), to 1-2 days (linear alkyl benzene
sulfonates), to several months (branched alkyl benzene sulfonates) and it depends on the
concentration of the surfactant, the pH of the environment and the temperature. Evaluating the
degradation of a surfactant means taking into consideration both primary and ultimate
degradation. Primary degradation consists in a structural change in the molecule and causes a
loss in surface activity of the surfactant. It is used to predict if a compound persists in the
environment, forming the typical foams on rivers. Ultimate degradation is the conversion in
carbon dioxide and is a function of time. If the surfactant does not undergo biodegradation, it
persists in nature (bioaccumulation).
Concerns about the ecological impact of surfactants have guided legislation and directives for
their use starting from the 1960s, and are today extended to all surfactant formulations. One of
the earliest detergent legislation was the German detergent law of 1961 that intended to regulate
the environmentally compatible composition of detergents and cleaners on the German
market.175,176 One of the main problems was the visible foam on the water surface of German
rivers due to the high concentration of tetrapropylene benzene sulfonate (TPS) and other
branched alkyl benzene sulfonates (ABS), surfactants widely used from the 1950s, whose
branched chains were very slowly degraded by bacteria.177,178 Starting from the mid-sixties,
they have been substituted by linear alkyl benzene sulfonates (LAS). By law, in most countries
today, the surfactant must have side chains which are not branched to be degraded more
rapidly.175 Phosphate detergents, which were widely used as additives to other detergents to
soften the water, resulted to be excellent fertilisers for algae in rivers and oceans, generating an
algae bloom (eutrophication) that depleted the oxygen in the water, causing the death of fishes.
Phosphates were then replaced with other softeners such as sodium carbonate. Also in the
Introduction
32
1960s, nonylphenols (NP) and nonylphenol ethoxylates (NPEs) started to rise big
environmental concerns. Incomplete degradation of NPE in the aquatic environment produces
NP, which resulted to be highly toxic and very persistent in the environment, taking from
months to years to degrade in surface water, soils and sediments.177,179–183 Moreover,
nonylphenol is believed to interact directly with the oestrogen receptors, mimicking the
hormone estradiol, and affecting the natural hormonal balance of living organisms.184,185 The
production and use of NP is nowadays prohibited in Europe, and they have been replaced by
more expensive alcohol ethoxylates.186 Moreover, nonylphenols have also been included in the
list of priority hazardous substances for water, in the Water Frame Directive and in the 3rd draft
Working Document on Sludge of the EU.184
The increasing demand for milder and greener surfactants has re-opened the pathways that use
renewable resources, mainly plant-based, as raw materials for surfactants synthesis. However,
the oleochemical and the petrochemical pathways can lead to identical products, equal also in
toxicity, regardless of the synthesis path. Yet, from the CO2-emissions point of view, surfactant
production starting from renewable raw materials is preferred. Various renewables such as
triglycerides or carbohydrate sources can serve as raw materials. Triglycerides, regardless of
their source, are one of the most used and can undergo full or partial hydrogenation, hydrolysis,
trans-esterification and other specific modifications to yield various surfactants and/or
surfactant precursors (e.g. fatty acid methyl ester, methyl ester sulfonate, fatty alcohol, fatty
amines, fatty chlorides).187 A remarkable class of triglyceride-based surfactants are the methyl
ester sulfonate (MES), which offers an environmentally friendly and viable alternative to LAS,
due to their high biodegradability and excellent detergency performances.188
Alkylpolyglucosides, glucose derivatives of fatty alcohols, are remarkable green surfactants
among the many carbohydrate-based surfactants: they are easily biodegradable, have good
compatibility with skin, eyes and mucous membranes and in combination with other surfactants
can even reduce their irritant effects.189 In addition, they are characterised by light colour, good
odour and result very appropriate in cosmetics, creams and other personal-care products.
However, most of the renewable-based surfactants derive from vegetable oils, widely used for
culinary purposes. An eco-friendly synthesis of surfactants starting from renewable sources
would be possible if the raw materials were not in competition with land for food or agricultural
uses. Among the natural resources that would be suitable candidates for surfactants synthesis,
cashew nut shell liquid (CNSL) represents the perfect choice. It is a waste by-product of
Introduction
33
industrial production, consisting of a mixture of phenolic compounds clothed with a linear alkyl
chain, thus evoking the structure of surfactants.
4.2 Tyrosinase inhibitors
Tyrosinase is a key enzyme in the pigment synthesis that controls the rate-limiting step in the
production of melanin (Scheme 13). It is an oxidase and catalyses the oxidation of the amino
acid tyrosine (I) to the corresponding diphenol (II), inserting a hydroxyl group in ortho-position
to the first one. A second oxidation of the two hydroxyl groups by tyrosinase leads to the o-
dopaquinone (II). The o-quinone undergoes several other reactions that lead to the production
of melanin.190
Tyrosinase TyrosinaseMelanin
O2 H2O O2 H2O
III III
Scheme 13. Conversion of tyrosine in o-quinone.
Uncontrolled tyrosinase activity can lead to an increased melanin synthesis and consequent skin
disorders. Therefore, in medical and cosmetic industries, the development of tyrosinase
inhibitors is an important field of research.191,192 Tyrosinase also catalyses the oxidation of
phenolic compounds into quinones in fruit and vegetables, giving an undesirable taste and
colour and decreasing the digestibility as well as the amino acid content of the products. Thus,
also in food industry, there is a high interest in developing tyrosinase inhibitors that avoid such
effects. Several tyrosinase inhibitors have been identified and discovered in natural sources or
chemically synthesised.191–195 Generally, the inhibition mechanism happens according to one
of the following pathways:191
Reduction of the dopaquinone by the action of reducing agents such as ascorbic acid that is
able to reduce back o-dopaquinone to dopa.
o-Dopaquinone scavengers such as sulphur-containing compounds that react with the o-
dopaquinone to form colourless compounds.
Non-specific inactivation of the enzyme, due to the denaturation of the tyrosinase by acids
or bases.
Introduction
34
Specific inactivation of the enzyme, reversible or irreversible. “Suicide” inhibitors (or
mechanism-based inhibitors) are molecules that form covalent bonds with the enzyme,
irreversibly deactivating it and catalysing its suicide reaction. Other compounds can
reversibly bind to tyrosinase, reducing its catalytic activity.
Among the different types of compounds, only specific tyrosinase inhibitors are considered
“true inhibitors” since they bind to the enzyme and deactivate it. Other compounds that can
intervene in any other step of the melanin synthesis, and not necessarily on the tyrosinase
enzyme, are also called inhibitors but will not be considered here. The modes of inhibition by
true inhibitors can be classified in four types: competitive, uncompetitive, mixed type
(competitive/uncompetitive) and non-competitive. A competitive inhibitor binds to the active
site of the enzyme, by mimicking the substrate of the tyrosinase and prevents the formation of
the enzyme-substrate complex. A competitive inhibitor might be a copper chelator such as
phenols or polyphenols. An uncompetitive inhibitor can bind only to the complex enzyme-
substrate, and a mixed type inhibitor can bind to both, the complex or the free enzyme, with
different equilibrium constants. A non-competitive inhibitor can be considered a special case
of the mixed type: it binds to the free enzyme and the complex, with the same equilibrium
constant. Inhibitory activity is usually expressed as the concentration of the inhibitor, necessary
to inhibit half (50%) of the tyrosinase activity, and is given as IC50 value in mg/ml. The IC50
value of a new inhibitor strongly depends on the assay conditions, that varies for different assay
methodologies (substrate concentrations, incubation time, tyrosinase batch). Thus, the IC50 of
the new inhibitor, is usually compared to the one of a positive standard: kojic acid. The relative
inhibitory activity (RA), calculated by dividing the IC50 value of kojic acid by the one of the
new inhibitor is an absolute value used to compare the inhibitory activity of different
compounds.
4.3 Alkynes
Nowadays, over a thousand naturally occurring alkynes have been discovered and reported,
often present as polyynes.196 According to Ferdinand Bohlmann, the first isolation of a naturally
occurring alkyne dates back to 1826 when dehydromatricaria ester was isolated from
Artemisia.197 Other representatives of naturally occurring alkynes are 8,10-octadecadiynoic
acid, Thiarubrine B, Neocarzinostatin and more (Figure 16). 8,10-Octadecadiynoic acid is
isolated from the root bark of the legume Paramacrolobium caeruleum and can serve as a
Introduction
35
photopolymerizable unit in the synthesis of phospholipids. Thiarubrine B is isolated from the
Giant Ragweed (Ambrosia Trifida), a plant used in herbal medicine and has have antibiotic,
antiviral, and nematocidal activity. The neocarzinostatin is an antitumor antibiotic produced by
Streptomyces.
hystrionicoxitin
neocarzinostatin dehydromatricariaester
Figure 16. Examples of naturally occurring alkynes.
There are several possible ways to synthesise alkynes. Commercially, the most important
alkyne is acetylene, produced by partial oxidation of natural gas. It is used as a fuel and
precursor to other compounds (see 4.3.2.1). Propyne is prepared by thermal cracking of
hydrocarbons. Higher homologues of acetylene and propyne can be prepared by dehalogenation
of vicinal dihaloalkanes or vinyl halides (Scheme 14a).198 Likewise, alkynyl anions, formed by
deprotonation of terminal alkynes with a strong base (e.g. BuLi or NaNH2) can couple with
primary alkyl halides to form the corresponding internal alkynes (Scheme 14b).199,200
Alternately, they can be formed from aldehydes or ketones via the Seyferth-Gilbert
homologation and Bestmann modification. Herein carbonyl compounds react with dimethyl
(diazomethyl) phosphonate in the presence of a base yielding alkynes (Scheme 14c). Later, a
safer approach was developed for the synthesis of alkynes from aldehydes, which uses a more
stable sulfonyl azide instead of tosyl azide, more suitable for base-labile substrates such as
enolizable aldehydes.201,202
Introduction
36
base
M+B-
-BH
R'-X
a) dehalogenation of vicinal dihaloalkanes
b) alkylation from alkynyl anions
c) Seyferth-Gilbert homologation and Bestmann modification
Br2 base
Scheme 14. Synthesis of alkynes.
4.3.1 Physical and chemical properties
Alkynes are unsaturated hydrocarbons containing at least one triple bond according to the
general empirical formula CnH2n-2. Ethyne (or acetylene) with n = 2 represents the simplest
representative of this class of compounds. It is a colourless and odourless gas with a sublimation
point at -84 °C. Propyne (bp.: -23.2 °C) and 1-butyne (bp.: 8.1 °C) are also gaseous under
standard conditions, while 2-butyne (bp.: 27 °C) and the other representatives occur in liquid
form. The chemical properties of the alkynes are affected by the triple bond. Each of the two
carbon atoms in acetylene possesses one sp-hybridised orbital plus two p-orbitals. By
overlapping of the two sp-orbitals the C–C -bond is formed, while the two mutually
orthogonal p-orbitals on each carbon overlap forming two -bonds, giving a total of three bonds
(Figure 17). The remaining sp-orbitals each bind with another atom, for example, hydrogen.
The -bond results in a linear geometry for alkynes: H–C≡C bond angles are 180°, with a
distance of 120.3 picometers, much shorter than the C–C distance in alkenes.
106.1 pm
120.3 pm
180°
Figure 17. Geometry and orbital representation of the triple bond of acetylene.203
Introduction
37
Due to the prevalent s-character of the sp-hybrid orbitals, alkynes have a high dissociation
energy of ~960 kJ/mol (C-C double bond ~700 kJ/mol).204 Another consequence of the
hybridisation is the high acidity of terminal alkynes. In fact, the pKa value for acetylene is 25,
whereas for ethene it is around 44, and for ethane it is around 50 (see 4.5.7).
4.3.2 Typical reactivity
The high electron density and acidity of the triple bond of alkynes determine the reactivity of
this class of compounds. Alkynes can be hydrogenated into the corresponding alkanes with the
help of hydrogenation catalysts, often palladium or platinum (Scheme 15a). Using modified
catalysts (e.g. Lindlar catalyst) the hydrogenation can be stopped at the stage of the Z-alkene
(Scheme 15b). The Lindlar catalyst, consist of three components: Pd deposited on CaCO3 and
then treated with lead acetate and quinoline.205 In contrast, the E-isomer can be obtained by
electron reduction of the alkyne with lithium or sodium in liquid ammonia (Scheme 15c).
H2, Pd/CaCO3 (5%)
Pb(OAc)2 Chinolin
Li or Na, NH3(l)
H2, [cat]
a) complete reduction of alkynes to alkanes
b) partial reduction with Lindlar´s catalyst
c) partial reduction with Li or Na
Scheme 15. Typical reactivities for alkynes.
Due to the high electron density of the triple bond, alkynes are subject to electrophilic attack,
with a regiochemistry that follows Markovnikov´s rule resulting in an anti addition. The
addition of hydrogen halides provides vinyl halides, or geminal dihaloalkanes in an excess of
hydrogen halide (Scheme 16a). Both of the steps follow Markovnikov´s rule, and the hydrogen
will be attached to the carbon with the higher number of hydrogens, leaving the halogen to the
most substituted carbon. Likewise, halogens can be added to a triple bond with a reaction
proceeding via cyclic halonium ion. If only one halogen molecule is used, a trans-dihalide is
formed, while under excess of halogen both of the two carbons of the triple bond will be
Introduction
38
substituted (Scheme 16b). Hydration of alkynes with water, usually catalysed by mercury ions,
follows Markovnikov´s rule and form enols that spontaneously tautomerise to ketones.
Terminal alkynes give methyl ketones (Scheme 16c).
X2
HX
HgSO4
H2O, H2SO4
X2
HX
a) addition of hydrogen
b) addition of halogens
c) hydration
Scheme 16. Electrophilic addition to the triple bond.
Most hydrogen halide reactions with alkynes occur following a Markovnikov addition.
However, there are two reactions where the Markovnikov selectivity can be reversed: the
radical addition of hydrogen halides to terminal alkynes and the hydroboration-oxidation
reaction. The presence of a radical initiator, or heat, leads to an anti-Markovnikov product
formation and the resulting alkene can be both cis and trans (Scheme 17a). Likewise, a
hydroboration-oxidation reaction selectively produces anti-Markovnikov products in which the
boron attacks the less substituted carbon. Here a syn addition is observed, and the resulting
product is a cis-alkene (Scheme 17b). In the case of terminal alkynes an aldehyde is obtained.
To stop the reaction at the alkenyl-borane stage and avoiding a second hydroboration, a bulky
borane reagent must be used. The second step is the oxidation to a vinyl alcohol and subsequent
tautomerisation by addition of a basic solution (e.g. aqueous sodium hydroxide). When instead,
the alkenyl intermediate reacts with bromine, the corresponding brominated alkene is formed.
Introduction
39
R2BH
HX
a) radical addition
b) hydroboration
radical initiator
H2O2, HO-
MeCO2D
Br2
MeO-
Scheme 17. Anti-Markovnikov addition to alkynes.
Terminal alkynes are comparatively acidic and by removal of the proton by strong bases such
as organolithium, Grignard compounds, or sodium amide, an acetylide anion is formed.
Acetylide anions are strong bases and strong nucleophiles and can undergo nucleophilic
substitutions or coupling reactions (Scheme 18a). Acetylide anions can displace leaving groups
such as halides from other organic compounds, mostly primary halides, in substitution
reactions. Alternatively, they can couple with aldehydes and ketones to form alkoxides, which
under protonation will give propargyl alcohols. Under oxidative conditions and in presence of
coppers salts, terminal alkynes can be dimerised to the corresponding symmetrical diynes, the
so-called Glaser coupling, Eglinton, and Hay coupling (Scheme 18b).
M+B-
a) Nucleophilic substitution and nucleophilic addition
-BH
R'-X
R'R''C=OH+
[CuI or CuII]
c) Glaser, Hay, Eglinton coupling
O22
Scheme 18. Nucleophilic reactivity of alkynes.
Introduction
40
4.3.2.1 Acetylene: production and industrial uses
Acetylene was accidentally discovered in 1836 by Edmund Davy, while attempting the isolation
of potassium.206 Until the 1950s, it was produced from coal through the calcium carbide process
that requires high temperatures (2200 °C) and an electric arc furnace. It consists of a hydrolysis
of CaC2, produced from calcium oxide and coke, with water (Scheme 19a). The by-product,
calcium hydroxide, can be thermally regenerated or used in the building materials industry.
Today, acetylene is mainly manufactured by partial combustion of methane, the BASF or
Sachsse-Bartholomé process that uses water-(or oil-)quenching to prevent complete
combustion (Scheme 19b),207 or by high-temperature pyrolysis (HTP) of hydrocarbons
(Scheme 19c).
1500 °C
O2
3 H2
10 H2
2 CH4
6 CH4
CaO 3 C CaC2
b) High-temperature pyrolysis (HTP)
CO2200 °
H2O Ca(OH)2CaC2
a) Calcium carbide process
2 CO
b) Sachsse-Bartholome
Scheme 19. Possible syntheses of acetylene.
Since the thirties, acetylene has been widely used for manufacturing of valuable products and
intermediates, especially at BASF in Ludwigshafen. A second major application of acetylene
is in welding and cutting. The founder of the large-scale industrial applications of acetylene is
Walter Reppe. While working at BASF, he developed the so-called “Reppe glasses” that
allowed high-pressure experiments with acetylene. Before that, in BASF it was forbidden to
compress acetylene over 1.5 bar. Due to its explosive nature indeed, accidents often occurred,
and only small quantities of acetylene were used at a time, and always without high pressures.
Acetylene has been employed in the chemical industry in combination with carbon monoxide
and carbonyl compounds, alcohols, or acids, mainly in Ni-catalysed reactions (Scheme 20).
Examples include numerous carbonylation reactions for the preparation of acrylic acid
derivatives and the Ni-catalysed trimerisation to benzene. Until the 1960s, acetylene was one
Introduction
41
of the most important C2 building blocks of the chemical industry, and many addition reactions
to the -bonds of acetylene were developed that yielded valuable products.
[Ni]
[Ni]
H2O, MeOH
or RNH2
[Cu] or [HgII]
addition products
carbonylation products
trimerisation
Scheme 20. Examples of Reppe´s synthesis from acetylene.
A very well-known Reppe process is the synthesis of 1,4-butanediol (BDO) from acetylene and
formaldehyde (see 4.4). Many large-scale applications of acetylene are known and some of
them are summarised in Scheme 21.
acetaldehyde acetadol 1,3-butanediol
butadienevinyl chloride
methyl vinyl ketone
polyene
ethyl acetateethanol
acetic acid
vinyl ether
vinyl ester
vinyl halide
acrylonitrile
acrylic acid
propargyl alcohol2-butyne-1,4-diol
1,4-butanediol
succinic acid
tetrahydrofuran adiponitrile
adipic acid
acetylene
hexemethylene diamine
2 CH2OCH2O
CO, HX
HCN
HX
RCO2H
ROH
H2O
Scheme 21. Acetylene as starting material in large-scale productions.
Introduction
42
4.4 C4-platform chemicals
C4-platform chemicals mainly consist of carboxylic acids, dicarboxylic acids (succinic, malic,
and fumaric acid) alcohols, diols, diamines, and act as building blocks to obtain important and
useful compounds. The biorefinery of these chemicals can be considered as a substitute for
petrochemical-based approaches, thus reducing the use of fossil fuels.
4.4.1 1,4-butanediol, BDO
1,4-butanediol is a colorless viscous liquid with a current production capacity around 4 Mt/y.208
It is used industrially as a solvent and in plastics or fibers manufacture. Almost half it is reserved
to the synthesis of THF to make fibers such as Spandex, but it is also an intermediate in the
synthesis of -butyrolactone (GBL), 2-pyrrolidones, polybutylene terephthalate or
polyurethanes (Scheme 22).209
n
BDO
THF poly-THF
GBL
R= Me, NMPR = H, 2-pyrrolidone
n
n
polyurethane
polybutylene terephthalate
Scheme 22. Common use of 1,4-butanediol in industrial syntheses.
Due to the great chemical importance of 1,4-butanediol and its follow-up products, various
synthetic routes to BDO, based on different raw material, were developed. Historically, the
Reppe process, discovered in the 1930s, is the oldest and still the most widely used process to
synthesise BDO. The reaction consists of two steps: first, 1,4-butynediol is synthesised by
reaction of acetylene and an aqueous solution of formaldehyde at 110 °C in the presence of
copper acetylide. In the second step, 1,4-butynediol is hydrogenated to BDO at high pressure
Introduction
43
(200 bar) and temperature (180-200 °C). The use of acetylene as a raw material is related to the
simpler and cheaper availability of hard coal compared to petroleum, from which acetylene is
traditionally produced. By the end of the 1990s other processes, such as Mitsubishi, Davy
Process Technology, ARCO (LyondellBasell), DuPont, have evolved, and nowadays the
production technology is shifting towards bio-based fermentation routes, but BDO produced
via Reppe chemistry still accounts for about 40% of the global BDO capacity (Scheme 23). A
biomass-based process applied now on industrial scale, use genetically modified bacteria coli
to ferment glucose or fructose directly to BDO (patented by Genomatica, licensed by
BASF).210–212
H2
H
2
H2H2
CO/H2
[H+]
AcO
H2
ROH
O2
E. ColiGenomatica
Reppe Mitsubishi-Kasei
Davi
Hydrogenation of
maleic anhydride
Arco
H2
Scheme 23. Synthetic routes to BDO.
Introduction
44
4.5 Catalysis in sustainable synthesis
A decisive tool to reach a more sustainable chemistry and tackle the challenge of minimising
the waste, is catalysis.213,214 Catalysis can increase the rate of a chemical reaction by addition
of a substance, a catalyst, that is not consumed during the reaction, and that can act multiple
times.215–217 The catalyst provides an alternative reaction pathway, with a lower energetic
barrier compared to the non-catalysed mechanism, thus allowing reactions to happen at lower
temperature or pressure and faster rate. The catalyst increases the rate of the reaction without
being consumed during the process, and creates an alternative reaction pathway with a lower
activation energy that usually implies a series of intermediates involved in a catalytic cycle
(Figure 18). A catalyst does not change the overall Gibbs free energy of a chemical reaction,
as the Gibbs energy is a state function and depends only on the state of the system, regardless
which pathway it takes.
G
Ea (with catalyst)
Ea (no catalyst)
Reaction progress
Energy
Figure 18. Energy diagram of the non-catalysed (blue) and catalysed (green) reaction.
Catalysts can be classified as homogeneous or heterogeneous, depending on their solubility or
insolubility in the same phase of the reactants. In homogeneous catalysis, reactants and catalyst
are usually dissolved in a solvent where the reactants can easily access the catalysts, thus
promoting high catalytic activity. Homogeneous catalysts are highly selective towards the
target product. In heterogeneous catalysis, the catalyst and reactants are in two different phases.
Therefore, an initial adsorption step of the reactants on the catalyst is essential for the reaction
to proceed. An advantage of heterogeneous catalysts is that they can be more easily separated
from the reaction mixture since they are in a different phase than the products and reactants.
Introduction
45
4.5.1 Hydrogenation
Hydrogenations are chemical reactions between molecular hydrogen (H2) and another
compound that usually, in the presence of a catalyst (e.g. nickel, palladium, platinum), gets
reduced or saturated.218 Non-catalytic hydrogenation takes place only at very high temperatures.
Hydrogen represents the most atom-economical and ecological reducing agent, especially if
compared to reductions that use stoichiometric amounts of LiAlH4 or NaBH4.219 About 50% of
the hydrogen is produced by steam reforming of natural gas, while about 30% from higher
hydrocarbons reforming, ca. 17% is generated by coal gasification and the rest (3-4%) by
electrolysis of water.220,221 Most of the hydrogen is used in the Haber-Bosch process for
producing ammonia, whereas another large amount is used by refineries for chemical processes,
such as removing sulfur from gasoline and converting heavy hydrocarbons into gasoline or
diesel fuel. Other industries, e.g. food, methanol, metallurgy, glass, pharmaceutical industry,
consume the rest.220 The production of hydrogen from natural gas has the drawback of
producing large amounts of carbon monoxide and carbon dioxide (approximately 7 kg CO2/kg
H2) during the reforming process, which represents a threat to sustainability. Hydrogen
production can be considered environmentally friendly only if its precursor is renewable. Due
to the great availability of water, its electrolysis to produce hydrogen is emerging as a valid
alternative to natural gas steam. Electrolysis consists of an electric splitting of water into
hydrogen and oxygen, and produce H2 gas with a purity > 99.99%.220 The electricity needed for
the process could come from renewable energy and, ideally in the future, production of
hydrogen from electrolysis of water could become highly economically and environmentally
sustainable.
One of the largest applications of hydrogenation reactions is in food industry for the controlled
reduction of unsaturated vegetable oils to create commercial goods. The degree of unsaturation
is controlled by restricting the amount of hydrogen, catalyst, reaction temperature and time.
Through the controlled reduction, is possible to convert liquid vegetable oils into solid or semi-
solid fats (e.g. margarine).
Other reductive applications, called transfer hydrogenation reactions, get the H-atom from
different molecules than H2 itself, e.g. formic acid or isopropanol, which in turn, get
dehydrogenated (to CO2 or acetone).
Introduction
46
4.5.1.1 Catalytic hydrogenation of C–C double bonds and C–C triple bonds
Hydrogenation of triple and double bonds usually proceed with a syn-addition (Scheme 24)222
and often already under mild conditions, e.g. room temperature and ambient pressure. Both
homogeneous (e.g. Wilkinson’s catalyst, Crabtree’s catalyst) and heterogeneous catalysts
(Raney nickel, Pd/C, platinum metal oxides) can catalyse the hydrogenations. Additional details
on hydrogenation of alkynes can be found in subchapter 4.3.2.
[cat] [cat]
Scheme 24. Catalytic hydrogenation of alkynes and alkenes.
The mechanism of the heterogeneous hydrogenation, though not yet fully understood, was
postulated in 1934 by Horiuti and Polanyi (Scheme 25).223 The catalyst adsorbs both the
unsaturated compound and the molecule of hydrogen, and the H–H bond cleaves. The two
hydrogen atoms are transferred to the alkene one after the other, creating two new C–H bonds.
The product is formed and released from the catalyst surface.
(catalyst surface)[cat]
Scheme 25. Mechanism of heterogeneous hydrogenation by Horiuti and Polanyi.223
4.5.1.2 Hydrogenation of carboxylic acids to alcohols
Carboxylic acids are inexpensive and readily available starting materials for chemical synthesis.
An example are the fatty acids found in large quantities in renewable raw materials, whose
catalytic hydrogenation to the corresponding fatty alcohols represents one of the most important
industrial processes.
The catalytic hydrogenation of carboxylic acids proceeds via the intermediate aldehyde, from
which, by adding another equivalent of hydrogen, the alcohol is formed. The corresponding by-
products of this implementation are simple hydrocarbons, formed by over-reduction of the
alochol, and esters formed by reaction of the alcohol with the starting material (Scheme 26).219
Introduction
47
H2 H2
- H2O
- H2O
- H2O
H2
Scheme 26. Hydrogenation of carboxylic acids.
4.5.2 Reductive amination
Reductive amination reactions consist on the conversion of a carbonyl group, mostly a ketone
or aldehyde, to an amine via the intermediate imine (Scheme 27).224 It is a versatile strategy to
obtain amines with different alkyl groups, and has emerged as valid alternative to the direct
alkylation of amines that inevitably brings to over-alkylation.225–229
hydrogenation or
reduction
hydrogenolysis
Scheme 27. General reductive amination pathway for coupling of a ketone with a primary amine.
The amine first reacts with the carbonyl group forming a hemiaminal. From here, there are two
possibilities: the carbinolamine can undergo hydrogenolysis to form the amine, or it can
reversibly lose one molecule of water to form the imine. This equilibrium can be shifted toward
the imine formation by physically or chemically removing the water. The imine can be
subsequently reduced to the amine with a suitable reducing agent. For primary amines and
ammonia there are two possible pathways, but when a secondary amine is involved, only the
hydrogenolysis is possible. Interesting features of this reaction are the sequential reductive
aminations with two different ketones, which leads to a trialkyl amine with three different alkyl
groups, and the intramolecular reductive amination of a molecule containing both an amine and
a carbonyl, to give a cyclic amine.
Several reducing agents can be used in reductive amination reactions: NaBH4, NaBH3(OAc)3,
NaBH3CN, H2/Pd. The borohydrides are more selective and tolerant to potentially reducible
functional groups, but create waste and do not satisfy the criteria of atom economy sought from
Introduction
48
the industries.230 On the contrary, reductions with molecular H2 produce water as the sole by-
product and clearly fit atom economical and environmentally friendly principles.
4.5.3 Olefin metathesis
Olefin metathesis are organic reactions that allow the redistribution of substituents between
different olefins, by scission and regeneration of carbon-carbon double bonds and formation of
new alkene fragments. Metathesis reactions were discovered in the 1950s at Du Pont Standard
Oil and Phillips Petroleum by several chemists, who reported the formation of ethylene and 2-
butene, when heating propene with molybdenum.231–233
For years several scientists proposed possible intermediates of the catalytic cycle.234–238
Today’s accepted mechanism, proposed by Chauvin in 1971, involves metal alkylidenes and
metallacyclobutane species (Scheme 28).239,240 After coordination of the olefin onto the metal
atom of the metal alkylidene 1, a cyclobutane 2, with the metal as one of the four atoms, is
formed. Following, a perpendicular shift of the new coordinated olefin to the initial direction
liberates the new metal alkylidene that contains the new olefin 3. After the second olefin
coordinated into this new metal alkylidene a new metallacyclobutene is formed 4, and the new
olefin is liberated releasing the metal alkylidene species. Depending on the orientation of the
coordinated olefin the catalytic cycle can give two different metallacyclobutenes, one leading
to the desired olefin, one leading to the starting olefin and metal alkylidene (degenerate olefin
metathesis).
1
2
3
4
Scheme 28. Simplified mechanistic cycle of olefin metathesis.
Introduction
49
Nowadays, the most widespread metathesis catalysts belong to the Grubbs and Hoveyda-
Grubbs generation catalysts, named after their inventors. In 1995, Ru(=CHPh)Cl2(PCy3)2, the
so-called Grubbs’ first generation catalyst, was reported by the group of Grubbs and is still one
of the most used metathesis catalysts due to its low price, high stability and compatibility with
many functional groups (Grubbs I, Figure 19).241,242 In the following years, improved Ru-
complexes were synthesised by Grubbs and other scientists where one phosphine was
substituted by a N-heterocyclic bis-amino carbene (NHC) with consequent increased catalytic
activity and thermal stability of the catalyst (second-generation catalysts, Grubbs II, Figure
19).243–246 Another significant contribution to the Ru-based metathesis catalysts came from the
Hoveyda group, who reported the synthesis of isopropoxystyrene-coordinated catalysts
(Hoveyda-Grubbs I and II, Figure 19).247,248 Improved catalytic activity was obtained by
incorporating a substituent on the alkoxybenzylidene ligand.249–251 An example are the Zhan
catalysts, which bear electron-withdrawing groups like dimethylsulfonamide on the aryl ring
(Figure 19). By substitution of the phosphine ligand with a pyridine in Grubbs II, third-
generation catalysts were obtained (Grubbs III, Figure 19).231,252–254
Zhan catalyst I
Grubbs I Grubbs II Hoveyda-Grubbs I Hoveyda-Grubbs II
Grubbs III
Figure 19. First-, second- and third-generation metathesis catalysts.
Olefin metathesis reactions include cross-metathesis (CM), ring-closing or opening metathesis
(ROM, RCM), isomerising metathesis and ethenolysis.
Introduction
50
4.5.3.1 Cross-metathesis and ethenolysis
Cross–metathesis reactions between two olefins can be classified into three types, depending
on the olefin involved in the process:
Chain-extending. Two olefins react with the metathesis catalyst to create a longer chain
molecule, usually releasing ethylene during the process (Scheme 29a)
Chain-shortening. Two olefins react with each other leading to a shorter olefin. The most
representative example of this class is the reaction of ethylene with an internal olefin
(ethenolysis, Scheme 29b).
Functionalising. A terminal olefin can be functionalised in a CM with a functional olefin
(Scheme 29c).
[cat]
77
3
[cat]
33
[cat]
7 7
a
b
c
Scheme 29. Representative examples of cross-metathesis.
Cross-metathesis between two olefins with similar reactivity can lead to a distribution of
metathesis products, including the homodimers of olefins that undergo CM with themselves
(Scheme 30).
[cat]
25%
50%
25%
Equilibrium ratio
Scheme 30. Cross-metathesis between olefins with similar reactivity.
Introduction
51
Some simple alkenes, polymers and other fine chemicals are produced via olefin metathesis on
industrial scale. Through the Triolefin process developed at Phillips Petroleum in 1960s,
propene is produced by CM from ethylene and 2-butene over a heterogeneous WO3/SiO2.231,255
Ethenolysis is an example of cross-metathesis, in which internal olefins are converted into
terminal alkynes if ethylene is used as reagent. Thanks to the very low cost of ethylene as a
reagent and the selectivity of the reaction to form terminal alkenes, this reaction is particularly
useful for industrial applications. A general reaction equation is given in Scheme 31
Scheme 31. General ethenolysis equation.
One of the most widespread industrial application of ethenolysis is the Shell higher olefin
process (SHOP) that converts high molecular weight internal olefins into -olefins. The SHOP
was discovered at Shell Development Emeryville in 1968. At that time, the main aim of the
process was the manufacture of C11-C14 fatty alcohols, as starting material for the synthesis of
alcohol sulfate detergents.256,257 These were desired substitutes for branched fatty alcohols and
alkyl benzene sulfonate, which were toxic to fish and whose degradation was very slow (see
4.1.2). The SHOP process involves three steps and reactions: 1) oligomerisation of ethylene, 2)
isomerisation of C4-C10 and > C18, 3) metathesis (Figure 20). First, a nickel-catalysed
oligomerisation of ethylene produces C6-C18 olefins that are separated out and used as feedstock
for lubricants, plasticisers and detergents. Lighter (< C6) and heavier (> C18) -olefins are
isomerised to internal olefins over a potassium metal catalyst. The resulting internal olefins are
redistributed by cross-metathesis over a molybdate-alumina catalyst to afford α-olefins of the
desired chain length (C11-C14). Those are either hydroformylated to give detergent alcohols, or
alkylated to afford linear alkyl benzenes. The large excess of ethylene moves the reaction
equilibrium towards the terminal α-olefins.
Introduction
52
Figure 20. Representation of the SHOP process.
4.5.4 Carboxylation reactions for C–C bond formation
Due to the thermodynamic restrictions in the conversion of CO2 (see 3.2.3.1), C–C bond
formations that employ CO2 as C1-building block, are facilitated by the means of a catalyst.258
4.5.4.1 Carboxylation of organometallic reagents: C–M bonds
The direct carboxylation of carbon nucleophiles with CO2 as electrophile is a well-known,
straightforward synthesis of carboxylic acids. To overcome the inertness of carbon dioxide,
stoichiometric amounts of organometallic species such as lithium, magnesium, sodium or
Grignard reagents are required, permitting the carboxylation already at ambient conditions and
without the addition of catalysts.129,259–261 However, as these substrates are highly reactive,
functionalities such as ketones, aldehydes or nitriles are not allowed resulting in a very limited
tolerance towards functional groups. By using less reactive tin, zinc or boron compounds in
combination with suitable catalysts, these limitations can be partially avoided and
functionalized starting materials can be employed (Scheme 32).129,261
M = Na, Li, Mg, Zn, Sn, B
catalyst = [Pd], [Ni], [Cu], [Rh], [Ag]
CO2
catalyst R = aryl, alkyl, alkinyl, allyl, H+
Scheme 32. Carboxylation of a C–M bond with CO2.
A pioneering work by Nicholas and co-workers in 1997 shows a CO2 insertion into less
polarised metal(tin)-carbon bonds, catalysed by palladium or platinum and phosphine
ligands.262 This work introduced a new concept for a catalytic carboxylation into less reactive
metal-carbon bonds, but still suffered from a limited substrates scope. Later, Iwasawa and Hou
Introduction
53
developed a transition metal catalysed carboxylation of organoboronic esters with CO2
employing rhodium and copper catalysts.263–265 Functional groups such as esters, ketones,
nitriles and protected amines were tolerated. However, stoichiometric amounts of nucleophilic
tert-butoxide or caesium fluoride for activating the borates are needed, and the product of the
reaction is actually a carboxylate, which requires an additional hydrolysis step. These two
factors together disqualify such processes from a sustainability standpoint.
4.5.4.2 Carboxylation of organohalides: C–X bonds
A complementary conversion of CO2 with carbon electrophiles into carboxylic acids has
recently attracted lots of attention. A pioneering work in this field was published by Osakada
and Yamamoto who could obtain benzoic acids through a stoichiometric conversion of
(Ph)Ni(bpy)Br with CO2.266 A direct catalytic carboxylation of aryl bromides, avoiding the
intermediate step to the organometallic compounds, was presented by the group of Martin using
a palladium phosphine complex.267 A wide number of functional groups ranging from amines,
ketones, (thio)ethers, or alkenes to even epoxides could be tolerated. However, a stoichiometric
amount of Et2Zn as reducing agent was necessary for the two positively polarised reaction
centres to react with each other and the success of the reaction was limited to aryl bromides.
Later, Tsuji and Fujihara described a Ni-catalysed carboxylation of aryl chlorides using simple
manganese as reductant and ammonium salts as additives (Scheme 33).268
CO2
HCl aq
NiCl2(PPh3)2 (5 mol%)
PPh3 (10 mol%)
1 atmMn (3 equiv)
Et4NI (10 mol%)
DMI, 25 °C, 20 hyields: 51-90%
Scheme 33. Carboxylation of aryl chlorides by Iwasawa, Tsuji et al.268
In addition to halides, sulfonates,269–271 benzyl,272,273 propargyl,274 (allyl)acetates,273,275,276 and
benzylic ammonium salts277 are carboxylated to the corresponding carboxylic acids, wherein
mainly Pd, Ni and Co are used as catalysts with phosphine or phenanthroline as ligands.
However, these transformations all have the intrinsic disadvantage that the catalyst must be
reduced after the oxidative addition of the organohalide or the resulting metal carboxylate with
stoichiometric amounts of reducing agent (usually Zn or Mn). Moreover, the final product of
Introduction
54
the reaction in this case is a carboxylate, resulting in a very low atom economy and classifying
these processes as environmentally unsustainable.
4.5.5 Reductive carboxylation of alkynes and alkenes
The discovery of Aresta's complex [Ni(CO2)(PCy3)] in 1975 showed for the first time that
electron-rich metals can activate CO2 by breaking the double bond and modify the linear
geometry of CO2.278 Thereon, a variety of Ni(0)-mediated (stoichiometric) carboxylations of
alkynes, enynes and diynes were reported.279–284
4.5.5.1 Catalytic reductive carboxylation of alkynes
The challenge to develop catalytic Ni(0)-mediated carboxylation reactions is the stability of
oxonickelacycle or nickel carboxylate intermediates that do not release acrylic acid products
spontaneously due to kinetic and thermodynamic factors.285 Attempts to close the catalytic
cycle have been made, by pushing the carboxylic acid product out of the coordination sphere
of Ni(0), e.g. by using diynes as substrates, that form a more stable lactone-type product and
help to overcome the energy barrier. Pioneering work has been done by Inoue and co-workers
in 1977,286 who developed a Ni-catalysed lactonisation of 1-hexyne and 1-butyne under CO2
pressure and by Tsuda, Saegusa and co-workers with a Ni-catalysed cycloaddition of CO2 to
diynes (Scheme 34a).287 In 2002, the group of Louie implemented the employment of N-
heterocyclic carbene (NHC) in the cycloaddition of diynes and CO2 (Scheme 34b).288
Ni(cod)2 (5 mol%)
IPr (10 mol%)CO2 (1 atm)
Ni(cod)2 (10 mol%)
PCy3 (20 mol%)
CO2 (50 atm)
90% yields 96% yields
a b
Scheme 34. Ni-catalysed cycloaddition of CO2 and diynes by a) Tsuda and b) Louie et al.287,288
In 2001 Ma and co-workers developed a Ni-catalysed hydrocarboxylation of internal alkynes
with CO2 and stoichiometric diethyl zinc as reducing agent, providing a method for the
preparation of (E)-acrylic acids.289 A new mechanism is proposed, that avoids the
oxonickelacycle intermediate and involves two catalytic cycles. Parallel to the development of
Introduction
55
this reaction, Tsuji and co-workers successfully employed NHC-Cu complexes for the
hydrocarboxylation of alkynes and hydrosilanes.290,291 The same group also reported a
CuCl(PCy3)2-catalysed silacarboxylation of alkynes with silylborane as reductant.292
4.5.5.2 Catalytic reductive carboxylation of alkenes
Pioneering works on the carboxylation of alkenes have been reported by Inoue, Behr and
Dinjus, who developed a Pd-catalysed lactonisation of butadiene and methylenecyclopropane
already in 1970s.293–296 More recently, Iwasawa reported the hydrocarboxylation of allenes and
1,3-dienes with a pincer-type palladium complex for the synthesis of ,-unsaturated carboxylic
acids.297,298 Takimoto and Mori, developed a catalytic ring-closing carboxylation process of
1,3-diene substrates with a Ni catalyst.299 Nozaki and co-workers reported a copolymerisation
of carbon dioxide and 1,3-dienes via a lactone intermediate in two steps (Scheme 35).300 The
first step is a Pd-catalysed lactone formation from diene and CO2, followed by a radical
polymerisation. This protocol provided a potential access to polymeric materials made from
carbon dioxide.
2 CO2
radicalcopolymer
Pd(acac)2 (0.3 mol%)
PPh3 (0.9 mol%)
ZnCl2 (0.5 equiv)
Scheme 35. Copolymerisation of CO2 and 1,3-dienes by Nozaki.300
The first direct hydrocarboxylation of a single alkene was reported by the group of Rovis, who
was able to convert a variety of styrenes, with electron-deficient and neutral substituents,
through a Ni-catalyst and diethyl zinc as reducing agent (Scheme 36).301 This work represents
an important expansion to previous works, since it involves extensive -electron systems and
is compatible with several functional groups.
Ni(acac)2 (10 mol%)
Cs2CO3 (20 mol%)CO2
Et2Zn (2.5 equiv)
HClaq
Scheme 36. Ni-catalysed hydrocarboxylation of styrenes by Rovis.301
Introduction
56
In 2012, the groups of Hayashi and Thomas independently reported a Fe-catalysed reductive
carboxylation of styrenes via a two steps mechanism:302,303 First, the conversion of alkenes into
hydromagnesiated intermediates with Grignard compounds, and then its carboxylation
(Scheme 37).
HClaqCO2 (1 bar)
FeCl2 (1 mol%),
L (1 mol%)EtMgBr (1.2 equiv)
Scheme 37. Fe-catalysed hydrocarboxylation of styrenes by Thomas et al.303
Lately, also rhodium and ruthenium have been employed in hydrocarboxylation reactions.
Leitner and Klankermayer reported a [RhCl(CO2)]2-catalysed alkenes hydrocarboxylation
employing CO2 and H2 as carbon and hydrogen source to access free carboxylic acids.304
Parallel to this reaction, a Ru3(CO)12-catalysed alkene hydrocarboxylation with CO2 via
alkoxycarbonylation process has been developed by the group of Beller.305 In both papers,
various terminal and internal alkenes were converted into the corresponding carboxylic acids
or esters, in good yields (Scheme 38).
[Bmim]Cl = 1-Butyl-3-methylimidazolium chloride
CO2R'OH
Ru3(CO)12 (1 mol%)
[Bmim]Cl (2 equiv)
[RhCl(CO)2]2 (2.5 mol%)
PPh3 (25 mol%)
TsOH (20 mol%)
H2
H+
Scheme 38. Rh- and Ru-catalysed hydrocarboxylation of alkenes.304,305
In conclusion, the majority of reductive carboxylations of alkenes and alkynes require the use
of stoichiometric amounts of waste-intensive and mostly air-sensitive reducing agents for
catalyst regeneration. As a result, the carboxylate is produced as a salt and needs an additional
step of hydrolysis, leading to an overall low atom economy and low sustainability of the entire
process. One exception is the lactonisation, where the amount of reducing agent is diminished.
4.5.6 CO2 as CO substitution for carbonylation reactions
Carbon monoxide is one of the most important intermediates in chemical synthesis. It is used
as a starting material for various basic chemicals, such as methanol, acetic acid
Introduction
57
(Monsanto/Cativa process), aldehydes (oxo process) or longer-chain hydrocarbons (Fischer-
Tropsch synthesis).306 The introduction of the carbonyl group into organic and inorganic
substrates is called carbonylation. This class of reactions, for example hydroformylations, Koch
reaction, Reppe reactions, employs carbon monoxide for the synthesis of aldehydes, carboxylic
acids, esters, lactones, and amides. However, the high toxicity of carbon monoxide makes its
handling and transport extremely problematic, both for the industrial and academic field. For
this reason, it is preferred to use a CO2/H2 mixture such as synthesis gas (syngas), occurring in
steam reforming of methane, or water gas, which is produced by gasification of coal, or by
partial oxidation of hydrocarbons.307 Hydroformylation is the addition of syngas to olefins in
the presence of a catalyst under the formation of aldehydes in an atom-economical manner.308
The reaction leads, unless ethylene is used as a substrate, to a mixture of isomeric products,
linear and branched aldehydes. Is possible to adjust the ratio between CO2 and H2 via the reverse
water-gas shift reaction (RWGS) in which a mixture of CO, CO2, H2O and H2 is formed at
temperatures above 300 °C (Scheme 39). By addition of water vapour, the CO content in the
synthesis gas is reduced, while the hydrogen content is increased, according to the water-gas
shift reaction (WGS). Conversely, it is possible to use hydrogen as a reducing agent for carbon
dioxide to increase the amount of carbon monoxide.
CO2 H2 H2OCO HR0 = 41.2 kJ/mol
reverse-water gas shift reaction
water gas shift reaction
Scheme 39. (Reverse) water-gas shift reaction.
The first report describing the hydrogenation of CO2 to CO was in 1993 by Tominaga and
Sasaki.309 In 2000, the same authors reported the first hydroformylation of alkenes using CO2,
in the presence of Ru3(CO)12 as catalyst and LiCl as additive.310 This work opened the
benchmark for the direct carbonylation of alkenes with CO2, in which CO is in situ generated
via CO2 hydrogenation (RWGS). Later, through the use of specific bulky phosphite ligands, the
group of Beller could optimise the yields of alcohols, the chemoselectivity of the process, and
the TON of the catalyst compared with the known ligand-free catalysis system.311 Finally, the
Rh-catalysed hydrocarboxylation of alkenes with CO2 and H2 by the group of Leitner, described
Introduction
58
in 4.5.5.2, Scheme 38, showed that the water, formed in situ with the RWGS, could be used as
the nucleophile in the transformation.304
Although H2 would be an efficient reducing reagent for CO2 both economically and
ecologically, the following carbonylation often competes with the hydrogenation of the
substrate. One successful approach is the use of alcohols as reductant. Carbonylation using CO2
offers a very attractive alternative to reductive carboxylations since the products obtained in the
two processes are similar, but the stoichiometric amounts of expensive reductants like Et2Zn or
silanes are substituted by hydrogen or simple alcohols, which are considered the "greenest" of
all reducing agents.
4.5.7 Carboxylation of C–H bonds
C–H bond activation is a potent tool for the construction of complex molecules. Also in the
field of carboxylation, direct C–H bond activation protocols have been developed that seem to
be a promising alternative to avoid preforming of the substrates and waste formation. In this
reaction, in addition to the thermodynamically stable CO2, also a relatively inert C–H bond
must be activated and then deprotonated to generate the nucleophilic carbon species. Indeed,
the difference in the pKa values for the differently hybridised carbons (pKa, ethane = 50, pKa, ethene
= 44 and pKa, ethyne = 25) means that the carboxylation of the different substrates is only possible
under certain conditions. A summary of the most important C–H bond carboxylation reactions
with regard to the hybridisation of the carbon will be presented below.
4.5.7.1 Carboxylation of sp3 C–H bonds
C(sp3)–H are very stable, and often considered unreactive. The carboxylation of this kind of
bonds was explored by the group of Yamada who developed two silver catalysed methods
(Scheme 40).312,313 The first protocol described the conversion of -keto-alkynes with CO2 (10
bar) catalysed by AgOBz into the corresponding lactones. The second method provides access
to dihydroisobenzofurans by reaction of ortho-alkynylacetophenones. Both reactions were
conducted with organic bases. The drawback is that these protocols have a very limited scope
of application.
Introduction
59
CO2
AgOAc (10 mol%)DBU (2 equiv)
MeCN, 30 °C, 24 h10 bar
CO2
AgOBz (20 mol%)MTDB (4 equiv)
DMF, rt, 2-9 d10 bar
Scheme 40. Carboxylation of C(sp3)–H bonds by Yamada.312,313
4.5.7.2 Carboxylation of sp2 C–H bonds
The carboxylation of C(sp2)–H bonds is better developed due to a lower activation barrier and
can already work in metal-free conditions. Purely base-mediated carboxylations of sufficient
acidic heteroaromatics can be run with 1-2 bar CO2 pressure at 100-120 °C.314–316 Less acidic
aromatic C–H bonds (pKa > 40), as benzoic or furancarboxylic acids, can be activated with
molten salts containing carbonate ions, moderate CO2 pressures and relatively high
temperatures > 200 °C.317
The groups of Nolan and Hou developed protocols using copper and gold complexes with N-
heterocyclic ligands for the carboxylation of electron-deficient (hetero)aromatics with acidic
C–H bonds (Scheme 41a).318–321 They applied significantly mild conditions, sometimes even
room temperature, hydroxide or alkoxide bases. However, regioselective carboxylation for the
most acidic C–H bond position, is only reported in a protocol from Nolan (Scheme 41b).322
The catalyst is easily regenerated from the product and reused.
Introduction
60
1 atm
1.5 atm
or
CO2
(IPr)CuCl (5 mol%) or(TPr)CuCl (5 mol%)
Y = O, S
X = F, Cl
Y = O, SZ = C, N
or CO2
(IPr)AuOH (1.5 mol%)KOH (1.5 equiv)
THF, rt
HClaq
R-Ia)
b)
KOtBu, THF, 80 °C
Scheme 41. Cu/Au-catalysed carboxylation of (hetero)aromatic C–H bonds by Hou and Nolan.265,322
Palladium catalysed carboxylation of aromatic C–H bonds has been reported by Fujiwara and
co-workers already in 1984.323 Using Pd(OAc)2 or Pd(NO3)2, 30 bar of CO2 and 150 °C anisole,
furane, thiophene and benzene were successfully converted into their corresponding carboxylic
acids. In the case of benzene and anisole, by using t-BuOOH as an oxidising agent, the yields
could be greatly increased, showing for the first time, a catalytic potential of Pd in this reaction.
Later, Iwasawa and co-workers developed a Pd-catalysed carboxylation of 2-hydroxystyrenes
to the corresponding coumarins under remarkably mild conditions, using catalytic Pd(OAc)2
and excess of Cs2CO3 (Scheme 42a).324 The lactonisation process is believed to be the driving
force of the reaction. The same group also succeeded in using rhodium as a catalyst for the
conversion of aryl substrates with pyridine or pyrazole as directing groups (Scheme 42b).325
[Rh(coe)2Cl]2 (5 mol%)
PCy3 or P(mes)3 (12 mol%)
AlMe2(OMe)) (2 equiv)CO2
DMA, 70 °C
Pd(OAc)2 (5 mol%)
Cs2CO3 (3 equiv)CO2
diglyme, 100 °C
a
b
1 bar
1 bar
Scheme 42. Pd/Rh-catalysed aryl carboxylation by Iwasawa.324,325
Introduction
61
The direct synthesis of acrylic acid or acrylates from ethene and CO2 is economically attractive,
but has also been one of the most challenging dream reactions for decades. Acrylates are
industrially very important compounds, e.g. sodium acrylate, especially used in the manufacture
of superabsorbent polymers, has a market volume of approximately four million tons per
year.326 A pioneering work by Hoberg showed the formation of nickelalactones, “Hoberg
complexes”, as intermediate in the catalytic coupling of ethylene and CO2.280 However, it took
three additional decades before the first catalytic protocol was developed, because of the big
challenge of breaking the stable nickelalactone structure. Reducing agents, in fact, would cause
reductive carboxylation. Limbach et al. succeeded in a Ni-catalysed synthesis of sodium
acrylates from CO2 and ethylene, by using sodium tert-butylate and a bisphosphine ligand. The
mechanism involved a cyclometalation step, followed by -hydride elimination by using the
strong base able to overcome the thermodynamic stability of the Ni-complex. The drawback of
this process is the limited set of ligands and substrates accessible and the incompatibility of
alkoxide bases with CO2 (formation of carbonates). These limitations were solved by the use
of phenoxides as base, as these are not prone to carbonate formation (Scheme 43).327 Recently,
also Pd-catalysed synthesis of sodium acrylate from CO2 was successfully developed.328–330
CO2
10 bar 20 bar
Ni(COD)2 (0.2 mmol)
BenzP* (0.22 mmol)Na-2-Fluorphenolat (10 mmol)
Zn (10 mmol)
THF, 100 °C, 20 h
Scheme 43. Ni-catalysed synthesis of sodium acrylate from ethene and CO2.
4.5.7.3 Carboxylation of sp C–H bonds
C(sp)–H bonds of terminal alkynes are comparatively acidic, thus easily deprotonated with
strong bases such as lithium diisopropylamide (LDA) or sodium hydride without the aid of a
catalyst. The coordination to coinage metals such as copper and silver to the triple bond
increases even more the acidity of the proton and already weaker inorganic carbonate or
phosphate bases are sufficient for the deprotonation. Hence, carbon dioxide can be inserted into
the C–M bond of the metal acetylides, thus generating a propiolate. However, due to the low
energetic gap of these two intermediates (just 4 kcal/mol), and the activation barrier of only 13
kcal/mol, the catalysts used for the carboxylation can also catalyse the reverse decarboxylation,
even at room temperature. As soon as the CO2 atmosphere is removed from the reaction
Introduction
62
medium, the extrusion of CO2 and its transition into the gas phase is entropically favoured, and
the chemical balance is shifted back towards the reactants. Thus, the isolation of the products
is only possible by an in situ esterification with alkyl halides, or reaction by transmetalation of
the unstable copper/silver propiolates into more stable salts.
The first stoichiometric study on the carboxylation of C(sp)–H bonds with coinage metals was
reported by Saeugusa and co-workers in 1974, who succeeded to insert CO2 into organocopper
and organosilver terminal alkynes in the presence of phosphine or nitrile ligands.331 Subsequent
studies on the carboxylation/decarboxylation equilibrium of Cu(I)-phenylpropiolate showed
that increasing the -donor strength of the phosphine ligands the equilibrium shifts in favour of
the carboxylated species.332 However, the first catalytic protocol was reported only in 1994 by
the group of Inoue.333 They were able to deprotonate terminal alkynes with simple potassium
carbonate in the presence of catalytic amounts of Cu(I) or Ag(I) salts generating acetylides,
subsequently carboxylated into the corresponding propiolic acids under CO2 atmosphere at
100 °C (Scheme 44). The in situ esterification with 1-bromohexane prevented the reverse
reaction (decarboxylation) of the thermally labile propiolates, thus increasing the yields.
CO2
[cat] (4 mol%)base (6 equiv)
n-hexyl-Br (2 equiv)
DMAc, 100 °C, 4 h
[cat] = CuI, CuBr, AgI, AgNO3
base = K3PO4 or K2CO3
R = Ph, Tol, n-hexyl
Scheme 44. The first catalytic C–H carboxylation of terminal alkynes by Inoue.333
Starting from 2010, different groups developed several protocols for carboxylation of terminal
alkynes at lower temperatures and moderate CO2 pressures, using copper or silver catalysts with
tetramethylethylenediamine (TMEDA), phenanthroline-based or recyclable heterogeneous
NHC ligands. Alkynes are converted to the corresponding propiolates that can be esterified in
situ or, for the first time, isolated as free acids.
In 2010, Lu,334 Gooßen,335 and Zhang,336 all independently disclosed a Cu-catalysed
carboxylation protocol as shown in Scheme 45. In Lu´s procedure, NHC copper(I) complex
(IPr)CuCl was used as catalyst, K2CO3 as base and several organochlorides as coupling
partners. Both alkyl and aryl propiolic esters were obtained in very good yields at a CO2
Introduction
63
pressure of 15 bar. However, 1.5 equivalents of cinnamyl chloride for the in situ esterification
are needed as well as 10 mol% of catalyst loading. The methods of Gooßen and Zhang, allowed
the isolation of the free propiolic acids without an in situ esterification and required a much
lower amount of catalyst. The Gooßen group used air-stable copper(I) phenanthroline-
phosphine complexes and caesium carbonate as the base. For the conversion of aliphatic
alkynes, 50 °C, 1 bar CO2 and PPh3-substituted copper complex were employed, while aromatic
alkynes were converted using P(4-F-C6H4)2-copper complexes at 35 °C, but a pressure of 5 bar
CO2 was necessary. Zhang and co-workers developed a carboxylation of aryl and aliphatic
alkynes, by employing a simple Cu(I)Cl catalyst with nitrogen ligands (e.g. TMEDA) under
CO2 atmospheric pressure, room temperature and with potassium or caesium carbonate as
bases.
CO2
Lu (IPr)CuCl (10 mol%)K2CO3 (2 equiv)
DMF, 60 °C, 15 bar, 24 h
GooßenCu(I) (1-2 mol%)Cs2CO3 (1.2 equiv)
DMF, 35-50 °C, 1-5 bar 16 h
ZhangCuCl (2-5 mol%)TMEDA or poly-NHC (1.5-10 mol%)K2CO3 (1.2 equiv)
DMF, rt, 1 bar, 16-48 h
Cl-R' or HCl
aq.
Scheme 45. Cu-catalysed carboxylation protocols of terminal alkynes.334–336
In 2012, Inamoto and Kondo proposed another Cu-catalysed system for the carboxylation of
terminal alkynes.337 They converted aryl and aliphatic alkynes in moderate to good yields
employing 8 mol% of CuI and ligand (PEt3), Cs2CO3 (3 equivalents) and esterification with
several alkyl-halides.
Similarly to Cu(I), also Ag(I) has been employed in the carboxylation of terminal alkynes.
Three independent works by Lu,338 Gooßen,339 and Zhang,340 were published between 2011 and
2012 all using Cs2CO3 as base (Scheme 46). The group of Lu reported that already 1 mol% of
ligand-free Ag(I)-catalysts (AgI) is sufficient for the carboxylation of terminal alkynes at 50 °C
and a CO2 pressure of 2 bar. Gooßen and co-workers developed a highly efficient system, where
Introduction
64
already 500 ppm of AgBF4 were sufficient for a quantitative carboxylation of 1-octene into the
corresponding 2-nonynoic acid. The excellent yields may be due to the formation of a DMSO-
ligated silver(I) carbonate species formed in situ from the silver salt, DMSO, and caesium
carbonate that could be the active catalyst. Along with the remarkable low catalyst loading, this
protocol uses for the first time a nontoxic, polar aprotic solvent. Parallel to the Gooßen protocol,
another method by Zhang and co-workers appeared. Based on the previously presented poly-
NHC ligand, but this time loaded with Ag nanoparticles, they presented a heterogeneous,
reusable catalyst for the carboxylation.
CO2
Lu AgI (1 mol%)Cs2CO3 (1.5 equiv)
DMF, 50 °C, 2 bar, 12 h
GooßenAgBF4 (0.05-0.25 mol%)
Cs2CO3 (1.2 equiv)
DMSO, 50 °C, 1 bar 16 h
Zhangpoly-NHC-Ag (0.3 mol% Ag)Cs2CO3 (1.2 equiv)
DMF, 25 °C, 1 bar, 16 h
HCl aq
Scheme 46. Ag-catalysed carboxylation of terminal alkynes.338–340
In addition to Cu- and Ag-catalysed carboxylations of terminal alkynes, the group of Zhang
also published a metal-free protocol.341 By using caesium carbonate as base and a temperature
of 120 °C in an atmosphere of 2.5 bar, they could efficiently convert aryl and alkyl substituted
terminal alkynes in good to very good yields (Scheme 47).
Cs2CO3 (1.2 equiv)
DMF, 120 °C(2.5 atm)
HClCO2
Scheme 47. Metal-free protocol for carboxylation of terminal alkynes.
In summary, C–H carboxylation of terminal alkynes is a very attractive option for the
incorporation of CO2 into organic substrates. It can be catalysed by coinage metals (Ag, Cu)
under very mild conditions, sometimes already at atmospheric CO2 pressure and room
temperature. In addition, it can also efficiently work in metal-free conditions, albeit it requires
Introduction
65
higher temperatures and higher pressures. The reaction has the big advantage that C–H bonds
can be directly carboxylated without any prefunctionalisation of the substrates. However, these
reactions require the deprotonation of the acidic proton of the alkynes, by the means of a base,
to initiate the CO2 insertion. Moreover, the carboxylation product has to be stabilised as a
carboxylate for providing a thermodynamic driving force to the reaction that is liable to
decarboxylation. This requires a hydrolysis of the carboxylate after the reaction, resulting in the
formation of a waste salt and a diminishing of the atom economy of the whole process. This
disadvantage could be solved by a suitable, waste-free derivatisation of the carboxylate with
recovery of the base. This topic will be treated in the chapter 6.3
Research objectives
66
5 Research objectives
The aim of this PhD work was to develop new green and waste-minimised strategies that use
recycled renewable resources as alternatives to fossil resources, to achieve more sustainable
chemical syntheses and reduce waste. Herein, cashew nut shell liquid, CNSL, and carbon
dioxide, CO2, both waste by-products of industrial production, were chosen as inedible,
renewable raw materials.
The first goal of the PhD was to develop sustainable processes to create valuable chemicals
from CNSL, an oil extracted from the shells of the cashew nuts. The first big challenge was to
synthesise commodity compounds, such as surfactants, starting from such impure oil, via an
ecologically and economically valuable process. The idea for achieving this goal was to apply
a reductive amination on the mixture of phenols, and the resulting cyclohexylamines should be
further functionalised to obtain valuable surfactant molecules. A second goal was to
demonstrate the utility of this waste resource in straightforward syntheses of drug-like
compounds. The big challenge was to reduce the number of compounds in the crude mixture to
obtain a single compound that could undergo cross-metathesis with a selected olefin leading to
the target product.
The second goal of the PhD work was to develop a waste-minimised catalytic inclusion of
carbon dioxide into aliphatic alkynes to access basic C4 chemicals. Common derivatisations or
esterifications of carboxylates lead inevitably to the production of salt waste. Therefore, the big
challenge to develop a sustainable process was to identify a salt-free derivatisation of the
carboxylates under regeneration of the free base. The idea for achieving this aim was to use
high CO2 pressure to acidify the reaction mixture and thus to enable an esterification of
carboxylates with simple alcohols. By applying this procedure to acetylene, a highly sustainable
synthetic route to the platform chemical 1,4-butanediol should be demonstrated, where two of
the carbon moieties come from the greenhouse gas CO2.
Results and discussion
67
6 Results and discussion
The following chapters summarise the aims, challenges and results of each project, including
the most relevant unpublished results. Each project is preceded by an introduction reporting
results published by other groups, as support of the research strategy that was adopted and
contains a depicted copy of the original publication, if present. The numbering of molecules,
including the experimental section, observes the numbers assigned in the publications.
6.1 Synthesis of bio-based surfactants from cashew nut shell liquid
During the last two decades, several surfactants have been synthesised starting from cardanol,
the main component of technical CNSL (Scheme 48). Most of the cardanol-based surfactants
are anionic such as sulfonates, generally obtained by aromatic sulfonation of cardanol with
sulfuric acid, or sulfate- and carboxylate-polyethenoxy ethers.98,103,342–344 Non-ionic and
zwitterionic cardanol-based surfactants have also been synthesised.99,100,345 Among them, the
cardanol polyethenoxy ether, has been used as surfactant in cement.102 Finally, also quaternary
ammonium salts, have been obtained as cationic surfactants representatives.345–347
cardanol
R=
anionic
non-ioniccationic zwitterionic
Scheme 48. Examples of cardanol-derived surfactants.
Results and discussion
68
All the synthesised cardanol-based surfactants retain the aromaticity, the unsaturation in the
aliphatic chains, and the oxygen atom connected to the aromatic ring. If those surfactants were
used as components in detergents and cleaning products, they would likely end up in sewage
and rivers, and eventually, they would be degraded to long-chain phenols. Those could in turn,
degrade to nonylphenols, highly toxic and persistent in the environment (see 4.1.2).
The goal of this project was the development of a greener and more sustainable synthesis of
surfactants from cardanol, that could be achieved if the targeted products were non-aromatic
and possibly, non-anionic compounds. Inspired by the recent discovery of reductive
aminations of phenols to cyclohexylamines, we saw the opportunity to apply this methodology
to cardanol and synthesise non-aromatic, amine-based surfactants.
6.1.1 Reductive amination of phenols
Reductive amination consists in the coupling of a primary or secondary amine with a carbonyl
compound (ketone or aldehyde) and is one of the greener methods to prepare amines (see
4.5.2). Recently, Li, Taddei, Beller, and Fu, have demonstrated that it is possible to apply this
method directly to phenols and obtain cyclohexylamines through the formation of the
cyclohexanone intermediate.348–351 The first discovery by Li in 2015, showed that palladium
on charcoal could efficiently catalyse the reductive amination of phenol with p-toluidine, in
toluene at 100 °C. Nonetheless, 7 mol% of catalyst loading and 6 equivalents of reducing
agent (sodium formate), were necessary to obtain the desired product in 94% yield (Scheme
49). Several aniline derivatives, as well as several substituted phenols, were converted into
the targeted products.
Pd/C (7 mol%)HCO2Na (6 equiv)
toluene, 100 °C, 24 h
Scheme 49. Reductive amination of phenols with anilines by Li.350
In 2015, independently from Li´s group, Vaccaro, Taddei and co-workers published a
reductive amination of phenols in water (Scheme 50). Although the catalyst loading was
decreased to 5 mol%, 20 equivalents of reducing agent were necessary to obtain full
conversion. By using the microwave (MW) dielectric heating, lower temperature (60 °C) and
Results and discussion
69
shorter time (20 min) were sufficient for the conversion. Most of the substrates were
efficiently converted in water with relatively good yields (35-85%). For the more lipophilic
substrates that could not fully solubilise in water, addition of MeOH to the solution was
necessary. The author probed the possibility of recycling the catalyst, which was used in at
least in five consecutive reactions without a marked decrease in activity. Moreover, this
reaction could successfully work also in a continuous flow protocol that allowed the synthesis
of bigger amounts of cyclohexylamines with reduced loading of catalyst (2.7 mol% Pd/C).
Pd/C (5 mol%)HCO2Na (20 equiv)
H2O
60 °C, MW, 20 min
Scheme 50. Reductive amination of phenols with amines by Taddei and Vaccaro.351
In 2016, Beller and co-workers obtained cyclohexylamines via direct coupling of phenols and
aromatic ethers with amines, using H2 as hydrogen source (Scheme 51). The reaction was
carried out in p-xylene at 60 °C, with Pd/C in 2 mol% as catalyst and a Lewis acid (LA) as
co-catalyst. Under these conditions, already 1 bar of H2 was sufficient to obtain the targeted
compounds. The use of LA was beneficial for the catalytic hydrogenolysis of C–O bonds of
ethers.
Pd/C (2 mol%)H2 (1 bar)
LA (5 mol%)
p-xylene
60 °C, 6 h
ororor
Scheme 51. Reductive amination of phenols and aryl ethers by Beller.349
Parallel to Beller, the group of Fu reported a Pd-catalysed hydrogenation and amination of
phenols over PdHx/Al2O3 in hexane, under H2 atmosphere (Scheme 52). They synthesised and
tested several Pd-catalysts and supports: PdHx/Al2O3 showed higher catalytic activity and
gave better yield if compared with Pd/Al2O3 and Pd/C. Additionally, PdHx/Al2O3 showed
Results and discussion
70
good stability and maintained good activity after being recycled five times. Non-polar
solvents, such as hexane or toluene, gave better yields than polar solvents or water (only 47%
yield). Several phenols and secondary amines were tested (anilines and aliphatic amines):
ortho-substituted phenols or bulky substituents on phenols, as well as bulky substituents on
anilines, negatively affected the yields.
PdHx/Al2O3
H2 (1 bar)
hexane 70 °C, 10 h
Scheme 52. Reductive amination of phenols by Fu.348
All four protocols presented above, propose a very similar mechanism: the phenol (1) is first
reduced to cyclohexanone (2) with molecular hydrogen or another hydrogen source. The
cyclohexanone can undergo reductive amination with the coupling amine and generate the
imine derivative (3). The imine is subsequently reduced to the corresponding cyclohexylamine
with a hydrogen source over the catalyst (4) (Scheme 53).
1
2 3
4
solvent
[Pd][H]
[Pd][H]
H2NR' or HNR'R''
H2O
or
or
[H] = HCO2Na. Toluene Li, 2015
[H] = HCO2Na. Water Taddei, 2015
[H] = H2. p-Xylene Beller, 2016
[H] = H2. Hexane Fu, 2016
amine, [Pd], [H]
Scheme 53. Proposed mechanism for the reduction amination of phenols.
6.1.2 Reductive amination of cardanol
We recognised in the reductive amination procedure a synthetic opportunity for the
valorisation of cardanol. However, compared to structurally simple and highly pure phenols
Results and discussion
71
as starting material for this process, reductive amination of technical CNSL is more difficult
and challenging. Technical CNSL is a dark-reddish oil, consisting of a mixture of compounds:
the main components (> 90%) are the four cardanols with different degrees of unsaturation;
the rest is impurities such as cardol, anacardic acid, methyl cardol and other smaller impurities.
Moreover, the ratio of impurities varies from batch to batch, depending on the country of
origins and on the extraction method. Ideally, a sustainable reductive amination of such
starting material should lead to only one compound that need a minimal purification to be
isolated.
A summary of the screening that led to the optimisation of the reaction conditions and the
final reaction process can be found in the following table (Table 1). The reductive amination
of technical CNSL (1) with di-n-butyl amine (2a) was chosen as model reaction. All organic
solvents tested, polar and apolar, as well as protic and aprotic, were not efficient for the
reaction, giving very low yields (entries 1-6). Addition of Lewis acids did not improve the
yields (entries 3-4). By employing an aqueous mixture of isopropanol and water, the yield was
raised to 52%, and by switching to solely water, the yield was remarkably increased to 90%
(entries 5-6). In water, Pd/C gave better performances than all the other catalysts and supports
tested (entries 7-11). Control experiments confirmed that the catalyst was necessary, and only
starting material was recovered in the absence of it (entry 12). Decreasing the catalyst loading
resulted in a drop of the yield, while increasing it to 3 mol% did not remarkably affect the
yield (entries 13-14). The screening of the loading of the amine confirmed that 1.1 equivalents
is the optimal amount (entries 15-17). By increasing the reaction time to 24 h, the yield
dropped, probably due to a decomposition of the cyclohexylamine (entry 18). Finally, the
pressure parameter was tested (entries 19-20), and while a pressure of 1 bar of H2 resulted not
efficient for the reaction outcome, 5 bar H2 was sufficient for a full conversion.
The obtained yield of 90% is based on the weight of the CNSL; thus it can be considered a
quantitative yield starting from the impure cardanol.
Results and discussion
72
Table 1. Summary of the optimisation of the reductive amination of cardanol.
cat (2 mol%)H2 (10 bar)
solvent 100 °C, 15 h
1 3a 4a 5a 6a2a
n = 0, 2, 4, 6
Reaction conditions: 1a (0.50 mmol), 2a (0.55 mmol), catalyst (2.00 mol%), H2 (10 bar), solvent (2
mL), 100 °C, 15 h. Yields determined by GC using n-hexadecane as internal standard. [a] 5 mol%
In(OTf)3. [b] 5 mol% Hf(OTf)4. [c] Pd/C (1 mol%). [d] Pd/C (3 mol%). [e] 24 h. [f] 5 bar H2. [g] 1 bar H2.
# 2a (equiv) solvent cat 3a (%) 4a (%) 5a (%) 6a (%)
1 1.1 EtOH Pd/C 15 75 trace -
2 " cyclohexane " 15 69 8 -
3[a] " p-xylene " 8 89 - -
4[b] " " " 7 91 - -
5 " H2O/ iPrOH " 52 25 6 trace
6 " H2O " 90 10 - -
7 " " Pd/(OH)2 66 33 - -
8 " " Rh/Al2O3 37 - 45 12
9 " " Ru/Al2O3 - - 97 -
10 " " Al/Ni - 92 - -
11 " " Pt/C - 97 trace -
12 " " - - - - -
13[c] " " Pd/C 18 80 - -
14[d] " " " 86 - trace -
15 0.9 " " 81 - 6 -
16 1.2 " " 81 14 - -
17 1.5 " " 42 56 - -
18[e] 1.1 " " 68 25 - -
19[f] " " " 90 - trace -
20[g] " " " 61 7 12
Results and discussion
73
To gain insights into the reaction mechanism, we tested whether cyclohexanone and
cyclohexanol would react under reaction conditions (Scheme 54), confirming our hypothesis
that the reaction proceeds through the formation of a cyclohexanone intermediate.
Pd/C (2 mol%)H2 (10 bar)
Pd/C (2 mol%)H2 (10 bar)
2a
2a
> 90%
0%
Scheme 54. Reductive amination of cyclohexanone and cyclohexanol. Cyclohexanone/cyclohexanol
(0.50 mmol), 2a (0.55 mmol), Pd/C (2 mol%), H2 (10 bar), H2O (2 mL), 100 °C, 15 h.
The optimised reaction conditions were applied to a variety of amines, leading to several
cyclohexylamine derivatives (see scope table in the enclosed publication). Cyclic and dialkyl
amines proved to be more suitable for this transformation than monoalkyl amines, and
functional groups such as dialkylamino, methoxy, acetals and heteroatoms were well
tolerated. A drawback of the procedure was that bulky amines and monoalkyl amines with
functionalities such as halides, hydroxyl, nitro or cyclic group were not transformed into
cyclohexylamines (Figure 21).
R = Me, Cl, NO2 R = OH, PiperidineR = CN, CO2Et
Figure 21. Substrates not suitable for the reductive amination of cardanol.
The reaction sequence was scaled up to 15 g scale for the di-n-butyl amine and to 20 g scale
for the dimethyl amine. The products, N,N-dibutyl-3-pentadecyl cyclohexylamine (3a) and
Results and discussion
74
N,N-dimethyl-3-pentadecyl cyclohexylamine (3b) were obtained in 66% yield and 64% yield
respectively. The purification and isolation of the products was accomplished via water/acid
extraction, without the use of waste-intensive purification techniques. The gram syntheses of
amines 3a and 3b have been repeated multiple times and an amount of 150 g of each
cyclohexylamine was collected and delivered to Clariant Specialty Chemicals for further tests.
Next, the synthesised cyclohexylamines were converted into the corresponding surfactants. A
representative of each class of surfactants, described in 4.1.1 was chosen: N-oxide as non-
ionic surfactant, betaine as zwitterionic surfactant, and quaternary ammonium salt for the
cationic class. The quat and the betaine were synthesised in 62% and 67% yield respectively,
from the cyclohexylamine 3b, upon addition of benzyl chloride in EtOH, or bromoacetic acid
in a MeOH:H2O mixture (Scheme 55). The isolation of the two surfactants was carried out
without column chromatography or other waste-intensive purification techniques. After the
reaction time, the quaternary ammonium salt (5b) was isolated by removing the solvent under
reduced pressure, and by washing the residue with Et2O. The betaine 6b was isolated in a very
similar way. Upon completion of the reaction and evaporation of the solvent, the residue was
washed with Et2O, which was then removed under vacuum. The residue was dissolved in
dichloromethane and washed twice with water. The organic layers were combined and the
solvent was removed yielding the betaine 6b. (for more details see experimental section 8.2.3)
Quaternary ammonium salt
Betaine
(1 equiv)
EtOH, 85 °C, 15 h
(1 equiv)
MeOH:H2O (1:1)
80 °C, 10 h
5b, 62%
6b, 67%
Scheme 55. Synthesis of quat and betaine from N,N-dimethyl-3-pentadecyl-cyclohexylamine.
In the case of the N-oxide, the synthesis was accomplished by oxidation of 3a and 3b. The
amines were added dropwise to H2O2, the solvent was removed under reduced pressure and
Results and discussion
75
the residue was dried under vacuum yielding the corresponding products in excellent yields,
93% for the dibutyl-N-oxide and 94% for the dimethyl-N-oxide. Moreover, the whole
sequence consisting of the reductive amination of technical CNSL and oxidation of
cyclohexylamine to N-oxide, was successfully combined in a one-pot procedure, delivering
the dimethyl N-oxide in 71% yield with an exceptionally low E-factor of 2 (Scheme 56).352,353
H2O2
rt, 30 min
3b 4b, 71%1
HNMe2, Pd/C, H2
H2O, 100 °C, 15 h
n = 0, 2, 4, 6
CNSL
Scheme 56. One-pot synthesis of N-oxide from technical CNSL and dimethyl amine.
The surfactant properties, surface tension and aggregation behaviour, have been examined for
each surfactant using the pendant drop (PD) method. The pendant drop method is an optical
method for determining the surface or interfacial tension of a drop of liquid by measuring its
geometry.354 Drops are generated at the tip of a needle. Surface tension results in the drops
assuming the smallest possible surface area, spherical if no other forces act upon them. Due
to the gravity the drops start deforming, thus changing their shape. The degree of variation
from the spherical shape gives the relationship between the weight of the drop and its surface
tension. The actual dimensions of the drop are used in the calculation of the surface tension,
which is plotted against the surfactant concentration to obtain the cmc value (see 8.2.2.7). The
surface tensions of aqueous solutions 4b, 5b and 6b were measured over a wide concentration
range to determine the critical micellar concentration (cmc). The resulting critical micellar
concentration values resulted favourably comparable with the cmc values of analogous
commercial surfactants (Table 2).
Table 2. CMC value of the synthesised surfactants compared to their commercial analogues
Surfactant cmc Analogue commercial surfactant cmc
Amine oxide (4b) 28 M Lauryldimethylamine oxide 1700 M
Quat (5b) 0.5 M Stearyldimethylbenzylammonium chloride 310 M
Betaine (6b) 10 Lauryl betaine 2860 M
Results and discussion
76
Authors´contribution:
This work was performed in collaboration with Dr Raja Rit, Robin Kirchmann, and Dr
Stefania Trita. I have been responsible to lead this project. I have carried out the screening
that led to the discovery of the final reaction conditions in collaboration with Dr Rit. I took
care of the scope with isolation and characterisation of the compounds and the big scale
reactions (ca. 300 g of N,N-dibutyl-3-pentadecyl cyclohexylamine and N,N-dimethyl-3-
pentadecyl cyclohexylamine for Clariant Specialty Chemicals, prepared in several batches).
During the synthesis of surfactants from the cyclohexylamines and the measure of their
surfactant properties, I was assisted by Mr Kirchmann. I wrote the first draft of the manuscript
and supporting information. The correction of the first draft of the manuscript was done by Dr
Trita. The final submitted version was realised by Prof Dr L. J. Gooßen and me.
The results of this project have been published in Green Chemistry. The original publication
has been adapted for this work and enclosed: V. Bragoni, R. K. Rit, R. Kirchmann, A. S. Trita
and L. J. Gooßen, Green Chem. 2018, 20, 3210-3213 “Synthesis of bio-based surfactants from
cashew nutshell liquid in water”.57 It is reproduced and adapted by permission of The Royal
Society of Chemistry. Additional license by this journal is not required.
Results and discussion
77
Results and discussion
78
Results and discussion
79
Results and discussion
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Results and discussion
81
6.2 Synthesis of a tyrosinase inhibitor from cashew nut shell liquid
Tyrosinase inhibitors from natural sources are sought after, especially in food and cosmetic
applications, due to their lower toxicity and better bioavailability than synthetic inhibitors.
Several simple phenols and polyphenols from plants or animals, flavones, azoles or
thiazolidine derivatives, and kojic acids, have been studied for their tyrosinase inhibitory
activity. A few representatives structures are given in Figure 22.192,193,195
Kojic acid TropoloneResorcinol ArbutinFlavone
Figure 22. Structure of a some natural tyrosinase inhibitors.
The components of cashew nut shell liquid and several ginkgolic acids (GAs) can be included
in the class of inhibitors.79,355
In 1994, Kubo extracted the sixteen major components of CNSL and found that among them,
cardols and 2-methylcardols exhibit the strongest tyrosinase inhibitory activity, followed by
anacardic acids and cardanols, though cardols and methylcardols are the least available
compounds.
Ginkgolic acids are naturally occurring 6-alkylsalicylic acids with an alkyl chain of 13, 15, or
17 carbons and 0-2 double bonds. They occur in various plant materials, such as pistachios,
nuts, brown algae, and in the leaves of the Ginkgo biloba. However, the extraction and
isolation of the single compounds from their natural sources is a laborious and expensive
process.356–358 Thus, many synthetic strategies have been developed to obtain GAs. The group
of Tyman obtained GA (15:0) in low yield starting from 2-fluoroanisole, via sequential
alkylation and carboxylation with alkyllithium and CO2, followed by demethylation with
BCl3.359 Fürstner and co-workers prepared GA (15:0) using Suzuki cross-coupling reaction to
build the side chain.360 In 2013, the group of Fu synthesised GA (13:0) from 2,6-
dihydroxybenzoic acid and tested his inhibitory activity for the tyrosinase enzyme.355 The
Results and discussion
82
synthesis of ginkgolic acid (13:0) by Fu required five steps and afforded the targeted product
in an overall yield of only 34% (Scheme 57).
SOCl2acetone
DME
KOH
Tf2O
pyridine
DMSO
67%
CH2Cl2
73%
90%
PdCl2(dppf)
1-trideceneDMF
Pd/CH2
EtOAc
98%
78%
Scheme 57. Synthesis of ginkgolic acid (13:0) from 2,6-dihyroxybenzoic acid, by Fu.355
6.2.1 Ethenolysis and cross-metathesis of cashew nut shell liquid
Due to the structural similarities between anacardic acids and ginkgolic acids, the synthesis
of GA (13:0) starting from CNSL would be conceivable via a cross-metathesis with a selected
olefin and hydrogenation sequence. Nevertheless, since this renewable starting material is a
mixture of differently unsaturated alkenyl phenols, a simple cross-metathesis of the mixture
with a short olefin would deliver an inseparable mixture of many compounds, without the
possibility of isolating the targeted GA (13:0).
The aim of this project was to develop a new, straightforward synthesis of GA (13:0) from
CNSL via cross-metathesis, with a focus on avoiding waste-intensive isolation and
purification steps.
We comminuted cashew nut shells, collected from Naliendele in Mtwara, Tanzania, into ~1
mm small particles, which were than treated by Soxhlet extraction with several solvents at
50 °C for 6 h. Removal of the solvent in vacuo resulted in a highly viscous brown oil, the
natural CNSL that was used without further purification. To prevent the formation of a mixture
of olefins, we first needed to reduce the number of components present in the CNSL and
isolate one single compound that could be further functionalised to obtain the desired product.
Results and discussion
83
In 2014, our group successfully converted the mixture of anacardic acids into one single -
nonenyl phenol via ethenolysis (Scheme 58).90 The reaction worked in dichloromethane
(DCM) and room temperature, using a first-generation Hoveyda-Grubbs (HG) catalyst.
[Ru]
DCM, 16 h, rt 7
n = 0, 2, 4, 6
Scheme 58. Selective ethenolysis of anacardic acids by Gooßen.90
We envisioned that the same strategy, if applied to natural CNSL, would already considerably
reduce the number of components in the oil. Since the side-chain double bond closest to the
ring is at the C8 position in all the unsaturated components of the mixture, the ethenolysis
would shorten the unsaturated chains, regardless of the number of double bonds, to -nonenyl
groups, while the saturated chains would remain unaffected. If we could isolate the terminal
alkene 2-hydroxy-6-(non-8-enyl)benzoic acid from the mixture, this could be used as
substrates for a cross-metathesis with 1-hexene and subsequently reduced to GA (13:0).
The ethenolysis of natural CNSL was carried out by slightly modifying the reaction conditions
used in our previous protocol. A 1.1 M solution of CNSL in DCM was converted in high yield
into a mixture consisting of -nonenyl phenols and saturated pentadecyl phenols in the
presence of 0.5 mol% of a HG catalyst (Ru-1) and 10 bar of ethylene (Scheme 59).
R2 =
ethenolysis
CNSL
R1 =
Ru-1 (0.5 mol%)
10 bar
DCM, rt, 12 h
2
Scheme 59. Ethenolysis of natural CNSL.
The desired compound, 2-hydroxy-6-(non-8-enyl)benzoic acid (2), was isolated from the
mixture via selective precipitation in cold pentane, in 56% yield based on the content of
Results and discussion
84
anacardic acid in the entire CNSL mixture. The saturated anacardic acid, together with
cardanols and cardols, remain dissolved in pentane, allowing a fast and easy isolation by
washing the precipitate with cold pentane.
We next investigated the cross-metathesis of 2 with 1-hexene and the first-generation
Hoveyda-Grubbs catalyst Ru-1 (Table 3). The following table shows additional results to the
ones reported in the enclosed publication. Initially, several solvents were screened at twelve
and six hours (entries 1 - 10). Among them, DCM gave the best results in terms of conversion
and yield. Greener solvents such as p-cymene and dimethyl carbonate gave very low yields
(entries 3 - 4). During this screening, we observed that an open system was necessary for
reaching a good yield, by constantly releasing ethylene from the reaction mixture (entry 1 vs
entry 10). Decreasing the concentration did not affect the yield (entry 11), while increasing it
caused a drop of the yield (entry 12). A variation in time showed that 6 hours were sufficient
to obtain 70% yield (entries 13, 14). Next, several Ru-catalysts and different equivalents of 1-
hexene were tested (entries 15 – 21 and Figure 23). Increasing the catalyst loading to 2 mol%
only slightly increased the yield (entry 22).
Results and discussion
85
Table 3. Optimisation of the cross-metathesis of 1-hexene and noneyl benzoic acid
77
[Ru]
solvent, T, h
25
Reaction conditions: 2 (0.50 mmol), 1-hexene (given equiv), [Ru] (1.00 mol %), DCM (1 mL) 60 °C,
given time, open system via oil bubbler. Yields determined by GC using n-tetradecane as internal
standard. a room temperature, closed system. b 2 mL of solvent. c 0.5 mL of solvent. d 2 mol% [Ru].
# solvent 1-hexene (equiv) time [Ru] 5 (%) 2 (%)
1[a] DCM 7 12 h Ru-1 33 65
2 DEC " " " 43 41
3 DMC " " " 44 34
4 p-cymene " " " 3 72
5 Et2O " " " 70 13
6 H2O " 6 h " n.d. 98
7 toluene " " " 51 41
8 1-hexene " " " 61 33
9 THF " " " 42 49
10 DCM " " " 74 3
11[b] " " " " 72 2
12[c] " " " " 59 3
13 " " 1 h " 67 10
14 " " 12 h " 73 "
15 " " 6 h Ru-2 72 2
16 " 5 " " 68 1
17 " 7 " Ru-3 65 2
18 " 5 " " 65 1
19 " " " Ru-9 54 1
20 " " " Ru-8 2 29
21 " 10 12 Ru-7 73 0
22[d] " 7 6 Ru-1 76 3
Results and discussion
86
Ru-1
Ru-8 Ru-9 Ru-7
Ru-6
Ru-3 Ru-2
Ru-4 Ru-5
Figure 23. Metathesis Ru-catalysts.
The complete reaction equation, including the by-products, is reported below (Scheme 60).
An advantage of the developed protocol is that both the ethenolysis step and the cross-
metathesis step are mediated by the same catalyst. Disadvantages of this reaction are the use
of harmful DCM that could not be substituted by greener solvents and the high amount of 1-
hexene used. The metathesis catalyst is also capable of catalysing self-metathesis, and 1-
hexene is converted into the less reactive 5-decene (7), in an undesired side reaction.
Therefore, to achieve good turnover, an excess of alkene is required. 2-Hydroxy-6-(non-8-
enyl)benzoic acid (2) also undergoes self-metathesis generating the second by-product of the
reaction 2-[16-(2-carboxy-3-hydroxy-phenyl)hexadec-8-enyl]-6-hydroxy-benzoic acid (6).
Product 6 could not be seen on gas chromatography because of the high molecular mass. It
was recovered from the equivalent amount of four reaction mixtures in 80% yield (greyish
solid), by precipitation in pentane at room temperature.
Results and discussion
87
77
1-hexene (7 equiv)Ru-1 (1 mol%)
DCM (1 mL), 60 °C, 6 h7
72 5
7
6
Scheme 60. Complete reaction equation of the cross-metathesis step.
The targeted product, GA (13:0), was obtained by hydrogenation of 2-hydroxy-6-(tridec-8-
enyl)benzoic acid (5). It is known that ruthenium-metathesis catalysts can decompose into
species capable of acting in situ as hydrogenation catalysts.361 Thus, we attempt a one-pot
process where the hydrogenation step is achieved just by adding charcoal and methanol to the
crude reaction mixture after the cross-metathesis. The reaction was then stirred under 5 bar
H2 and the target product GA (13:0) (3) was obtained by precipitation in cold pentane in 72%
yield (Scheme 61). Combined with the ethenolysis/precipitation step, the overall sequence
afforded GA (13:0) in 61% yield based on the unsaturated anacardic acid content in CNSL.
1-hexene (7 equiv)Ru-1 (1 mol%)DCM 60 °C, 6 h
charcoalH2 (5 bar)
MeOH, 50 °C, 2 h
CNSL
C2H4 (10 bar)
Ru-1 (0,5 mol%)
DCM, rt, 12 h
1. cross-metathesis
2. hydrogenation
ethenolysis
2, 84% 3, 72%
7
Scheme 61. Three steps synthesis of GA (13:0) from natural CNSL.
Results and discussion
88
Authors´ contribution:
This work was performed in collaboration with Jacqueline Pollini. The project was started in
Kaiserslautern in 2015 by Ms Pollini. I joined the project in September 2016 in Bochum. Ms
Pollini has carried out the ethenolysis of the largest amount of CNSL in Kaiserslautern, and
Bochum. She has performed the first screening experiments already in Kaiserslautern. The
screening was repeated in Bochum: the plan and the set up of the reactions, as well as the data
analysis and interpretation was done by Ms Pollini and me together. I revised the first draft of
the manuscript written by Ms Pollini. I wrote the experimental part of the paper and the
supporting information. Ms Pollini and me wrote the first draft of the cover letter. The final
version of the manuscript was realised Ms Pollini, Dr Wolf M. Pankau, and Prof Dr Lukas J.
Gooßen.
The results of this project have been published in Beilstein Journal of Organic Chemistry. The
original publication has been adapted for this work and enclosed: Jacqueline Pollini, Valentina
Bragoni and Lukas J. Gooßen, Beilstein J. Org. Chem. 2018, 14, 2737–2744 “Synthesis of a
tyrosinase inhibitor by consecutive ethenolysis and cross-metathesis of crude cashew nutshell
liquid”.57 It is reproduced and adapted by permission of Beilstein-Institut under the terms of
the Creative Commons Attribution License. Additional license by this journal is not required.
Results and discussion
89
Results and discussion
90
Results and discussion
91
Results and discussion
92
Results and discussion
93
Results and discussion
94
Results and discussion
95
Results and discussion
96
Results and discussion
97
6.3 Catalytic, waste-free alkoxycarboxylation of terminal alkynes
The development of the reaction concept was done by Dr Timo Wendling, Dr Eugen Risto, and
Dr Thilo Krause and is described in section 6.3.1.
The preliminary studies of the carboxylation of aliphatic alkynes were carried out by Dr Thilo
Krause, Dr Benjamin Exner and Mr Marco Dyga and are described in section 6.3.2.
The rest of the chapter describes my work, performed in collaboration with Dr Benjamin Exner,
Mr Marco Dyga and Mr Tim van Lingen.
The repeated screening of all the three steps of the reaction was shared by Dr Exner and me
(sections 6.3.3.1and 6.3.3.2). I set up and performed the major part of the scope. I took care of
the isolation of the compounds and their characterisation, while Dr Exner was screening the
carboxylation of acetylene. I carried out the three-step reaction sequence starting from
potassium propiolate to dimethyl succinate and isolated the product. The alkoxycarboxylation
of acetylene to dimethyl succinate was set up by Dr Exner, but I accomplished the isolation of
the product. I took care of building the apparatus that served for the big scale reaction,
including ordering parts, connectors and safety measurements. I eventually ran the reaction
that unfortunately did not work. I carried out the final distillation of the big scale, with the
assistance of Mr Dyga.
Section 6.3.3.3 describes the recovery tests of K3PO4. This work was carried out in
collaboration with Mr Dyga.
Section 6.3.3.4 describes the new optimisation of the alkoxycarboxylation sequence with
Cs2CO3, which I accomplished in collaboration with Mr Dyga and Mr van Lingen.
6.3.1 Carboxylation of aromatic alkynes
Almost all known strategies involving the introduction of CO2 into organic molecules employ
prefunctionalised substrates such as organometallic compounds or aryl halides and/or the use
of stoichiometric amounts of reducing agent or base, representing a major drawback regarding
sustainability (see 4.5.4 and 4.5.5). Moreover, the isolation of the products requires either a
hydrolysis step or an esterification, leading inevitably to stoichiometric amounts of salt waste
and thus to a meager atom economy of the whole process (Scheme 62).
Results and discussion
98
HX
base or reducing agent [M]
+H-Base
X- +H-Baseor [MX]
or
Scheme 62. Classic carboxylations under basic or reductive conditions [M = reducing agent].
Sustainable use of CO2 as C1-building block should exploit carbon dioxide from available
resources (e.g. waste gas) and possibly, used without further workup. Solvents, additives,
catalysts, bases and ligands should ideally be completely recyclable, and the products easily
separated. Moreover, in order to make a significant contribution to the carbon dioxide
sequestration from the atmosphere, the obtained products should have a large-scale application
and ideally a long retention time of the CO2.
In this respect, the carboxylation of terminal alkynes has an enormous potential. This process
exploits the intrinsic acidity of the substrates activating the C–H bond by using copper or silver
salts. Sustainable catalytic C–H carboxylation should lead to carboxylic acids. However, this
reaction is thermodynamically unfavourable (for the free acid: ΔG° = 19.1 kcal/mol) and only
by stabilising the product as a carboxylate salt, a sufficient driving force to the reaction is
provided (for the carboxylate: ΔG° = -10.1 kcal/mol).362 Subsequent derivatisation steps for a
carboxylate, such as hydrolysis or esterification via nucleophilic substitution, inevitably lead to
the formation of a waste salt. An example of a salt-free process would be the hydrogenation of
the carboxylate upon regeneration of the base. However, the addition of a base, essential for the
carboxylation step, precludes the subsequent hydrogenation of the carboxylate, because only
the hydrogenation of a free carboxylic acid is thermodynamically feasible (for acetic acid: ΔG°
= -5.3 kcal/mol, for sodium acetate: ΔG° = 12.6 kcal/mol).127
A solution to overcome this apparently unbeatable thermodynamic hurdle was recently
proposed from our group who developed a Cu-catalysed hydroxymethylation of terminal
alkynes (Scheme 63).363 Gooßen and co-workers identified a suitable base, 2,2,6,6-
tetramethylpiperidine (TMP), which met the two opposite requirements of carboxylation and
hydrogenation, and that was subsequently regenerated in reasonable yield (40%).
Results and discussion
99
(15 bar)
+H-TMP
CuCl (1 mol%)BPhen (1 mol%)poly-PPh3 (2.5 mol%)
NMP, rt, 12 h
MeOH, filtrationRh/Al2O3 (2 mol%)
H2 (10 bar ), rt, 18 h
step 1
step 2
step 3
+H-TMP
Mo(CO)6 (2 mol%)
H2 (70 bar )
NMP, 180 °C, 14 hrecovery of the base
TMP
Scheme 63. Cu-catalysed hydroxymethylation of terminal alkynes with base recovery.
A catalyst system consisting of CuCl, bathophenanthroline (BPhen) and polymer-bound
triphenylphosphine (poly-PPh3) was employed in the carboxylation step with TMP as the base.
The resulting mixture was filtered after the carboxylation step (step 1) to remove poly-PPh3 and
copper ions that would hamper the subsequent hydrogenation. The hydrogenative reduction of
the carboxylate to the alcohol was catalysed by Rhodium on alumina at high temperature and
pressure with the addition of Mo(CO)6 as co-catalyst. To avoid the decarboxylation of the
carboxylate, a two-step approach was necessary: the triple bond was hydrogenated first yielding
a saturated ammonium carboxylate, which was hydrogenated to the corresponding alcohol,
regenerating the base TMP, which was separated and recovered in 40% yield by fractional
distillation. The key for the success of this reaction was the discovery of the base TMP (pKa in
MeCN = 18.6) that was just strong enough to deprotonate the alkyne and produce the acetylide
anion, while still allowing the hydrogenation of the ammonium carboxylate. This reaction
demonstrates the possibility of bridging the pKa gap between carboxylation and hydrogenation,
which enabled a hydroxymethylation of alkynes without formation of salt waste. However, the
substrate scope was limited to only aromatic alkynes that were converted into the corresponding
alcohols with yields staying around 70%, while aliphatic alkynes could not be carboxylated
Results and discussion
100
under these conditions. Possible reasons for this limitation could be: the copper acetylide
intermediate is more stabilised by conjugation to the aromatic ring; the aliphatic alkynes have
poor solubility in the polar TMP/NMP mixture, thus preventing their efficient carboxylation;
or as last, the difference in acidity of the aliphatic alkynes from the aromatic substrates.
Although this gap is only minor (pKa = 23.2 for phenylacetylene vs 25.5 for tert-
butylacetylene),364 it can have a significant effect on the yield of the carboxylation.
More details on this reaction can be found in the PhD theses of Dr Timo Wendling, Dr Eugen
Risto and Dr Thilo Krause.365–367
6.3.2 Carboxylation of aliphatic alkynes
The ambitious aim of this project was to develop a new zero-waste carboxylation-
hydrogenation sequence applicable to both aryl and aliphatic alkynes. No organic base able to
induce the carboxylation of aliphatic substituted alkynes could be identified. Hence, inorganic
bases had to be employed, resulting in the formation of inorganic carboxylates, whose direct
hydrogenation to alcohols was hindered due to thermodynamic limitations. To overcome their
thermodynamic stability, we opted for an esterification of the intermediate carboxylates.
(Scheme 64).368
carboxylation hydrogenation
hydrogenation
esterification
Scheme 64. Design of the new reaction concept. MX = inorganic base.
Classical esterification methods use alkyl halides in basic conditions, or alcohols with
acidification of the reaction mixture, but both approaches would inevitably generate significant
amounts of waste (Scheme 65a-b). However, promising results showed that CO2 can enable
the esterification of sodium, calcium and caesium carboxylates by acting as a Lewis acid, thus
acidifying the reaction medium (Scheme 65c).317,369,370
Results and discussion
101
R'-X
R'OH
HX
R'OH
CO2, T
M+X-
H2O
MHCO3
M+X-
a
b
c
Scheme 65. Possible esterification methods of carboxylic acids.
It is not yet clear how the CO2-mediated esterification exactly works. The group of Kulkarni
studied the influence of different amounts of water on the reaction: in the absence of water, the
reaction is slow, but high contents of water also slow down the esterification rate.369 Their
studies indicated an optimal concentration of water in a range between 1.5 and 6%. On the
contrary, Kanan and co-workers carried out this reaction in anhydrous alcohols claiming an
improvement of the yields of esterification, by in situ removal of the produced water.317 The
assumption of Kulkarni’s group seems more plausible since carbonic acid is formed in situ from
carbon dioxide and water, leading to acidification of the reaction mixture. Thus, the
esterification should follow the classical addition-elimination mechanism with alcohols. We
reckoned in this method a valuable tool for the design of our desired “dream reaction”. To
follow such an approach, however, an optimisation of the upstream carboxylation conditions of
aliphatic alkynes was needed.
The first screening, which led to the discovery of the optimal base and catalyst, was carried out
by Dr Thilo Krause with the support of Dr Benjamin Exner and Mr Marco Dyga. The initial
screening carried out by Dr Krause will be briefly summarised here, but detailed information
can be found in the PhD theses of Dr Krause367 and Dr Exner.371
To screen the conditions for the carboxylation of aliphatic terminal alkynes, 1-heptyne was
chosen as model substrate. The optimisation started from the bases: among them, potassium
phosphate was the only inorganic base able to yield the desired product, so being compatible
with both the carboxylation and hydrogenation steps as indicated by an initial test reaction.
Polar aprotic solvents such as DMF, DMAc, NMP gave reasonable yields, while 1,4-dioxane,
MeCN or polar protic solvents such as methanol did not afford the product in good yields.
DMSO could not be used in this protocol, because of incompatibility with the downstream
Results and discussion
102
hydrogenation step. Several Cu(I) and Cu(II) species were tested, as well as some silver salts
and N-containing ligands. The best results were obtained with simple copper bromide.
To screen the downstream hydrogenation step, 2-octynoic acid was chosen as substrate and
added to a reaction mixture mimicking the conditions after the carboxylation of 1-heptyne
(CuBr, NMP and K3PO4). Heterogeneous palladium on alumina, Pd/Al2O3, yielded the product
quantitatively already at room temperature and 20 bar of hydrogen.
At last, initial tests for the CO2-induced esterification were performed. The model substrate was
potassium octanoate, which was expected to be the product of the sequential carboxylation-
hydrogenation of 1-heptyne with potassium phosphate as base. The first experiments at 230 °C
and 50 bar CO2, showed similar results to the publications of Kanan317 and Kulkarni369 with
methanol, both, as reactant and solvent. Addition of 100 μl of water to the reaction mixture did
not negatively influence the reaction, as reported by the group of Kanan. However, at this stage
of the screening, 15 mL of solvent were necessary to assure an optimal stirring of the solution,
and 25 mL were necessary for a quantitative conversion, probably because a deposit of the
reaction mixture on the walls of the autoclave (autoclave vessel 50 mL) occurred when using
less solvent. A short screening on the solvents showed that more than 13% of NMP in the total
volume caused a drop in the yield. This result is of vital importance, because it highlighted the
necessity of using as less NMP as possible in the carboxylation step and thus, the necessity to
add the alcohol as co-solvent from the hydrogenation step. The alcohol needed to be in excess
since it had to act not only as solvent in the hydrogenation step to assure a good stirring, but
also as solvent and reactant in the following esterification step. The choice of employing
methanol as alcohol brought a substantial limitation to the reaction setup because, at 180 °C,
the pressure in the gas phase was over 100 bar due both to the CO2 and MeOH(g) pressures. The
only autoclave suitable for high pressure and temperatures in our laboratories is the Parr 4590
(set for 345 bar and 350 °C) where only one reaction at a time can be set up, limiting the
possibility of a rapid and efficient screening. To speed up the investigation, it was decided to
switch back to autoclaves with space for eight parallel experiments. However, those autoclaves
can hold a maximum pressure of 100 bar, which at the same time affected the choice of the
alcohol that needed to act as solvent and reactant. Thus, a higher-boiling alcohol, octanol (b.p.
= 195 °C), was chosen. Several temperatures and pressures were tested but, in each case, the
by-product, dimethylbis(octyloxy) silane was observed, which derived from the reaction of the
alcohol with the silicon caps of the vials, and whose separation from the product was very hard.
Results and discussion
103
Finally, the first overall sequence of carboxylation, hydrogenation and esterification was
developed by Dr Krause, Dr Exner and Mr Dyga (Scheme 66). However, this procedure still
carried the big problem of the non-reproducibility of the results. At this stage of the project,
even though the recycling of the base was not yet tested, there was great confidence that a
thermal recycling of the mixture of KHCO3 and K2HPO4, which would form during the
reaction, would regenerate the tribasic phosphate base upon release of CO2 in a waste-
minimised procedure, in which water was the sole by-product.
possible recycling of the base KHCO3
K2HPO4
K3PO4
T
H2O + CO2
CO2
CuBr (3 mol%)K3PO4 (2 equiv)
NMP, 70 °C, 12 h
carboxylation esterificationhydrogenation
30 bar
Pd/Al2O3 (2 mol%)
H2 (20 bar)
R'OH, rt, 12 h
CO2 (45 bar)
180 °C, 12 h
yields: 58-70%
Scheme 66. First developed alkoxycarboxylation sequence of terminal alkynes.
Starting from this moment, I joined the project in collaboration with Dr Exner.
6.3.3 Own work
6.3.3.1 Alkoxycarboxylation of aliphatic alkynes with K3PO4 as base
The poor reproducibility of the developed alkoxycarboxylation (Scheme 66) was the main issue
to be tackled. Hence, a more accurate optimisation of all the three steps of the reaction was
repeated. To keep compatibility with the previous screening we chose 1-heptyne as model
substrate, but this time we decided to perform the first optimisation with the sequence of the
carboxylation and hydrogenation steps, since the hydrogenated carboxylate was more stable in
the following esterification compared to the non-hydrogenated carboxylate. In order to do so,
the downstream hydrogenation step was optimised first, starting from the potassium 2-
octynoate, obtained by placing 2-octynoic acid (4a) in a simulated reaction mixture present
after carboxylation (Table 4). Different transition metals and supports were tested (entries 1-
9). Among them, palladium on alumina and palladium on charcoal resulted to be the best and
we decided to pursue the screening with the cheaper Pd/Al2O3 that gave quantitative conversion
Results and discussion
104
after 2 hours at room temperature. Different amounts of NMP and other solvents were screened
(entries 10 to 16). Finally, the pressure parameter was tested (entries 17 to 19), and the product
was obtained in 96% yield at atmospheric H2 pressure.
Table 4. Optimisation of the triple bond hydrogenation of potassium 2-octynoate
MeI (8 equiv)
MeCN (2 mL)50 °C, 2 h
4a 3ad
cat (2 mol%)K3PO4 (2 equiv)
H2 (bar)
solvent, rt, time
hydrogenation esterification
Reaction conditions: 4a (0.50 mmol), cat. (2.00 mol%), K3PO4 (2 equiv), solvent (2 mL), H2 (bar), rt.
Yields of methyl octanoate determined by GC analysis using n-tetradecane as internal standard.
# cat solvent (mL) H2 (bar) t (h) 3ad (%)
1 Pd/C NMP (2) 20 12 98
2 Pd/Al2O3 " " " 97
3 Pt/C " " " 91
4 Pd(OH)2/C " " " 84
5 Ru/ Al2O3 " " " 70
6 Rh/ Al2O3 " " " 81
7 Ru/C " " " 57
8 Pd/ Al2O3 " " 6 97
9 " " " 2 97
10 " " " 3 87
11 " NMP (3) " " 91
12 " NMP (1) " " 92
13 " NMP (0,5) " " 96
14 " MeOH (2) " " 85
15 " Octanol (2) " " 82
16 " NMP/MeOH (1:1) " " 96
17 " NMP (2) 10 " 95
18 " " 5 " 95
19 " " 1 " 96
Results and discussion
105
With the optimised hydrogenation conditions in our hands (2 mol% Pd/Al2O3, 2 mL MeOH,
5 bar H2, rt, 3h) we started the screening of the carboxylation/hydrogenation sequence of 1-
heptyne (1a) (Table 5). The preliminary solvent screening confirmed that NMP and DMF were
the best solvents for the reaction (entries 1 to 5). Among the tested bases, K3PO4 and Cs2CO3
gave the highest yields (entries 6 to 10). It was decided to continue the screening with K3PO4
due to its lower price. By testing K2HPO4, which did not provide product, we proved that
potassium phosphate could only act once as a base. Following, we tested several copper and
silver catalysts, as well as P-based ligands (entries 11 to 18). With delight, we found that already
0.2 mol% of CuBr was sufficient to catalyse the reaction and the use of ligands did not further
improve the yield. This allowed us to lower the catalyst load considerably, compared to the
initial reaction conditions (Scheme 66). A brief screening of the amount of NMP showed that
already 0.1 mL of NMP were enough to carboxylate the substrate (entries 19 to 21). Finally,
while higher or lower pressures than 10 bar CO2 diminished the yield, this could be improved
to 76% by increasing the reaction temperature to 80 °C (entries 22 to 27).
Table 5. Optimisation of the carboxylation and following hydrogenation of 1-heptyne
1a
cat (mol%)base (2 equiv)CO2 (bar)
solvent, T, t
PdAl2O3 (2 mol%)
H2 (5 bar)
MeOH (2 mL) rt, 3 h
carboxylation hydrogenation
3ad
esterification
MeI (8 equiv)MeCN (2 mL) 50 °C, 2 h
# cat (mol%) ligand (mol%) base solvent (mL) T (°C) p (bar) t (h) 3ad (%)
1 CuBr (1) - K3PO4 NMP (0.2) 70 10 12 72
2 " - " DMF (0.2) " " " 73
3 " - " DMAC (0.2) " " " 69
4 " - " DMSO (0.2) " " " 14
5 " - " PC (0.2) " " " 15
6 " - K2HPO4 NMP (0.2) " " " 0
7 " - Cs2CO3 " " " " 75
8 " - K2CO3 " " " " 3
9 " - DBU " " " " 20
Results and discussion
106
Reaction conditions: Step 1: 1a (0.50 mmol), base (2 equiv), catalyst (0.20 mol% metal), ligand (0.50
mol%), solvent (0.10 mL), 80 °C, 10 bar CO2 (at rt), 12 h; Step 2: Pd/Al2O3 (2.00 mol%), MeOH (2
mL), rt, 5 bar H2, 3 h. Yields of methyl octanoate determined by GC analysis using mesitylene as internal
standard.
Once the first two steps of the sequence were optimised, we investigated the CO2-mediated
esterification of potassium octanoate by mimicking the reaction mixture that is present after the
triple-bond hydrogenation. In this step, we decided to employ a different alcohol than n-octanol,
which was chosen in the first optimisation screening by Dr Krause. Due to a very low polarity
the isolation of the aliphatic long-chain octanol esters from the reaction mixture appeared to be
extremely difficult, causing a dramatic drop in the isolated yields. Therefore, we looked for a
low vapour pressure alcohol, which still allowed parallel screening in the 100 bar-autoclaves,
yet more polar than octanol to achieve a separation from the products. 2-(2-
methoxyethoxy)ethanol (2a) was chosen for the esterification of octanoic acid (Table 6).
Already 43% yield was obtained by performing the reaction at 160 °C for 14 hours (entry 1).
10 " - TMP " " " " 0
11 CuBr (0.75) - K3PO4 " " " " 73
12 CuBr (0.5) - " " " " " 74
13 CuBr (0.2) - " " " " " 71
14 CuCl (0.2) - " " " " " 43
15 AgNO3 (0.2) - " " " " " 59
16 Ag3PO4 (0.067) " " " " " 51
17 CuBr (0.2) BathoPhen (2.5) " " " " " 51
18 " Poly-PPh3 (2.5) " " " " " 36
19 " - " NMP (1) " " " 77
20 " - " NMP (0.5) " " " 73
21 " - " NMP (0.1) " " " 71
22 " - " " 60 " " 6
23 " - " " 80 " " 76
24 " - " " " 5 " 50
25 " 30 " 48
26 " - " " " 10 16 55
27 " - " " " " 8 52
Results and discussion
107
By increasing the reaction time to 20 h, the amount of co-solvent, and the temperature to 180 °C,
the reaction worked quantitatively (entries 2 to 4), while increasing the amount of base or
lowering the CO2 pressure had a negative impact on the reaction outcome (entries 5 to 7).
Table 6. Optimisation of the esterification of potassium octanoate under CO2 pressure
CuBr (1 mol%)K3PO4 (2 equiv)
NMP (0.1 mL)CO2 (bar), T (°C), t
2 2
2a 3aa5a
Reaction conditions: octanoic acid, (5a) (0.50 mmol), 2-(2-methoxyethoxy)ethanol (2a), K3PO4 (2
equiv), CuBr (1.00 mol%), NMP (0.10 mL). [a] Pressures at room temperature. [b] K3PO4 (3 equiv). Yields
determined by GC analysis using mesitylene as internal standard.
Finally, a three-step sequence, which uses carbon dioxide as a C1-building block for the
alkoxycarboxylation of terminal alkynes and K3PO4 as base, was developed and applied to a
variety of substrates (Table 7). Both alkyl and aryl alkynes were converted into the
corresponding esters in moderate to good yields. Most of the substrates were isolated as esters
of methylcarbitol (2a), due to its high polarity and thus, easier purification, but also other esters
from methanol, n-octanol and isopropanol, have been isolated (3db, 3nc, 3nd). Various
substituted-arylacetylenes have been tested to probe the robustness of the reaction. The
trifluoromethyl substituent gave a very low reaction outcome (3ma). A free amino group was
not tolerated, probably due to the carbamate formation. However, starting from the nitro group
and, reduction of this group during the hydrogenation, yielded the amino-substituted ester in
62% yield (3ka). Methyl propargyl ether could be transformed into the corresponding ester
when n-octanol and methylcarbitol were used as alcohols (3da and 3db).
# 2a t (h) T (°C) p (bar)[a] 3aa (%)
1 3 mL/51.4 equiv. 14 160 50 43
2 3 mL/51.4 equiv. 20 " " 58
3 5 mL/85.7 equiv. " " " 70
4 5 mL/85.7 equiv. " 180 " 95
5[b] 5 mL/85.7 equiv. " " " 87
6 5 mL/85.7 equiv. " " 30 83
7 5 mL/85.7 equiv. " 200 " 75
Results and discussion
108
Table 7. Scope for the alkoxycarboxylation of terminal alkynes
CO2
carboxylation
CuBr (0.2 mol%)K3PO4 (2 equiv)
80 °C, 12 h, NMP
hydrogenation-esterification
Pd/Al2O3 (2 mol%)
180 °C, 20 h
10 bar
R'' OH (2a-d)H2 (5 bar), rt, 3 h
CO2 (45 bar)
1a-r 3aa-qa, db,nc-nd
3ca: 65%n = 4, 3aa: 81%n = 5, 3ba: 69%
n
R'' = (C2H4O)2Me 3da: 24%
R'' = n-octyl, 3db: 47%
3ma, 24%
R' = o-OMe, R'' = Me, 3nd: 95%
R' = o-OMe, R'' = (C2H4O)2Me, 3na: 99%
R' = o-OMe, R'' = iPr, 3nc: 13%
R' = m-OMe, R'' = (C2H4O)2Me, 3oa: 87%
R' = p-OMe, R'' = (C2H4O)2Me, 3pa: 55%
R = Me, 3ha: 63%R = F, 3ia: 65%
3qa: 68%
n = 2, 3ea: 68%n = 1, 3fa: 41%n = 0, 3ga: 52%
R = m-NH2, 3ja: 30%
R = p-NH2, 3ka: 62%[a]
R = p-NMe2, 3la: 78%
n
Reaction conditions: Step 1: 1 a–r (1.00 mmol), K3PO4 (2.00 mmol), CuBr (0.20 mol%), NMP (200
µL), 80 °C, 10 bar CO2, 12 h. Step 2: 2 a–d (10 mL), Pd/Al2O3 (2 mol%), rt, 5 bar H2, 3 h. Step 3:
180 °C, 45 bar CO2 (at rt), 20 h. Isolated yields. [a] Starting from 4-nitrophenylacetylene. 2a: 2-(2-
methoxyethoxy)ethanol. 2b: n-octanol. 2c: 2-propanol. 2d: methanol.
A few substrates appeared to be non-compatible with the reaction conditions (Figure 24).
Thienyl aryls gave non-reproducible results during the hydrogenation, resulting in mixtures of
non-hydrogenated to fully hydrogenated products in varying ratios. Small substrates such as
propargyl alcohol, amine, acetate, methyl or ethyl propiolate, t-butyl- or cyclopropyl acetylene
were not converted. Probably due to their low boiling points and therefore an high volatility
under those reaction conditions, these substrates become “unavailable” starting materials for
the reaction.
Results and discussion
109
propargyl acetate methyl/ethyl propiolate
2-ethynylthiophene
propargyl alcoholor propargyl amine
tert-butylacetylene cyclopropyl acetylene
3-ethynylthiophene1,4-diethynylbenzene
methyl propargyl ether
Figure 24. Substrates not suitable for the alkoxycarboxylation of terminal alkynes.
6.3.3.2 Carboxylation of acetylene and potassium propiolate
The most desirable substrate for industrial application would be acetylene, which would be
converted in 1,4-butanediol (BDO). Acetylene is produced by thermal cracking of methane,
which might derive from renewable resources, and a twofold carboxylation of acetylene,
followed by a waste-free hydrogenation-esterification sequence, could represent a zero-waste
synthesis of the bulk chemical BDO based on renewable resources. The proof of the feasibility
of this reaction was already previously provided in our group by Dr Timo Wendling and Dr
Eugen Risto in a patent with BASF SE, wherein the authors obtained the desired product in 7%
yield calculated on the amount of base used (Scheme 67)372.
2 CO2 2 K3PO4
CuI (1 mol%)NMP (20 mL)
70 °C, 14 h
Pt/Al2O3 (0.5 mol%)
MeOH (80 mL)H2 (70 bar)
rt, 14 h
1) distillation of the solvent2) MeOH (80 mL)CO2 (20 bar)
165 °C, 14 hRu-MACHO (1 mol%)
NaOMe (10 mol%)MeOH (3 mL)
H2 (50 bar)
100 °C, 16 h
2 HK2PO4
2 HK2PO4
2 HK2PO4
2 KHCO3
1.7 bar 3.3 bar 17.3 g
400 mg7% based on the base
Scheme 67. Synthesis of BDO from acetylene and CO2 by Gooßen et al.
Results and discussion
110
Despite being a great achievement, this process suffered from the low overall yield. With the
new developed reaction sequence in our hands, we first tried to convert potassium propiolate
(1r), which is an intermediate in the twofold carboxylation of acetylene into dimethyl succinate
(DMS). Dimethyl succinate can be reduced to 1,4-butanediol in 98% yield following the
process reported by Kuriyama373 and already proofed in the Gooßen group. A brief screening
showed that a few changes in the reaction conditions optimised for 1-hetpyne were necessary:
with higher amount of NMP and base, and longer reaction time in the carboxylation and
esterification steps, DMS (3rd) was obtained in 57% yield (Scheme 68).
CuBr (0.2 mol%)K3PO4 (3 equiv)
NMP (4 mL)
80 °C, 16 hCO2
10 bar
45 bar CO2
180 °C, 45 h
3rd: 57%
MeOH (20 mL)2 h, rt
Pd/Al2O3 (2 mol%)
H2 (5 bar)
1r
carboxylation hydrogenation
esterification
Scheme 68. Synthesis of dimethyl succinate from potassium propriolate. Reaction on 2 mmol scale.
Encouraged by this promising result, we applied our procedure to acetylene. Here, a longer
reaction time was necessary in the carboxylation step, possibly because of the two sites that
needed to be carboxylated, and of the solvation competition between acetylene and CO2 in
NMP. In parallel, the amount of NMP was increased to 8 mL to ensure a better stirring of the
two gases into the solution. Under these conditions, DMS was synthesised in 53% yield
(Scheme 69).
Results and discussion
111
1 bar
CuBr (0.2 mol%)K3PO4 (3 equiv)
NMP (8 mL)
80 °C, 40 hCO2
10 bar
45 bar CO2
180 °C, 46 h
3ra: 53%
MeOH (30 mL)2 h, rt
Pd/Al2O3 (2 mol%)
H2 (5 bar)
carboxylation hydrogenation
esterification
Scheme 69. Synthesis of dimethyl succinate from acetylene. Reaction in 2.5 mmol scale.
At this stage of the project, the recyclability of the base was yet to be proved. Thus, to probe
the plausibility of a waste-free industrial utilisable process, we intended to run the reaction in
larger scale to isolate the product from the filtrated mixture by distillation and collect enough
solid-residues to perform the recyclability tests.
To yield a sufficient amount of solid residue, it was decided to start the reaction with potassium
propiolate since the acetylene partial pressure may not exceed 1.7 bar due to safety reasons and
thus limiting the maximum yield of the reaction. Initially, since we did not possess a suitable
apparatus to run a big scale reaction at high pressures and high temperatures, I was assigned to
build an appropriate equipment. One limitation encountered was the autoclave: because of the
high volume needed, it was impossible to run the complete reaction sequence in the 50 mL
vessel of the Parr autoclave. The 1-litre autoclave in our possession had a maximum allowable
working pressure of 130 bar. Thus, we decided to employ a lower boiling point alcohol since
with methanol (b.p. = 64 °C) the pressure could have likely increased above 130 bar during the
esterification step. The alcohol chosen was n-propyl alcohol (b.p. = 97 °C), which would
produce dipropyl succinate according to the reaction design in Scheme 70. At the same time, a
proper heating bath, a heating transfer medium and proper connections between the bath and
the autoclave needed to be found and built. Once the apparatus was ready to be safely operated,
we could run the reaction. For the first two steps of the sequence, the Parr autoclave was used,
where two different batches of potassium propiolate, 20 mmol each, were run subsequently.
The resulting mixtures, containing potassium succinate, catalysts, alcohol, and residual bases
were transferred into the 1L autoclave with additional 300 mL of n-propanol for the
Results and discussion
112
esterification step. Unfortunately, during this step, an overpressure caused a rupture of the
safety disk of the autoclave preventing the completion of the experiment.
CO2
10 bar
CO2 (50 bar)
n-PrOH (300 mL)
180 °C, 40 h
CuBr (0.2 mol%)K3PO4 (3 equiv)
NMP (20 mL)80 °C, 16 h
Pd/Al2O3 (2 mol%)
H2 (5 bar)
n-PrOH (10 mL)
2 h, rt
1) carboxylation (x 2)
2) hydrogenation (x 2)
3) esterification
4) filtration
5) distillation
6) regeneration of the base(2 x) 2.2 g
Scheme 70. Big scale alkoxycarboxylation of potassium propiolate with n-propanol.
Nevertheless, we were confident that, with proper equipment, this reaction sequence could be
successfully performed on larger scale. Thus, to prove the feasibility of a sustainable process,
we ran the distillation of a simulated 6 g scale reaction mixture expected after the three steps
sequence. At first, propanol was removed under reduced pressure, and most of NMP was
distilled, leaving a residue consisting of dipropyl succinate and a small quantity of NMP. An
additional fine distillation of this residue was carried out, and dipropyl succinate was recovered
as a colourless oil in 80% yield.
6.3.3.3 K3PO4-recovery experiments
According to our waste-free dream reaction, the collected bases, filtrated after the reaction
sequence, should be “reactivated” for a second-round of alkoxycarboxylation. Since this
essential part of the designed reaction was not proofed before, I focused on investigating
whether K3PO4 could be recycled from the obtained mixture of bases. Hypothetically, at the
end of the three-step sequence a mixture of dibasic potassium phosphate (K2HPO4) and
potassium bicarbonate (KHCO3) would form via a reaction between the base and carbonic acid,
which is formed from water and carbon dioxide during the esterification. Under thermal
treatment, this mixture subjected to thermal treatment should in principal regenerate tribasic
potassium phosphate (K3PO4) upon releasing of CO2 and H2O(g) (Scheme 71).
K2HPO4 KHCO3
K3PO4 CO2H2O
Scheme 71. Hypothesised thermal recovery of potassium phosphate and bicarbonate.
Results and discussion
113
As a first recycling-attempt, we run the three steps sequence starting from 1-heptyne, with
methyl carbitol as alcohol. The solid-precipitate, which possibly contained residual base,
catalysts and residual unreacted potassium octanoate, was filtered, washed with methanol,
diethyl ether and dried under reduced pressure. Five aliquots were taken and dried for 2h at
different temperatures (100 °C, 200 °C, 300 °C, 400 °C, 500 °C). The dried solids were then
reused for the carboxylation of 1-heptyne, but no product formation was observed.
Thus, we decided to investigate more in-depth the state of the base after the reaction and why
the thermal treatment did not regenerate K3PO4. To do so, we needed to generate more material
for further analysis and experiments. Only the last step of the reaction, the CO2-mediated
esterification of our model substrate potassium octanoate with methyl carbitol, was performed
without placing the catalysts in the mixture (Scheme 72).
K3PO4 (2 equiv)
NMP (0.1 mL)CO2 (50 bar)
180 °C, 20h
2K2HPO4 KHCO3
expected solid-residue
after reaction
Scheme 72. Expected solid-residu after esterification of octanoic acid with methyl carbitol.
After filtration, we washed the salts with diethyl ether and methanol and dried them under
reduced pressure. Five aliquots, each containing ca. 300 mg each of the solid, were taken and
subjected to high temperature-treatments (100 °C, 200 °C, 300 °C, 400 °C, 500 °C for 16 h).
They were all characterised by pH measurement, 31P- and 13C-NMR, and IR spectroscopy and
additionally tested in the carboxylation of 1-heptyne, which, as expected from the results of the
prior thermal recovery, did not work.
As shown by Stewart and Mcdowell in 2005,374 31P-NMR can be used as pH probe in aqueous
solutions (Figure 25). Therefore, we decided to verify the basicity-return of the base by 31P-
NMR and pH of the aqueous solutions of the solids after heat treatment (Figure 26 and Figure
27). The analyses were compared with the reference analytics of pure K3PO4 (4.02-6.19 ppm),
K2HPO4 (2.81 ppm), and KH2PO4 (0.12 ppm).
Results and discussion
114
Figure 25. 31P-NMR shift and pH correlation for pyrophosphate and orthophosphate solutions.374
Both 31P-NMR and pH paper of the recovered base confirmed that heat treatments increased the
pH value to more alkaline conditions. However, while the pH results seemed to indicate a return
of basicity (Figure 26), 31P-NMR spectra showed that instead of the regeneration of K3PO4, the
main reaction during heat treatment is the condensation of several units of orthophosphate, into
pyro- and polyphosphates. The condensation removes H2O and thus increases pH, but do not
seem to contribute in the release of CO2 and up-following regeneration of K3PO4 (Figure 27).
The IR spectra (KBr pellet) of the recovered bases, compared to pure K3PO4, showed a small
shoulder next to the phosphate peak (1015 cm-1), which corresponds to pyrophosphate (Figure
28). Moreover, the 13C-NMR spectra of the recovered bases showed a small peak at 169 ppm,
confirming the presence of carbonate ions in the solids, meaning that the release of potassium
carbonate did not occur.
Figure 26. pH paper of recovered salts after heat treatments (100 °C < T < 500 °C).
Results and discussion
115
Figure 27. 31P-NMR of recovered salts after heat treatments (100 °C < T < 500 °C). All 31P-NMR
spectra were referenced to tetrabutylphosphonium bromide, Bu4PBr (33.33 ppm), which was
previously referenced with phosphoric acid (0.00 ppm).
Figure 28. IR of K3PO4 subjected to carboxylation conditions (180 °C, 45 bar CO2 at rt).
Results and discussion
116
Thus, for further investigations, several batches of K3PO4 were treated under either
carboxylation or esterification conditions in the presence of varying components of the reaction
mixture (Table 8). The resulting salt mixtures were characterised by pH measurement, 31P- and
13C-NMR, and IR spectroscopy, and some of them have been reused in a follow-up
carboxylation of 1-heptyne. As a starting point, K3PO4 was placed in the reaction mixture of
the CO2-promoted esterification without catalyst, under CO2 pressure at 180 °C for 20 h. The
solids, recovered by filtration, showed a 31P-NMR signal shifted towards neutral pH, which was
also confirmed by pH paper, indicating that the base lost its basicity during esterification.
To gather information if the loss of basicity occurs already during carboxylation, we decided to
place the base under carboxylation conditions (10 bar, 80 °C). By systematically reducing the
number of components in the reaction mixture, we found that the acid and alcohol were not
responsible for the deactivation (entries 1-4), since the base, analysed by NMR and pH paper,
still showed a shift towards more neutral pH. To get more accurate values, starting from entry
5 we changed the method to determine the pH: instead of evaluating the basicity of unknown
concentrated solutions of the base via indicator paper, we measured the pH of equally
concentrated solutions (10 mg base in 1 mL H2O) via pH meter. Next, we tested whether the
solvent played a role in the deactivation of K3PO4 (entries 5-9). The base was subjected to
carboxylation conditions (80 °C, 10 bar CO2) with several solvents, which were then removed
by distillation. The pH values and 31P-NMR of the bases seemed to indicate a return to basicity,
but they all showed inactivity in the follow-up carboxylation. Following, the recovery method
was tested. Independently from the subjection of the base to CO2 pressure, it remained inactive
in the follow-up carboxylation when a recovery via distillation was carried out, whereas
centrifugation or direct use of the base without any work-up, seemed to affect its activity less
(entries 9-12). As last, we wanted to verify whether only the CO2 pressure, affected the basicity,
by subjecting the neat base without solvent under CO2 pressure (entries 13-14). After being
subjected to carboxylation conditions (80 °C, 10 bar CO2), the base resulted to be still active
for a follow-up carboxylation of 1-heptyne. On the contrary, subjecting K3PO4 to esterification
conditions (180 °C, high CO2 pressures), completely deactivated the base for a follow-up
carboxylation.
Results and discussion
117
Table 8: Study of the deactivation of K3PO4
3aa
K3PO4"base"
solvent, 80 °C, 12 h
CO2
2 2
5a 2a
Reaction conditions: K3PO4 (1.0 mmol) was heated under stirring with a mixture of the following
substances, if checked: octanoic acid (0.5 mmol), methyl carbitol (5 mL), solvent (0.1 mL), and CO2.
Afterwards, the salt was worked up according to the “base recovery” method described below. [a] CO2
pressure at rt. [b] 31P-NMR shift of orthophosphate in D2O/H2O (1:1, varying concentrations) using
Bu4PBr (δ=33.33 ppm) as internal standard. [c] pH determined by indicator paper or pH meter (from
entry 5, 0.67 M in H2O). [d] 45 bar CO2 at rt, 180 °C, 20 h. Filtration: The bases were filtrated through a
filter paper, washed with diethyl ether and methanol, dried in vacuum. Distillation: Solvents were
removed by Kugelrohr distillation (180 °C, 0.02 mbar). Centrifugation: The bases were collected and
centrifuged by addition of toluene (x 3). [e] Reaction conditions of follow-up carboxylation: 1-heptyne
(0.50 mmol), base (2 equiv.), CuBr (0.2 mol%), NMP (0.1 mL), CO2 (10 bar); then: iodomethane (8
equiv.), MeCN (2 mL). Yields determined by GC analysis using mesitylene as internal standard. nd =
not detected. PC = propylene carbonate. DMAc = dimethyl acetamide. GVL = gamma valerolactone.
In parallel, base-regeneration experiments were carried out on the solid collected from mixtures
of the CO2-mediated esterified potassium octanoate with methanol. Since the solubility of
K3PO4 in MeOH is higher than in methyl carbitol, no filtration or centrifugation allowed full
# 5a 2a solvent p (bar)[a] recovery 31P-NMR
ppm[b] pH[c] carboxylation yield (%)[e]
1 ✗ ✔ NMP 10 " 0.63 6 –
2 ✗ ✔ " " Distillation 2.87 9 –
3 ✗ ✗ " " Filtration 2.69 8 –
4 ✗ ✗ " " Distillation 2.82 9 –
5 ✗ ✗ DMF " " 2.86 11.84 nd
6 ✗ ✗ PC " " 3.21 11.99 "
7 ✗ ✗ DMAc " " 3.12 11.88 "
8 ✗ ✗ GVL " " 2.84 11.74 "
9 ✗ ✗ NMP " " 3.16 11.93 "
10 ✗ ✗ " " – 3.54 12.33 68
11 ✗ ✗ " ✗ Distillation 4.52 12 nd
12 ✗ ✗ " ✗ Centrifugation 3.77 12.57 61
13 ✗ ✗ ✗ 10 – 3.46 12.32 75
14[d] ✗ ✗ ✗ 45 – 3.42 11.66 nd
Results and discussion
118
recovery of the precipitates. Hence, we opted for an aqueous work-up as recovery method. After
the reaction, we dissolved the entire mixture in 100 mL of ethyl acetate and 50 mL of water and
the organic phase was extracted two more times with 30 mL of water. The collected water
phases were then dried under reduced pressure (65 °C, 10 mbar). The resulting salts were
centrifuged three times with toluene to remove residual NMP and H2O and dried under vacuum
at 180 °C for 2 hours. The recovered bases were reused in a follow-up carboxylation-
hydrogenation sequence of 1-heptyne, but did not yield the desired product.
All our attempts of regenerating the base after the three steps sequence failed, proving that
K3PO4 did undergo an irreversible deactivation upon treatment with supercritical CO2. Our
strongest hypothesis for its deactivation is a reaction between K3PO4 and carbonic acid, which
is formed in situ in the presence of water during esterification. Since K3PO4 (pKa=12.4) is a
stronger base than K2CO3 (pKa=10.30), and KHCO3 is not stable at temperatures above 200 °C,
this generates a mixture of K2HPO4 and K2CO3. When this mixture is subjected to heat
treatment (T ≥ 200 °C), the condensation of K2HPO4 to pyro- and polyphosphates occurs, while
K2CO3 is stable up to 900 °C. The pyrophosphates cannot easily be converted back to
orthophosphate, and the carbonates remain present in the salt mixture, without releasing CO2
(Scheme 73). The presence of the pyrophosphates in the treated bases, even in small amounts,
hinder the carboxylation of alkynes.
pKa=12.32 pKa=10.30
Scheme 73. Plausible deactivation-pathway of K3PO4 after treatment with CO2.
6.3.3.4 Alkoxycarboxylation of aliphatic alkynes with Cs2CO3 as base
Since our dream reaction of a waste-free alkoxycarboxylation of alkynes was not achievable
using K3PO4 as base due to its irreversible deactivation, we decided to opt for another base.
According to the screening of the carboxylation-hydrogenation sequence of 1-heptyne, carried
out at the beginning of the project (Table 5), Cs2CO3 was the next suitable base. We started
Results and discussion
119
with a few preliminary experiments to test its recyclability, very similar to the series of
experiments showed in Table 8. Several batches of Cs2CO3 in NMP were prepared and the
other components of the reaction (H2O, catalysts, methyl carbitol, octanoic acid) were
systematically added to test their effect on the return to basicity. All the batches were subjected
to a CO2 pressure of 60 bar at 100 °C for about 2 hours. The mixtures were distilled to get the
residual bases, which were employed in a follow-up carboxylation of 1-heptyne that gave some
positive results.
Encouraged from the positive outcome of the first experiments with “recycled” Cs2CO3, we
then tried recovering the base from reaction mixtures after esterification of caesium octanoate
with methyl carbitol or methanol as alcohols. Because of the high solubility of Cs2CO3 in
alcohols, recovery by centrifugation, filtration, or distillation failed. Finally, we were able to
recover Cs2CO3 from the reaction mixture of the esterification with methanol by adding ethyl
acetate and water and carrying out an aqueous work-up. The base ended up in the aqueous
phase, which was dried under reduced pressure (65 °C, 15 mbar). The residual solid was
centrifuged three times with toluene and dried at 180 °C for about 2 hours. We decided to test
the recovered Cs2CO3 as base in a follow-up carboxylation-hydrogenation sequence of 1-
heptyne. In order to do so, 1H-NMR of a weighted aliquot of the salts was measured with 1,3,5-
trimethoxybenzene as internal standard, to quantify the Cs-octanoate present in it, and deduct
it from the yield of Me-octanoate formed in the follow-up carboxylation-hydrogenation of 1-
heptyne. We started with the reaction conditions optimised for the sequence with K3PO4 (Table
9). A preliminary set of experiments showed that the sequence of carboxylation-hydrogenation
was possible with both, the pure as well as the reactivated Cs2CO3, while K3PO4, recycled in
the same way, resulted inactive (entries 1-4). Next, we screened the reaction with Cs2CO3 to
improve the yield. In the view of the base-recovery after completion of the alkoxycarboxylation
sequence, we decided to test whether the hydrogenation catalyst, which would be present in the
recovered solids, could hamper the carboxylation step. With delight, we discovered that
employing Pd/Al2O3 from the beginning still gave a reasonable yield (entry 5). Varying the
amount of Cu-catalyst negatively influenced the reaction outcome (entries 6-8), while
increasing the amount of NMP to 0.15 mL gave better yields (entries 9-12). At last, the
influence of pressure and temperature was tested. Decreasing the temperature to 60 °C
increased the yield to 88% (entries 13-15), while less or more CO2-pressure caused a drop of
the yield (entries 16-17).
Results and discussion
120
Table 9. Screening of carboxylation/hydrogenation sequence of 1-heptyne with Cs2CO3
1a
cat (mol%)base (2 equiv)CO2 (bar)
NMP, T, t
PdAl2O3 (2 mol%)
H2 (5 bar)
MeOH (2 mL) rt, 3 h
carboxylation hydrogenation
3ad
esterification
MeI (8 equiv)MeCN (2 mL) 50 °C, 2 h
Reaction conditions: Step 1: 1a (0.50 mmol), base (2 equiv), catalyst (0.20 mol% metal), NMP (0.15
mL), 60 °C, 10 bar CO2 (at rt), 12 h; Step 2: Pd/Al2O3 (2.00 mol%), MeOH (2 mL), rt, 5 bar H2, 3 h.
Yields of the corresponding methyl ester determined by GC analysis using mesitylene as internal
standard. [a]Recycling method: The mixture of the reaction after CO2-mediated esterification of (K or)Cs-
octanoate with methanol was diluted in 100 mL of ethyl acetate and 50 mL of water. The organic phase
was additionally extracted with water (2 x 30 mL) and the collected aqueous phases were dried under
reduced pressure (65 °C, 10 mbar). The residual solids were centrifuged with toluene (x 3) and dried at
180 °C for 2 h. 1H-NMR of the salts was taken to calculate the amount of residual (K or)Cs-octanoate,
which was deducted from the yield of Me-octanoate of the follow-up carboxylation-hydrogenation of
1-heptyne.
# cat (mol%) base solvent (mL) T (°C) p (bar) t (h) 3ad (%)
1 CuBr (0.2) K3PO4 NMP (0.1) 80 10 12 78
2 " Cs2CO3 " " " " 80
3[a] " recycled K3PO4 " " " " 0
4[a] " recycled Cs2CO3 " " " " 80
5 CuBr/0.2 + PdAl2O3/2 Cs2CO3 " " " " 75
6 CuBr (0.1) " " " " " 76
7 CuBr (0.3) " " " " " 74
8 CuBr (0.5) " " " " " 72
9 CuBr (0.2) " NMP (0.15) " " " 84
10 " " NMP (0.2) " " " 84
11 " " NMP (0.3) " " " 81
12 " " NMP (0.5) " " " 82
13 " " NMP (0.15) 70 " " 83
14 " " " 60 " " 88
15 " " " 50 " " 31
16 " " " 60 30 " 70
17 " " " " 5 " 76
Results and discussion
121
Simultaneously to the screening of the first two steps, the screening of the CO2-promoted
esterification of caesium octanoate was conducted. It appeared to be more challenging to
achieve as high yields as achieved with K3PO4, probably because of the higher solubility of
Cs2CO3 in organic media. Initial screening was carried out in batch autoclaves with the high-
boiling alcohol 2-(2-methoxyethoxy)ethanol (2a) (Table 10). The conditions optimised for
K3PO4, were less efficient in the case of Cs2CO3 (entry 1). Varying the amount of alcohol,
temperature, CO2-pressure, and reaction time did not remarkably increase the yield (entries 2-
8). Lewis acids, which in some cases positively affected the yield (entries 9-13), hampered the
carboxylation-hydrogenation sequence and thus had to be excluded.
Table 10. Optimisation of the CO2-mediated esterification of Cs-octanoate with Me-carbitol
5a 2a 3aa
CuBr (1 mol%)Cs2CO3 (2 equiv)
Lewis acid (10 mol%)
CO2 (bar), T, t
NMP (0.1 mL)
Reaction conditions: octanoic acid (0.50 mmol), 2-(2-methoxyethoxy)ethanol (2a), Cs2CO3 (2 equiv),
LA (10 mol%), CuBr (1 mol%), NMP (0.1 mL), T (°C), CO2 (bar), t (h). [a] Pressures at rt. Yields
determined by GC analysis using mesitylene as internal standard.
# 2a (amount) LA T (°C) p (bar)[a] t (h) 3aa (%)
1 5 mL/84 equiv. - 180 45 20 60
2 3 mL/50 equiv. - " " " 42
3 7 mL/118 equiv. - " " " 64
4 5 mL/84 equiv. - " 35 " 53
5 " - 160 " " 49
6 " - 200 " " 54
7 " - 180 " 24 48
8 " - " " 16 48
9 " Al triflate " " 20 71
10 " Fe (II) triflate " " " 78
11 " Li triflate " " " 47
12 " Zn triflate " " " 49
13 " Mg triflate " " " 67
Results and discussion
122
At this stage of the esterification screening, the tests on the recyclability of the base revealed
that MeOH was the best alcohol from which the base could be recovered and regenerated.
Hence, the CO2-mediated esterification screening continued with MeOH as alcohol (Table 11).
To test pressures that were higher than the CO2 pressure provided by a simple gas bottle, more
CO2 was added by condensing the gas inside the autoclave with liquid nitrogen as coolant. After
flushing three times the autoclave´s atmosphere with CO2, the weight of the autoclave was taken
as tare. Then, after collecting a certain amount of the gas, the autoclave was thawed, and the
load of inserted CO2 was determined by weighing, and adjusted by venting excess CO2 until
the desired amount was reached. We started with 35 g of CO2, which corresponded to about 53
bar (at room temperature), 180 °C and 15 mL of MeOH, which gave a yield of 35% (entry 1).
Addition of a Lewis acid, which positively influenced the esterification with methyl carbitol,
was harmful in this case (entry 2). Higher temperatures increased the yield (entries 3-5). Since
similar yields were obtained between 200 °C and 220 °C, we decided to keep the lower
temperature for better maintenance of the equipment. The Teflon gasket present in the autoclave
indeed seemed to suffer a lot at temperatures above 200 °C. Lower amounts of CO2 also
positively affected the reaction outcome (entries 6-7), while the variation of amount of alcohol
caused a drop in the yield (entries 8-9). The optimised conditions for the CO2-mediated
esterification of caesium octanoate with methanol (15 mL MeOH, 15 g CO2, 200 °C, 20 h) were
tested in a reaction of 1 mmol scale and gave 92% product (entry 10).
Results and discussion
123
Table 11. Optimisation of the CO2-promoted esterification of Cs-octanoate with methanol
5a 2d 3ad
CuBr (1 mol%)Cs2CO3 (2 equiv)
Lewis acid (10 mol%)
CO2 (g), T, 20 h
NMP (0.1 mL)
MeOH
Reaction conditions: octanoic acid (0.50 mmol), methanol (2d), Cs2CO3 (2 equiv), LA (10.0 mol%),
CuBr (1.00 mol%), NMP (0.10 mL), CO2 (g), T (°C), 20 h. Yields determined by GC analysis using
mesitylene as internal standard. [a] Reaction in 1 mmol scale.
Having optimised the three steps, we needed to prove the recyclability of the base after
completion of the alkoxycarboxylation sequence. We ran the alkoxycarboxylation of 1-heptyne
and obtained methyl octanoate in 72% yield (Scheme 74). We recovered the bases via water
extraction, centrifuged it three times with toluene and thermally regenerated Cs2CO3. 1H-NMR
of the regenerated base was taken to calculate the amount of Cs-octanoate present in it, which
resulted to be 2 mol% of the base. The resulting base, with a 98% purity, was employed in
another alkoxycarboxylation of 1-heptyne that provided methyl octanoate in 67% yield, from
which the above-mentioned Cs-octanoate was deducted. The complete sequence of
carboxylation-hydrogenation-esterification of 1-heptyne with methanol and recycled Cs2CO3,
afforded the product in 65% yield, proving that the base can be reactivated and reused for a
second round of alkoxycarboxylation.
Entry 2d LA T (°C) CO2 (g) 3ad (%)
1 15 mL/ 741 equiv. - 180 35 63
2 " Fe (II) triflate " " 35
3 " - 200 " 76
4 " - 220 " 77
5 " - 160 " 21
6 " - 200 25 77
7 " - " 15 92
8 10 mL/ 494 equiv - " " 82
9 20 mL/ 988 equiv - " " 83
10[a] 15 mL/ 741 equiv. - " " 92
Results and discussion
124
1a
CuBr (0.2 mol%)CO2 (10 bar)
PdAl2O3 (2 mol%)
H2 (5 bar)
carboxylation
CO2 (15 g)
hydrogenation
3ad, 72% (65%)[a]
esterification
NMP (0.15 mL)60 °C, 12 h
MeOH (2d) (15 mL)rt, 3 h
200 °C, 20 h
2 x CsHCO3
Cs2CO3
2 equiv
T
CO2 + H2O
recycling of the base
Scheme 74. Alkoxycarboxylation of 1-heptyne with methanol, with fresh and with regenerated base[a].
GC yields obtained using mesitylene as internal standard.
Finally, our proof-of-concept of a waste-free alkoxycarboxylation of aliphatic alkynes,
including the recyclability of the base, was proven with the model substrate 1-heptyne. We
intended to test whether the optimised process could be applied to the target substrate acetylene.
A test-methoxycarboxylation of acetylene with Cs2CO3 as base was run. The reaction
conditions developed with the new base where applied to the old reaction sequence (Scheme
69). The targeted product DMS was obtained in only 10% yield, highlighting the necessity of
an optimisation of the reaction with acetylene (Scheme 75).
0.4 bar
CuBr (0.2 mol%)Cs2CO3 (3 equiv)
NMP (8 mL)
60 °C, 40 hCO2
10 bar
CO2 (15 g)
200 °C, 46 h
3ra: 10%
MeOH (15 mL)2 h, rt
Pd/Al2O3 (2 mol%)
H2 (5 bar)
carboxylation hydrogenation esterification
Scheme 75. Methoxycarboxylation of acetylene with Cs2CO3 as base.
Since the only autoclave in our possession where the acetylene reaction can be run is the Parr
4590, only one reaction at a time can be set up, slowing down the optimisation, which is
currently ongoing. The plan is to follow the same systematic screening carried out for 1-
heptyne. The first two steps, carboxylation-hydrogenation, will be screened together with focus
on the amount of NMP and the reaction time, which we expect to be longer since two sites have
to be carboxylated, and because of the solubility competition between the two gases. Next, the
esterification step will be optimised: here, the amount of alcohol, CO2, and reaction time will
be decisive. Once all the steps are optimised, we will perform the whole alkoxycarboxylation
of acetylene, recycle the base and re-do the complete sequence with the regenerated base.
Conclusion and outlook
125
7 Conclusion and outlook
This PhD work describes the development of new sustainable catalytic methods that involve
the chemical exploitation of the renewable reagents cashew nut shell liquid, CNSL, and carbon
dioxide, CO2. The protocols have been designed to maximise atom efficiency and to overcome
waste formation, two essential steps in the stairway of sustainability.
In the first part of the thesis, two chemical processes were developed that use cashew nut shell
liquid for the synthesis of surfactants and a tyrosinase inhibitor.
In the first project, technical cashew nut shell liquid, a mixture containing mainly cardanol, was
used as starting material in a straightforward and sustainable synthesis of amine-based
surfactants (Scheme 76). The key step of the procedure was a reductive amination of the
technical CNSL mixture with molecular hydrogen and palladium on charcoal, in water. The
resulting cyclohexylamine derivatives were further converted into N-oxide, betaine and
quaternary ammonium tensides. Their surfactant properties were measured and appeared
comparable with the properties of analogous benchmark surfactants. The two-step procedure
was shown to work in one-pot with an overall E-factor of 2 in water as the sole solvent,
affording the N-oxide in 71% yield.
Cardanol
Technical CNSL
N-oxide, 94%
one-pot: 71%R =
betaine67%
quat, 62%
Me2NH (1.1 equiv)
Pd/C (2 mol%)H2 (5 bar)
reductive amination
H2O, 100 °C, 15 h
Scheme 76. Chemical utilisation of technical CNSL for the synthesis of surfactants.
Further studies should aim to adapt this protocol to industrial processes, by searching close
collaborations with chemical companies. The reductive amination could be attempted in a flow
reactor, which would release the amines directly into the oxidant mixture for the synthesis of
the N-oxides. The application of such industrial protocol in countries where the production of
Conclusion and outlook
126
CNSL is relevant, e.g. Tanzania, Brasil, Nigeria, etc., would establish locally, a sustainable
industrial plant where the use of renewable resources in chemical syntheses has replaced fossil
raw materials.
In the second project, natural cashew nut shell liquid, containing mainly anacardic acids, was
chemically exploited in the synthesis of a tyrosinase inhibitor. The chemical valorisation of
anacardic acids is less explored compared to cardanols because the separation and purification
of this component from the CNSL mixture are laborious and relie on wasteful and tedious
processes such as fractionate precipitation or column chromatography. Because of structural
similarities of anacardic acids with ginkgolic acids, a straightforward synthesis of ginkgolic
acid (13:0) was attempt starting directly from the crude CNSL mixture, without laborious
isolation of the anacardic acid components (Scheme 77). By ethenolysis of the natural CNSL,
it was possible to remarkably reduce the number of phenols in the mixture and isolate 2-
hydroxy-6-(non-8-enyl)benzoic acid just by precipitation in cold pentane. The isolated acid was
coupled with 1-hexene via cross-metathesis, and a following one-pot hydrogenation step
provided the targeted ginkgolic acid (13:0) in 61% yield based on the unsaturated anacardic
acid content in CNSL.
Anacardic acid
Natural CNSL
R =
ginkgolic acid (13:0), 61%
tyrosinase inhibitor
7
C2H4 (10 bar)
[Ru] (0.5 mol%)
DCM, rt, 12 h
ethenolysis 1) cross-metathesis
1-hexene (7 equiv)[Ru] (1 mol%)DCM, 60 °C, 6 h
2) hydrogenation
charcoalH2 (5 bar)
MEOH, 50 °C, 2 h
Scheme 77. Synthesis of a tyrosinase inhibitor from natural CNSL.
Further studies should focus on improving the sustainability of the process. A drawback of the
reaction is the use of chlorinated solvent. If new generation metathesis-catalysts that work in
non-chlorinated solvents may be found, greener solvents might be employed in the process.
Also, collecting and recycling the ethylene released during the cross-metathesis step, and
reutilise it in loop in the same reaction or other reactions would benefit to the overall feasibility
of the process. The possibility of isolating a single compound from the entire mixture after
Conclusion and outlook
127
ethenolysis by precipitation is of high relevance and it might open up a series of various other
derivatisations of this renewable starting material.
The second part of the thesis describes a zero-waste use of carbon dioxide as C1-building block
in chemical synthesis. A catalytic inclusion of carbon dioxide into terminal alkynes is reported
as part of a three-step alkoxycarboxylation sequence, consisting of the carboxylation of a
terminal alkyne, followed by hydrogenation of the triple bond, and the CO2-promoted
esterification of the corresponding carboxylate (Scheme 78). The first challenge of this project
was to identify a suitable base that was strong enough to activate aliphatic alkynes in the
carboxylation step. The second challenge was to find a waste-free derivatisation of the resulting
carboxylates under regeneration of the base: common esterifications of carboxylates lead
inevitably to the production of salt waste, whereas common derivatisations without salt
generation usually require acidic conditions. An inorganic base had to be employed to have
sufficient driving force in the carboxylation of aliphatic alkynes. A subsequent waste-free
derivatisation of the resulting carboxylates was achieved via Pd-catalysed hydrogenation of the
triple bond and a downstream esterification with simple alcohols to yield the
alkoxycarboxylated product. After hydrogenation of the triple bond to stabilise the intermediate
product, highly pressurised CO2, reaching supercritical conditions, was used to increase the
acidity of the reaction mixture, thus enabling the acid-catalysed esterification of the carboxylate
salts with simple alcohols.
[Cu], CO2
base
carboxylation hydrogenation
[Pd], H2
R'OH
esterification
CO2
Tbase-H+
base-H+
base-H+
recycling of the base
Scheme 78. Desirable waste-free alkoxycarboxylation of terminal alkynes.
The first sequence optimisation was achieved with potassium phosphate (K3PO4) as base, and
a wide range of aromatic and aliphatic alkynes was converted into esters with several alcohols.
The target compound acetylene was transformed into dimethylsuccinate in 53% yield.
However, K3PO4 could not be efficiently reactivated for a second round of
alkoxycarboxylation. Hence, a change in the employed base was needed. Caesium carbonate
(Cs2CO3), seemed to be strong enough to activate aliphatic alkynes and a new optimisation of
Conclusion and outlook
128
the sequence was carried out. Several recovery methods were investigated and finally, the base
was recovered via aqueous work-up of the mixture after the alkoxymethoxylation of 1-heptyne
into methyl octanoate, and thermally regenerated. The reactivated base was efficiently
employed in a second round of alkoxycarboxylation, providing the product in 65% yield
compared to the 72% yield obtained with “fresh” base (Scheme 79).
CuBr (0.2 mol%) PdAl2O3 (2 mol%)
H2 (5 bar)
carboxylation
CO2 (15 g)
hydrogenation esterification
NMP (0.15 mL)60 °C, 12 h
MeOH (15 mL)rt, 3 h
200 °C, 20 h
2 x CsHCO3
Cs2CO3
2 equiv
T
CO2 + H2O
recycling of the base
CO2 (10 bar)H2
O
64
72% (65%)a
Scheme 79. Methoxycarboxylation of 1-heptyne. a Yield of the reaction with recovered base.
A demonstration of an useful industrial application has been done with acetylene to obtain
dimethyl succinate, which can be hydrogenated to the platform chemical 1,4-butanediol.
Current studies aim at the optimisation of the reaction sequence from acetylene. Acetylene gas
is mainly obtained through the BASF process from natural gas. Therefore, a successful coupling
of acetylene (C2-moiety) and carbon dioxide to obtain 1,4-butanediol (C4-moiety), would
represent a zero-waste conversion from natural gas to butanediol, where two of the carbon
moieties come from the waste product CO2. A further improvement in the sustainability of the
overall process could be achieved if the downstream CO2-promoted esterification of caesium
succinate is carried out with 1,4-butanediol as alcohol. This would produce the corresponding
1,4-bis(4-hydroxybutyl) ester, which after hydrogenation of the ester groups would directly
release three equivalents of 1,4-butanediol. Moreover, an implant that allows the recovering of
the unused CO2 from the reactor after reaction. The recovered CO2 could be employed in loop
in a follow-up alkoxycarboxylation, leading to a zero-waste process where every component of
the reaction comes from inedible by-products or is recycled.
Experimental section
129
8 Experimental section
8.1 General methods
8.1.1 Chemicals and solvents
Commercially available chemicals and solvents (puriss p.a.) were used as received unless
otherwise stated and/or purified following standard literature techniques.375 Air- and moisture-
sensitive compounds were handled and stored under argon atmosphere using standard Schlenk
techniques. NMP was dried via azeotrope distillation with toluene and stored over molecular
sieves (3 Å or 4 Å), which were heated before in a microwave oven (2x2 min, 600 W) and
cooled under vacuum (103 mbar) to room temperature. Inorganic salts such as phosphates and
carbonates were dried 2 hours under vacuum (103 mbar) at 180 °C and stored under argon.
8.1.2 Reactions set-up: equipment and procedure
8.1.2.1 Equipment
Reactions not involving the use of gases as reagents, were performed in a set of 10 parallel
ovendried 20 mL headspacevials closed with a dry septum cap.
All carboxylation and hydrogenation reactions with pressure > 1 bar, were performed in
autoclaves self-constructed by the metal workshop of the TU Kaiserslautern, or autoclaves from
Parr Instrument Company.
Reactions pressurized up to 100 bar were performed in the self-constructed autoclaves with
internal volume of 378 mL and allowed working pressure and temperature of 100 bar and
200 °C. Reactions were set-up in 10 mL headspace vials closed with a dry septum cap and
placed in the autoclave reactor built for eight parallel reactions (Figure 29a).
Reactions at pressures exceeding 100 bar were conducted in a Parr 4590 stirred benchtop
microreactor (allowed for 345 bar and 350 °C) with a removable 50 mL stainless steel (4571)
vessel (Figure 29b). The pot was filled with the reactants and fixed to the upper part of the
autoclave by the split-ring. Pressure, temperature and speed were recorded electronically.
Experimental section
130
Big scale pressure-reactions were carried out in a 1 L Parr autoclave (series 4600), allowed
for 131 bar and 350 °C, (Figure 29c). The pot was filled with the reactants, and the upper
part was fixed to the pot with the split-ring.
a b c
Figure 29. Autoclaves for pressurised reactions (> 1 bar). a) self-constructed. b) Parr 4590. c) 1L Parr.
8.1.2.2 Procedure
Solid and liquid compounds were weighted under air if non-sensitive to air and moisture, and
the reaction vessels were equipped with a 20 mm Teflon-coated stirring bar. Air and moisture
sensitive compounds were weighted in the glovebox with nitrogen as inert gas. Three parallel
vacuum/argon flushing cycles of the reaction vessels were carried out using a vacuum
distributor (spider), which was connected to the Schlenk line. Each distributor had a steel tube
connected to 10 vacuumtight Teflon tubes equipped with adapter for mounting LuerLock
syringe needles. The needles are pierced into the cap septum, thus connecting the vials to the
Schlenk line. The spider was also used for the addition of liquid components in the vial via
syringe through the Tefloncoated rubber septum. The vials were stirred and heated in an 8 cm
high cylindrical heating block, which fits on the hot plate of a regular laboratory heater in
diameter, having 10 holes appositely drilled of the size of the 20 mL vials, and one additional
hole for the temperature sensor (Figure 30).
Experimental section
131
Figure 30. Set-up for 10 parallel non-pressure reactions.
A similar setup was used for reactions in autoclaves, except that a 4 cm aluminium block
containing 8 holes for 10 mL headspace vials and a small hole for the thermometer was
employed. This aluminium block is designed to fit inside the autoclave. In this case, after adding
the reagents in the vials, a spirally bent needle was inserted into each 10 mL vial before placing
it in the block into the autoclave. The autoclave was closed and the atmosphere was flushed
three times with the necessary gas (H2 or CO2). Finally, the autoclave was pressurised at the
final pressure and set at the final temperature.
For heating the self-constructed autoclaves, aluminium-based heating jackets with a hole
appositively drilled for the thermometer were used. To heat the 1 L Parr autoclave, an external
bath for the heat-transfer medium was used. To heat the Parr 4590, the Parr´s heating jacket
was used.
8.1.2.3 Analysis work-up
After the reaction time, the reactions were allowed to cool down to room temperature by cooling
the aluminium block or the autoclave, and the pressure was released. The reactions were
analysed via gas chromatography. If necessary, a derivatisation (esterification) was carried out,
with iodomethane in acetonitrile (60 °C, 2h) or sulphuric acid in methanol (65 °C, 2h). A
suitable internal standard was added to the reaction mixture and diluted with a suitable organic
solvent after which the reaction vial was shaken and the cap carefully opened. 0.25 mL sample
Experimental section
132
was further diluted in a 10mL vial, usually with EtOAc (3mL) and washed with water or sat.
NaHCO3 solution. The organic layer was filtered and dried directly into a GC vial through a
glass pipet filled with MgSO4 (Figure 31).
Figure 31. Work-up setup for 10 parallel reactions.
8.1.3 Analytical methods
8.1.3.1 Thin layer chromatography (TLC) and column chromatography
TLC was performed using silica gel plates 60 F254 from Macherey-Nagel. The substances were
detected either by fluorescence at 254 nm or by staining agents such as KMnO4 solution (3 g
KMnO4, 20 g K2CO3, 15 g NaOH, 300 mL H2O).
Isolation of products was performed via column chromatography on a CombiFlash
CompanionChromatographySystem (IscoSystems) or on a Reveleris X2 (BUCHI) Flash
Chromatography-System. Ready packed silica gel cartridges Grace Reveleris (12 g or 24 g) and
Macherey & Nagel (15 g) were used for separation.
8.1.3.2 Gas chromatography
The gas chromatographic analyses were carried out on a Hewlett-Packard 6890 and Agilent
7890B. For separation, columns of type HP-5 with 5% phenyl-methyl-siloxane (30 m x 320
microns x 0.25 microns) from Agilent and nitrogen as carrier gas at a flow rate of 149 mL/min
(0.5 bar pressure) were used. The injection temperature was 220 °C; the temperature of the
flame ionisation detector was set at 330 °C. Usually, the following temperature program was
Experimental section
133
applied: starting temperature 60 °C for 2 min, a linear temperature increase from 30 ° C/min up
to 300 °C after which the temperature was kept constant for additional 3 min.
8.1.3.3 Mass spectrometry
Mass spectra were recorded on a Varian GCMS Saturn 2100 T or on an Agilent GCMS 5977B
System. Ionisation was performed via electron impact ionisation (EI). High-resolution mass
analyses were performed with a Waters GTC Premier CAB163 with a TOF mass analyser or on
a Bruker Q-TOF Compact.
8.1.3.4 Nuclear magnetic resonance spectroscopy
Proton and carbon NMR spectra were recorded with a Bruker Avance 400 or a Avance 300
spectrometer. Proton decoupled 19F NMR spectra was recorded with a Bruker DPX 250
spectrometer. Chemical shifts are given in units of the δ-scale in ppm. Shifts for 1H- and 13C-
spectra are calibrated to the signals of chloroform-d1 at 7.26 ppm (1H) and 77.0 ppm (13C). The
frequency and solvent used are described separately for each substance. Coupling constants are
given in Hertz (Hz). Processing and interpretation was performed with ACD/Labs 7.0 and
ACD/Labs 12.0 software (Advanced Chemistry Development Inc.). The multiplicity of the
signals is abbreviated by the following letters: s (singlet), d (doublet), dd (doublet of doublet),
ddd (doublet of doublet of doublet), td (triplet of doublet), q (quartet), quin (quintet), sext
(sextet), hept (heptet), m (multiplet), and br (broad).
8.1.3.5 Infrared spectroscopy (IR), melting point, and elemental analysis
IR measurements were performed on a Bruker Vertex or Bruker Alpha with Universal ATR or
KBr Sampling Accessory.
Melting points were measured in a capillary glass tube with a Mettler FP61 automatic
measuring apparatus.
Elemental analysis were performed on a Hanau Elemental Analyser vario Micro cube.
8.1.3.6 Surface tension
Surface tension was determined by the drop Shape analyser DSA 100 (KRUESS) connected to
a syringe pump 100DX (Isco). Each measurement was taken at room temperature (ca. 25 °C).
Experimental section
134
8.2 Synthesis of surfactants from cashew nut shell liquid
8.2.1 Chemicals
The cardanol mixture NC700 [CAS No.: 8007-24-7] was received from Cardolite and used after
brief purification via acidic and basic aqueous work-up with a final purity of ca. 90%. Each
purified batch had different ratio of impurities.
8.2.2 Synthetic procedures
8.2.2.1 General procedure 1 for the synthesis of cyclohexylamines
An oven-dried 10 mL headspace vial with Teflon-coated stirring bar was charged with
palladium on charcoal (0.02 mmol, 10 wt%, 21.3 mg), cardanol (1, 1.00 mmol, 332 mg), an
amine (1.10 mmol) and water (3 mL). The vial was closed with a septum cap, penetrated with
a cannula for pressure equilibration and placed into an autoclave. The system was purged twice
with H2 (10 bar) and finally pressurized to 5 bar. The resulting mixture was stirred (300 rpm)
at 100 °C for 15 h. After cooling down to r.t., the pressure was slowly released under constant
stirring at 300 rpm. The mixture was diluted with 20 mL of diethyl ether, washed with KOH
solution 2M (20 ml) and water (2 x 10 ml). The aqueous phases were extracted with diethyl
ether (2 x 15 ml), the combined organic layers were washed with brine (10 ml), filtered over
celite and MgSO4 and the solvent was removed under reduced pressure. The residue was
separated by column chromatography (SiO2, Chloroform containing 1.5 vol% NEt3/ethyl
acetate gradient) yielding the corresponding cyclohexylamine derivative.
8.2.2.2 General procedure 2 for the large scale synthesis of cyclohexylamines
A 1 L Parr autoclave was charged with Pd/C, cardanol and an amine. A solution of water (165
ml) and isopropanol (85 ml) was added. The system was purged twice with H2 (30 bar) and
finally pressurized at 40 bar. The mixture was stirred at 1000 rpm at 100 °C for 15 h. After
cooling down to r.t., the pressure was slowly released. The mixture was filtered through celite
and diluted with 150 mL of pentane. Sulfuric acid was added to reach pH 2 and the organic
layer was removed. The water phase was washed with pentane (2 x 50 mL) and ethyl acetate
(50 mL). The water phase was neutralized with NaOH and extracted with diethyl ether
Experimental section
135
(4 x 40 mL). The solvent was removed under reduced pressure yielding the corresponding
product.
8.2.2.3 General procedure for the synthesis of N-oxides
Hydrogen peroxide (3.00 mmol, 35 wt%, 292 mg, 0.26 mL) was added to a headspace vial and
cooled to 0°C. Corresponding cyclohexylamine (1 mmol) was added dropwise over 5 minutes.
The solution was allowed to warm to room temperature and stirred for 30 minutes before
heating to 30 °C for additional 10 minutes. After that, the solvent was removed under reduced
pressure (60 °C). The residue was dried under vacuum yielding the corresponding product
8.2.2.4 Procedure for the one-pot amination/oxidation sequence
The reductive amination of cardanol 1 (1.00 mmol, 332 mg) and dimethyl amine (1.10 mmol,
40 wt%, 124 mg, 146 L) with Pd/C (0.02 mmol, 10 wt%, 21.3 mg) was performed following
the general procedure 1. After the reaction time, the mixture was cooled down to 0 °C.
Hydrogen peroxide (10.0 mmol, 35 wt%, 972mg, 875 L) was added dropwise over 5 minutes
via syringe.The mixture was allowed to warm to room temperature and stirred for 30 minutes.
The solution was heated to 30 °C and stirred for additional 10 minutes. The mixture was diluted
with 3 ml of water and washed with pentane (2 x 5 mL). The combined organic phases were
extracted with water (2 x 5 mL) and the combined aqueous phases were concentrated under
reduced pressure at 60 °C. The residue was dried under reduced pressure yielding 3b as
yellowish solid (252 mg, 71%).
8.2.2.5 E-factor calculation:352,353
𝐸 (withouth water) =(332 + 49.6 + 21.3 + 340.2 − 248) 𝑚𝑔
248 𝑚𝑔= 1.99
𝐸 (including water) =(332 + 124 + 21.3 + 972 − 248) 𝑚𝑔
248 𝑚𝑔= 4.84
Experimental section
136
8.2.2.6 Mechanistic investigations: Reductive amination of cyclohexanone and cyclohexanol
Pd/C (2 mol%)H2 (10 bar)
Pd/C (2 mol%)H2 (10 bar)
2a
2a
Yield > 90%
Yield = 0%
Scheme S1. Control experiments. 0.5 mmol of cyclohexanone or cyclohexanol, 0.55 mmol 2a, 2 mol% Pd/C, 10 bar H2, 2 mL H2O, 100 °C, 15 h.
8.2.2.7 Determination of surface tension and cmc
The cmc is the surfactant concentration at and above which micelles are formed. It can be
determined for surfactant solutions by measuring the surface tension at different concentrations.
The surface tension of aqueous solutions of the surfactants 4b, 5b and 6b and their critical
micellar concentration were determined via the pendant drop method. The surface tension of
deionised water, was determined at the beginning of the measurements. The surface tension of
aqueous solutions 4b, 5b and 6b were measured over a wide concentration range to determine
the critical micellar concentration (cmc). The concentration range of the solutions for each
surfactant, spaced from 0.1 M to 30 mM aqueous solution. The surface tension of water (68-69
mN/m) was measured before each set of measurements. The surface tension of the surfactant
solutions was measured three times for each concentration and the average values of the three
measurements were plotted as a function of log C (figure S1). An extrapolation of the regression
lines of the surface tension and log C, yields the cmc at the intersection.
Experimental section
137
Fig. S1. The plots of the surface tension ( in mN/m) versus log C (concentration of surfactant in M) at r.t..
8.2.3 Synthesis and characterisation of products
8.2.3.1 N,N-dibutyl-3-pentadecylcyclohexylamine (3a)
Compound 3a was prepared following the general procedure 1 from 1 (0.50 mmol, 166 mg)
and di-n-butyl amine (0.55 mmol, 71.4 mg) but with a hydrogen pressure of 10 bar. 3a was
isolated as yellow oil (181 mg, 86%, mixture of diastereomers).
Additionally, compound 3a was prepared in preparative scale following general procedure 2,
starting from 1 (50.0 mmol, 14.92 g) and di-n-butyl amine (50.0 mmol, 6.53 g), yielding 3a
(14.0 g, 33.0 mmol, 66%).
1H–NMR (300 MHz, CDCl3) = 2.56 - 2.70 (m, 1 H), 2.35 - 2.48 (m, 4 H), 1.77 (d, J=3.1 Hz,
1 H), 1.14 - 1.70 (m, 44 H), 0.84 - 0.95 (m, 9 H) ppm. 13C–NMR (75 MHz, CDCl3) = 60,
54.3, 50.5, 50.1, 37.7, 37.6, 35.9, 33.4, 33.2, 32.9, 31.9, 31.6, 30.8, 30.7, 30.0, 29.9, 29.71,
29.67, 29.44, 29.37, 28.5, 27.8, 27.0, 25.6, 22.7, 21.0, 20.75, 20.74, 14.14, 14.10 ppm. IR
(ATR) max/cm1 = 2955 (m), 2921 (s), 2852 (s), 1464 (m), 1377 (w), 721 (w). MS (EI-TOF)
m/z (%): 421 (4) [M+], 379 (25), 378 (100), 322 (7), 210 (16), 168 (15), 97 (12). HRMS-EI
(TOF): [M+] calcd. for C29H59N: 421.4648; found: 421.4641.
25
30
35
40
45
50
55
60
65
70
75
-1,5 -0,5 0,5 1,5 2,5 3,5 4,5
(m
N/m
)
log C
Betaine
N-Oxide
quat
~
Experimental section
138
8.2.3.2 N,N-dimethyl-3-pentadecylcyclohexylamine (3b)
Compound 3b was prepared following the general procedure 1 from 1 and dimethyl amine (1.1
mmol, 124 mg) but with a hydrogen pressure of 10 bar. 3b was isolated as yellow oil (287 mg,
85%, mixture of diastereomers).
Additionally, compound 3b was prepared in preparative scale following general procedure 2,
starting from 1 (68 mmol, 20 g) and dimethyl amine (81.6 mmol, 40 wt%, 9.2 g), yielding 3b
(14.8 g, 43.0 mmol, 64%).
1H–NMR (300 MHz, CDCl3) = 2.24 (s, 6 H), 2.14 - 2.21 (m, 1 H), 1.13 - 1.78 (m, 37 H), 0.88
(s, 3 H) ppm. 13C–NMR (75 MHz, CDCl3) = 60.0, 42.7, 34.8, 34.6, 32.2, 31.9, 31.7, 29.9,
29.7, 29.6, 29.3, 29.1, 27.4, 22.7, 20.5, 14.1 ppm. IR (ATR) max/cm1 = 2920 (s), 2852 (s),
2810 (w), 2766 (m), 1463 (m), 1042 (w), 998 (w), 721 (w). MS (EI-TOF) m/z (%): 337 (29)
[M+], 295 (22), 294 (100), 266 (9), 127 (10), 126 (99), 84 (63). HRMS-EI (TOF): [M+] calcd.
for C23H47N: 337.3709; found: 337.3705.
8.2.3.3 N-cyclohexyl-N-methyl-3-pentadecylcyclohexylamine (3c)
Compound 3c was prepared following the general procedure 1 from 1 and N-methylaniline (1.1
mmol, 119 mg) and isolated as colorless oil (283 mg, 70%, mixture of diastereomers).
1H–NMR (300 MHz, CDCl3) = 2.61 - 2.75 (m, 1 H), 2.53 (d, J=7.6 Hz, 1 H), 2.17 - 2.28 (m,
3 H), 1.77 (br. s., 6 H), 1.53 - 1.67 (m, 3 H), 1.45 (d, J=7.1 Hz, 3 H), 1.14 - 1.36 (m, 35 H), 0.89
(t, J=6.2 Hz, 3 H) ppm. 13C–NMR (75 MHz, CDCl3) = 59.3, 58.4, 54.1, 37.7, 37.6, 34.8,
33.6, 32.8, 32.87, 32.8, 31.9, 31.1, 30.5, 30.4, 30.0, 29.9, 29.8, 29.78, 29.71, 29.69, 29.65, 29.3,
27.7, 26.9, 26.4, 26.3, 26.2, 22.7, 20.9, 14.1 ppm. IR (ATR) max/cm1 = 2920 (s), 2851 (s),
~
~
Experimental section
139
2783 (w), 1451 (m), 1262 (w), 1013 (w), 891 (w), 721 (w). MS (EI-TOF) m/z (%): 405 (24)
[M+], 404 (30), 363 (26), 362 (100), 334 (21), 195 (12), 194 (77), 152 (54). HRMS-EI (TOF):
[M+] calcd. for C28H55N: 405.4335; found: 405.4342.
8.2.3.4 N1,N1,N2-trimethyl-N2-(3-pentadecylcyclohexyl)ethane-1,2-diamine (3d)
Compound 3d was prepared following the general procedure 1 from 1 (0.5 mmol, 166 mg) and
N,N,N'-trimethylethylenediamine (0.55mmol, 56.8 mg) and isolated as pale yellow oil (145 mg,
74%, mixture of diastereomers).
1H–NMR (300 MHz, CDCl3) = 2.57 (br. s., 3 H), 2.42 (s, 2 H), 2.21 - 2.33 (m, 9 H), 1.73 -
1.87 (m, 1 H), 1.53 (br. s., 4 H), 1.14 - 1.48 (m, 32 H), 0.83 - 0.94 (m, 3 H) ppm. 13C–NMR
(75 MHz, CDCl3) = 58.0, 57.4, 51.5, 45.8, 38.6, 33.2, 32.9, 31.9, 30.8, 30.3, 29.9, 29.7, 29.65,
29.3, 28.8, 27.7, 22.7, 20.7, 14.1 ppm. IR (ATR) max/cm1 = 2921 (s), 2852 (s), 2815 (w),
2765 (w), 1746 (w), 1463 (m), 1365 (w), 1263 (w), 1037 (m), 721 (w). MS (EI-TOF) m/z (%):
394 (1) [M+], 337 (30), 336 (100), 297 (7), 280 (2), 236 (1), 126 (9), 84 (16). HRMS-EI (TOF):
[M+] calcd. for C26H54N2: 394.4287; found: 394.4279.
8.2.3.5 N,N-tetramethylen-3-pentadecylcyclohexylamine (3e)
Compound 3e was prepared following the general procedure 1 from 1 and pyrrolidin (1.1 mmol,
79 mg) with a hydrogen pressure of 10 bar. 3g was isolated as yellowish solid (270 mg, 74%,
mixture of diastereomers).
m.p.: 35-37 °C. Elemental analysis found: C, 82.2; H, 13.4; N, 3.8. Calc. for C25H49N: C,
82.6; H, 13.6; N, 3.8%. 1H–NMR (300 MHz, CDCl3) = 2.51 (br. s., 4 H), 1.93 - 2.21 (m, 2
H), 1.77 (s, 9 H), 1.27 (s, 31 H), 0.89 (s, 3 H) ppm. 13C–NMR (100 MHz, CDCl3) = 63.7,
~
Experimental section
140
60.1, 51.9, 51.5, 39.1, 37.5, 37.1, 36.7, 35.3, 32.7, 32.03, 32.0, 31.9, 31.5, 30.0, 29.7, 29.66,
29.4, 27.3, 26.9, 25.0, 23.4, 23.2, 22.7, 20.4, 14.1 ppm. IR (ATR) max/cm1 = 2949 (w), 2916
(s), 2849 (s), 2781 (m), 1463 (m), 907 (w), 720 (m). MS (EI-TOF) m/z (%): 363 (22) [M+],
321 (20), 320 (85), 153 (12), 152 (100), 110 (66), 97 (17). HRMS-EI (TOF): [M+] calcd. for
C25H49N: 363.3865; found: 363.3871.
8.2.3.6 N-(3-pentadecylcyclohexyl)piperidine (3f)
Compound 3f was prepared following the general procedure 1 from 1 and piperidine (1.1 mmol,
94.6 mg). 3j was isolated as orange-yellow solid in 80% yield (300mg) when a pressure of 5
bar was used and in 84% yield (317 mg) when a pressure of 10 bar was employed (mixture of
diastereomers).
m.p.: 32-33 °C. Elemental analysis found: C, 82.2; H, 13.5; N, 3.5. Calc. for C26H51N: C,
82.7; H, 13.6; N, 3.7%. 1H–NMR (300 MHz, CDCl3) = 2.41 - 2.58 (m, 4 H), 2.25 - 2.39 (m,
1 H), 1.18 - 1.92 (m, 43 H), 0.88 (s, 3 H) ppm. 13C–NMR (75 MHz, CDCl3) = 64.21, 58.9,
50.37, 50.1, 37.61, 37.60, 35.7, 33.42, 33.38, 33.3, 32.96, 31.9, 31.02, 29.95, 29.93, 29.69,
29.65, 29.4, 28.9, 28.03, 27.7, 26.9, 26.6, 26.5, 25.6, 24.97, 24.9, 22.7, 20.9, 14.1 ppm. IR
(ATR) max/cm1 = 2916 (s), 2850 (s), 1469 (m), 1150 (w), 1112 (m), 717 (m). MS (EI-TOF)
m/z (%): 377 (30) [M+], 335 (22), 334 (89), 167 (14), 166 (100), 124 (67), 84 (11). HRMS-EI
(TOF): [M+] calcd. for C26H51N: 377.4022; found: 377.4026.
8.2.3.7 N,N-Hexamethylen-3-pentadecylcyclohexylamine (3g)
~
~
Experimental section
141
Compound 3j was prepared following the general procedure 1 from 1 and hexamethyleneimine
(1.1 mmol, 110 mg) with a hydrogen pressure of 10 bar. 3f was isolated as light yellow oil (302
mg, 77%, mixture of diastereomers).
1H–NMR (300 MHz, CDCl3) = 2.77 - 2.95 (m, 4 H), 1.34 - 2.05 (m, 17 H), 1.13 - 1.33 (m,
29 H), 0.81 - 0.89 (m, 3 H) ppm. 13C–NMR (75 MHz, CDCl3) = 51.2, 51.1, 48.2, 39.1, 37.31,
37.27, 36.6, 32.9, 31.9, 31.3, 29.9, 29.8, 29.7, 29.64, 29.62, 29.3, 28.7, 27.7, 27.1, 27.0, 26.8,
25.3, 25.1, 22.6, 20.5, 14.1 ppm. IR (ATR) max/cm1 = 2919 (s), 2851 (s), 1456 (m), 1356
(w), 1127 (w), 967 (w), 921 (w). MS (EI-TOF) m/z (%): 391 (26) [M+], 390 (10), 376 (13),
349 (21), 348 (100), 181 (12), 180 (94), 138 (63). HRMS-EI (TOF): [M+] calcd. for C27H53N:
391.4178; found: 391.4173.
8.2.3.8 4-methyl-1-(3-pentadecylcyclohexyl)piperidine (3h)
Compound 3g was prepared following the general procedure 1 from 1 and 4-methylpiperidine
(1.1 mmol, 111 mg) and isolated as pale-yellow oil (239 mg, 61%, mixture of diastereomers).
1H–NMR (300 MHz, CDCl3) = 2.81 - 2.95 (m, 2 H), 1.96 - 2.42 (m, 3 H), 1.62 (d, J=13.6
Hz, 7 H), 1.26 (s, 35 H), 0.84 - 0.93 (m, 6 H) ppm. 13C–NMR (75 MHz, CDCl3) = 63.8, 58.6,
49.9, 49.8, 49.6, 49.1, 37.59, 37.56, 35.8, 34.9, 34.8, 33.6, 33.4, 33.2, 32.9, 31.9, 31.2, 31.1,
31.0, 30.0, 29.9, 29.68, 29.65, 29.4, 29.0, 28.1, 27.7, 26.9, 25.5, 22.7, 22.0, 21.9, 20.8, 14.1
ppm. IR (ATR) max/cm1 = 2919 (s), 2851 (s), 1456 (m), 1259 (w), 1075 (w), 971 (w), 720
(w). MS (EI-TOF) m/z (%): 391 (43) [M+], 349 (20), 348 (83), 181 (13), 180 (100), 138 (57).
HRMS-EI (TOF): [M+] calcd. for C27H53N: 391.4178; found: 391.4174.
~
~
Experimental section
142
8.2.3.9 N-(3-pentadecylcyclohexyl)morpholine (3i)
Compound 3h was prepared following the general procedure 1 from 1 and morpholin (1.1
mmol, 95.8 mg) and isolated as colorless solid (322 mg, 85%, mixture of diastereomers).
m.p.: 49-51 °C. Elemental analysis found: C, 78.8; H, 12.8; N, 3.4. Calc. for C25H49NO: C,
79.1; H, 13.0; N, 3.7%. 1H–NMR (300 MHz, CDCl3) = 3.71 (t, J=4.6 Hz, 4 H), 2.42 - 2.61
(m, 4 H), 2.16 - 2.32 (m, 1 H), 1.14 - 1.96 (m, 37 H), 0.84 - 0.92 (m, 3 H) ppm. 13C–NMR
(75 MHz, CDCl3) = 67.5, 67.4, 63.7, 58.9, 50.2, 49.6, 37.5, 37.3, 35.8, 34.6, 33.9, 32.9, 32.2,
31.9, 31.6, 29.9, 29.7, 29.6, 29.4, 28.6, 28.3, 27.4, 26.9, 25.3, 22.7, 20.5, 14.1 ppm. IR (ATR)
max/cm1 = 2951 (w), 2915 (s), 2848 (s), 1463 (m), 1267 (m), 1122 (s), 988 (m), 884 (m),
719 (w). MS (EI-TOF) m/z (%): 379 (27) [M+], 337 (20), 336 (79), 169 (12), 168 (100), 126
(63), 97 (29). HRMS-EI (TOF): [M+] calcd. for C25H49NO: 379.3814; found: 379.3820.
8.2.3.10 8-(3-pentadecylcyclohexyl)-1,4-dioxa-8-azaspiro[4.5]decane (3j)
Compound 3i was prepared following the general procedure 1 from 1 and 1,4-Dioxa-8-
azaspiro[4.5]decane (1.1 mmol, 161 mg) and isolated as colorless solid (291 mg, 67 %, mixture
of diastereomers).
m.p.: 36-37 °C. Elemental analysis found: C, 77.0; H, 12.2; N, 3.1. Calc. for C28H51NO2: C,
77.2; H, 12.3; N, 3.2%. 1H–NMR (300 MHz, CDCl3) = 3.95 (s, 4 H), 2.62 (br. s., 4 H), 2.33
- 2.52 (m, 1 H), 1.33 - 1.98 (m, 13 H), 1.07 - 1.32 (m, 28 H), 0.88 (s, 3 H) ppm. 13C–NMR
(75 MHz, CDCl3) = 107.5, 65.5, 64.2, 58.1, 47.1, 46.8, 37.5, 35.1, 33.6, 33.4, 32.9, 31.9, 30.9,
29.94, 29.90, 29.68, 29.65, 29.4, 29.1, 27.7, 26.9, 25.5, 22.7, 20.8, 14.1 ppm. IR (ATR)
max/cm1 =2952 (w), 2917 (s), 2849 (s), 1466 (m), 1133 (w), 1070 (m), 1038 (m), 914 (m),
~
~
Experimental section
143
943 (w), 721 (w). MS (EI-TOF) m/z (%): 435 (36) [M+], 393 (18), 392 (70), 349 (6), 225 (15),
224 (100), 182 (51), 156 (10). HRMS-EI (TOF): [M+] calcd. for C28H53NO2: 435.4076; found:
435.4060
8.2.3.11 N-cyclohexyl-3-pentadecylcyclohexylamine (3k)
Compound 3k was prepared following the general procedure 1 from 1 and cyclohexylamine
(1.1 mmol, 110 mg) and isolated as yellowish oil (332 mg, 85%, mixture of diastereomers).
1H–NMR (300 MHz, CDCl3) = 2.84 - 2.95 (m, 1 H), 2.38 - 2.63 (m, 1 H), 1.37 - 1.94 (m, 11
H), 0.92 - 1.36 (m, 35 H), 0.84 - 0.91 (m, 3 H), 0.55 - 0.83 (m, 1 H) ppm. 13C–NMR (75 MHz,
CDCl3) = 53.3, 53.2, 53.1, 42.2, 41.5, 38.1, 37.4, 36.9, 35.4, 34.5, 34.4, 34.3, 34.1, 32.9, 32.1,
32.0, 31.9, 31.8, 29.94, 29.92, 29.7, 29.65, 29.64, 29.3, 27.2, 26.9, 26.21, 26.18, 25.3, 25.2,
25.1, 22.7, 20.4, 14.1 ppm. IR (ATR) max/cm1 = 2920 (s), 2851 (s), 2667 (w), 1464 (m), 1448
(m), 1368 (w), 1144 (w), 1113 (w), 887 (w), 719 (m). MS (EI-TOF) m/z (%): 391 (1) [M+],
337 (31), 336 (7), 295 (17), 294 (100), 126 (62), 84 (31). HRMS-EI (TOF): [M+] calcd. for
C27H53N: 391.4178; found: 391.4166.
8.2.3.12 N-(2-methoxyethyl)-3-pentadecylcyclohexylamine (3l)
Compound 3l was prepared following the general procedure 1 from 1 and 2-methoxyethylamine
(1.1 mmol, 83.5 mg) and isolated as yellow oil (283 mg, 70%, mixture of diastereoisomers).
1H–NMR (300 MHz, CDCl3) = 3.46 - 3.55 (m, 2 H), 3.32 - 3.39 (m, 3 H), 2.77 (dd, J=5.4,
1.4 Hz, 2 H), 1.85 - 1.98 (m, 1 H), 1.41 - 1.81 (m, 7 H), 0.94 - 1.39 (m, 31 H), 0.83 - 0.93 (m,
3 H) ppm. 13C–NMR (75 MHz, CDCl3) = 72.4, 72.3, 58.74, 52.72, 57.0, 52.4, 49.7, 46.4,
40.5, 37.5, 37.3, 36.7, 35.5, 33.5, 32.9, 32.0, 31.9, 31.8, 31.5, 30.0, 29.9, 29.7, 29.6, 29.3, 27.2,
~
Experimental section
144
26.9, 24.9, 22.7, 20.3, 14.1 ppm. IR (ATR) max/cm1 = 2920 (s), 2851 (s), 1458 (m), 1116
(m), 721 (m). MS (EI-TOF) m/z (%): 367 (2) [M+], 323 (22), 322 (100), 294 (3), 156 (5), 114
(4), 97 (18). HRMS-EI (TOF): [M+] calcd. for C24H49NO: 367.3814; found: 367.3831.
8.2.3.13 N,N-dibutyl-3-pentadecylcyclohexan-1-amine oxide (4a)
Compound 4a was prepared following the general procedure for synthesis of N-oxides from 3a
(1 mmol, 422 mg) and isolated yellowish oil (406 mg, 93 %).
1H–NMR (300 MHz, CDCl3) = 2.99 - 3.38 (m, 5 H), 2.11 - 2.46 (m, 1 H), 1.49 - 2.01 (m, 9
H), 1.13 - 1.42 (m, 34 H), 0.96 (t, J=7.3 Hz, 6 H), 0.69 - 0.91 (m, 4 H) ppm. 13C–NMR (75 MHz,
CDCl3) = 73.6, 69.4, 62.2, 61.8, 37.4, 37.1, 36.6, 33.7, 31.9, 31.4, 30.2, 29.8, 29.7, 29.65,
29.62, 29.3, 28.6, 28.1, 26.8, 26.1, 24.8, 24.5, 22.6, 20.5, 20.3, 20.2, 14.1, 13.9, ppm. IR (ATR)
max/cm1 = 2956 (m), 2921 (s), 2852 (s), 1458 (m), 1377 (m), 976 (w), 897 (m), 720 (m). MS
(EI-TOF) m/z (%): 421 (1) [(M - O)+], 337 (23), 323 (14), 295 (20), 294 (100), 290 (54), 126
(69), 112 (29). HRMS-ESI (TOF): [(M + H)+] calcd. for C29H59NOH: 438.4669; found:
438.4667.
8.2.3.14 N,N-dimethyl-3-pentadecylcyclohexan-1-amine oxide (4b)
Compound 4b was prepared following the general procedure for synthesis of N-oxides from 3b
(1.0 mmol, 338 mg) and isolated as pale-yellow solid (331 mg, 94%).
Compound 4b was also prepared following the procedure for the one-pot amination/oxidation
sequence from 1 and dimethyl amine and isolated as yellowish solid (252 mg, 71%)
~
~
Experimental section
145
m.p.: 92-93 °C. 1H–NMR (400 MHz, CDCl3) = 3.23 - 3.38 (m, 1 H), 3.09 - 3.22 (m, 6 H),
2.34 - 2.46 (m, 1 H), 2.13 - 2.25 (m, 1 H), 1.87 - 2.09 (m, 1 H), 1.66 - 1.81 (m, 1 H), 1.16 - 1.65
(m, 33 H), 0.83 - 0.91 (m, 3 H) ppm. 13C–NMR (100 MHz, CDCl3) =78.1, 74.0, 55.1, 54.8,
54.7, 54.3, 37.11, 33.9, 33.5, 31.9, 31.2, 31.1, 29.8, 29.62, 29.59, 29.56, 29. 3, 28.4, 27.8, 27.3,
27.2, 26.7, 24.7, 22.6, 20.2, 14.1 ppm. IR (ATR) max/cm1 = 2953 (w), 2916 (s), 2849 (s),
1585 (w), 1469 (m), 963, 1427 (m), 1377 (w), 1190 (w), 936 (w), 718 (m). MS (EI-TOF) m/z
(%): 337 (23) [(M - O)+], 323 (28), 322 (12), 295 (18), 294 (91), 281 (20), 280 (100), 278 (10),
126 (66), 124 (10), 112 (54). HRMS-ESI (TOF): [(M + H)+] calcd. for C23H47NOH: 354.3730;
found: 354.3717.
8.2.3.15 N-benzyl-N,N-dimethyl-3-tetradecylcyclohexan-1-aminium (5b)
An oven-dried 20 mL headspace vial with Teflon-coated stirring bar was charged with
cyclohexylamine 3b (0.50 mmol, 169 mg), EtOH (2mL) and benzyl chloride (0.5 mmol, 63.9
mg). The vial was closed with a septum cap, and the resulting mixture was stirred at 85 °C for
15 h. After the reaction was complete, the solvent was removed under reduced pressure. The
residue was washed with Et2O (2 x 5 mL) and dried under reduced pressure yielding the desired
product 5b as colorless solid (87 mg, 62%).
m.p.: 179-181 °C. 1H–NMR (300 MHz, CDCl3) = 7.62 - 7.73 (m, 2 H), 7.46 (dd, J=1.5, 0.4
Hz, 3 H), 5.06 (s, 2 H), 3.47 - 3.65 (m, 1 H), 3.25 (d, J=8.4 Hz, 5 H), 1.70 - 2.43 (m, 5 H), 1.10
- 1.68 (m, 33 H), 0.81 - 0.91 (m, 3 H) ppm. 13C–NMR (75 MHz, CDCl3) = 133.2, 133.1,
130.5, 129.14, 129.05, 127.6, 66.8, 64.7, 47.4, 47.1, 37.1, 36.9, 33.7, 33.0, 31.8, 31.0, 30.4,
29.7, 29.62, 29.59, 29.57, 29.55, 29.5, 29.48, 29.3, 27.8, 27.6, 26.8, 26.7, 22.6, 20.1, 14.0 ppm.
IR (ATR) max/cm1 =2921 (s), 2852 (s), 1633 (w), 1456 (m), 1418 (m), 1378 (w), 1216 (w),
907, (w), 737 (m), 703 (m). MS (EI-solid) m/z (%): 445 (2) [(M – Cl, Me)+], 370 (5), 337 (24),
295 (23), 294 (100), 266 (6), 202 (6), 126 (95). HRMS-ESI (TOF): [(M – Cl)+] calcd. for
C30H54N: 428.4251; found: 428.4250.
~
~
Experimental section
146
8.2.3.16 2-(dimethyl(3-tetradecylcyclohexyl)ammonio)acetate (6b)
An oven-dried 20 mL headspace vial with Teflon-coated stirring bar was charged with
bromoacetic acid (2.00 mmol, 278 mg), cyclohexylamine 3b (2.00 mmol), MeOH (2 mL) and
H2O (2 mL). Sodium bicarbonate (2.00 mmol, 338 mg) was added dropwise to the mixture to
keep the solution at pH 7-8. The resulting mixture was stirred at 80°C for 10h. Upon
completion, the solvent was evaporated under reduced pressure and the residue was washed
with Et2O (3 X 5 mL). Residual Et2O was removed under vacuum. The residue was dissolved
in dichloromethane (10 mL) and washed with water (2 x 5 mL). The combined organic layers
were filtered over MgSO4 and the solvent was removed under reduced pressure yielded the
corresponding betaine 6b as light brown solid (529 mg, 67%).
m.p.: 154 - 156 °C. 1H–NMR (300 MHz, CDCl3) = 4.05 - 4.21 (m, 1 H), 3.83 (s, 2 H), 3.12
- 3.25 (m, 6 H), 1.88 - 2.24 (m, 3 H), 1.69 - 1.81 (m, 1 H), 1.51 - 1.63 (m, 2 H), 1.24 (s, 31 H),
0.86 (s, 3 H)ppm. 13C–NMR (75 MHz, CDCl3) = 165.4, 165.2, 71.2, 68.3, 63.9, 63.6, 48.1,
47.9, 47.8, 36.9, 36.8, 33.5, 32.7, 31.7, 31.2, 30.7, 30.3, 29.6, 29.5, 29.48, 29.4, 29.2, 27.8, 27.7,
26.6, 26.4, 26.1, 24.4, 22.5, 20.2, 13.9 ppm. IR (ATR) max/cm1 =2917 (s), 2850 (s), 1628 (s),
1467 (m), 1392 (m), 1324 (m), 880 (w), 721 (m). MS (Ion trap, EI) m/z (%): 337 (10) [(M -
CH2CO2)+], 308 (1), 294 (70), 156 (100), 84 (75), 71 (15). HRMS-ESI (TOF): [(M + H)+]
calcd. for C25H49NO2H: 396.3836; found: 396.3828.
8.3 Synthesis of a tyrosinase inhibitor from cashew nut shell liquid
8.3.1 Chemicals
All solvents and liquid reactants were degassed with Argon for 15 min prior to use. Ethylene
was purchased from Air Liquide GmbH (purity 99,95%). The following metathesis catalysts
were donated by Umicore:
M31: [1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(3-phenyl-1H-inden-1-
ylidene)(pyridyl)ruthenium(II) [CAS No.: 1031262-76-6]. M51: [1,3-Bis(2,4,6-
~
Experimental section
147
trimethylphenyl)-2-imidazolidinylidene]dichloro[[2-(1-methyl-2-
oxopropoxy)phenyl]methylene] ruthenium(II) [CAS No.: 1031262-71-1]. M20: 1,3-Bis(2,4,6-
trimethylphenyl)-2-imidazolidinylidene]dichloro(3-phenyl-1H-inden-1-
ylidene)(triphenylphosphine)ruthenium(II) [CAS Number : 340810-50-6]. M22: cis-[1,3-
Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(3-phenyl-1H-inden-1-
ylidene)(triisopropylphosphite)ruthenium(II) [CAS Number : 1255536-61-8]. M2: [1,3-
Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(3-phenyl-1H-inden-1-
ylidene)(tricyclohexylphosphine)ruthenium(II) [CAS Number : 536724-67-1]. M23: [1,3-
Bis(2,6-diisopropylphenyl)-2-imidazolidinylidene]dichloro(3-phenyl-1H-inden-1-
ylidene)(triphenylphosphine) ruthenium(II) [CAS Number : 1307233-23-3]. M73: [1,3-
Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro[5-(isobutoxycarbonylamido)-2-
isopropoxybenzylidene]ruthenium(II) [CAS Number : 1025728-57-7]. HG I: Dichloro(2-
isopropoxyphenylmethylene) (tricyclohexylphosphine)ruthenium(II) [CAS Number 203714-
71-0 ]. HG II: Dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-
isopropoxyphenylmethylene)ruthenium(II) [CAS Number 301224-40-8]. G I:
Dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II) [CAS Number 172222-30-9].
8.3.2 Preparation of CNSL
Cashew nut shells (250 g), collected from Naliendele in Mtwara, Tanzania, were comminuted
into ~1 mm small particles, which were than treated by Soxhlet extraction with several solvents
(500 mL) at 50 °C for 6 h. Removal of the solvent in vacuo resulted in a highly viscous brown
oil. The CNSL was used without further purification. Following is reported a list of solvents
used for extraction and yield of the obtained CNSL, starting from 250 g of shells.
Aceton: 73 g of CNSL (29%)
EtOH: 75 g of CNSL (30%)
Cyclohexane: 67 g of CNSL (27%)
Dichloromethane: 66 g of CNSL (26%)
Diethylether: 69 g of CNSL (29%)
Experimental section
148
8.3.3 Synthesis and characterisation of products
8.3.3.1 Synthesis of 2-hydroxy-6-(non-8-enyl)benzoic acid (2) via selective ethenolysis of
CNSL
(CAS 1629257-80-2)
A 1 L Parr autoclave was charged with the metathesis catalyst Ru-1 (330 mg, 0.55 mmol),
CNSL (37.7 g, 110 mmol) and DCM (100 ml) under ethylene atmosphere. The system was
evacuated and back-filled with ethylene (5 bar) three times and finally pressurized to 10 bar.
The mixture was stirred at 500 rpm at room temperature for 12 h. After the reaction time, the
reaction mixture was filtered through celite and the filter cake was washed with DCM
(2 x 10 ml). The solvent was removed in vacuo and the residue was dissolved in pentane (50
mL) and stored in the freezer until precipitation of the solid. The precipitate was filtered and
washed with cold pentane (2 x 20 ml) yielding the product 2-hydroxy-6-(non-8-enyl)benzoic
acid (2) as colorless solid (16,2 g, 84%).
Elemental analysis calc. for C16H22O3: C, 73.25, H, 8.45. Found C, 73.55, H, 8.53. 1H-NMR
(300 MHz, CDCl3): = 10.98 (br. s., 1 H), 7.38 (dd, J = 8.4, 7.5 Hz, 1 H), 6.89 (dd, J = 8.3,
1.3 Hz, 1 H), 6.79 (dd, J = 7.5, 1.3 Hz, 1 H), 5.82 (ddt, J = 17.0, 10.2, 6.7, 6.7 Hz, 1 H), 5.03
(q, J = 1.7 Hz, 1 H), 4.89 - 4.99 (m, 1 H), 2.94 - 3.05 (m, 2 H), 2.00 - 2.10 (m, 2 H), 1.56 - 1.68
(m, 2 H), 1.29 - 1.44 (m, 8 H) ppm. 13C-NMR (75 MHz, CDCl3): = 176.1, 163.7, 147.8,
139.2, 135.5, 122.8, 115.9, 114.1, 110.3, 36.4, 33.8, 31.9, 29.7, 29.3, 29.1, 28.9 ppm.
The analytical data matched those reported in the literature.90
8.3.3.2 Synthesis of 2-hydroxy-6-(tridec-8-enyl)benzoic acid (5)
(CAS 88640-88-4)
An oven-dried 20 mL vial was charged with Ru-1 (3.00 mg, 5.00 μmol), 2 (131 mg,
0.50 mmol) and closed with a crimp cap. The vial was evacuated and back-filled three times
with argon. 1-Hexene (3.50 mmol, 0.45 ml) and DCM (1 ml) were added simultaneously via
Experimental section
149
syringe under an argon atmosphere. The continuous elimination of formed ethylene was
performed by connecting the reaction vessel via an open system to an oil bubbler. The resulting
mixture was stirred at 60 °C for 6 h. After the reaction was complete, the mixture was filtered
through celite and the filter cake was washed with DCM (2 x 5 mL). The solvent was removed
in vacuo and the residue was dissolved in pentane (5 mL) and stored in the freezer until
precipitation of the solid. Product 5 was isolated as colorless solid (120 mg, 76 %).
Elemental analysis calc. for C20H30O3: C, 75.43, H, 9.50. Found C, 75.43, H, 9.36. 1H-NMR
(400 MHz, CDCl3): = 11.00 (s, 1 H), 7.38 (t, J = 7.9 Hz, 1 H), 6.86 - 6.91 (m, 1 H), 6.76 -
6.82 (m, 1 H), 5.33 - 5.44 (m, 2 H), 2.95 - 3.03 (m, 2 H), 1.92 - 2.08 (m, 4 H), 1.56 - 1.66 (m,
2 H), 1.25 - 1.43 (m, 12 H), 0.86 - 0.92 (m, 3 H) ppm. 13C-NMR (75 MHz, CDCl3): = 175.9,
163.7, 147.8, 135.5, 130.4, 130.3, 129.9, 129.8, 122.8, 115.9, 110.3, 36.5, 32.6, 32.3, 32, 31.8,
29.8, 29.6, 29.3, 29.1, 26.9, 22.3, 22.2, 14 ppm.
The analytical data matched those reported in the literature.376
8.3.3.3 One-pot synthesis of 2-hydroxy-6-tridecylbenzoic acid (3)
(CAS 20261-38-5)
An oven-dried 20 mL vial was charged with Ru-1 (3.00 mg, 5.00 μmol), 2 (131 mg, 0.50 mmol)
and closed with a crimp cap. The vial was evacuated and back-filled three times with argon. 1-
Hexene (3.50 mmol, 0.45 ml) and DCM (1 ml) were added simultaneously via syringe under
an argon atmosphere. The continuous elimination of formed ethylene was performed by
connecting the reaction vessel via an open system to an oil bubbler. The resulting mixture was
stirred at 60 °C for 6 h. After the reaction was complete, methanol (0.5 mL) and activated
charcoal (20.0 mg) were added. The vial was closed with a septum cap, penetrated with a
cannula for pressure equilibration and placed into an autoclave. The system was purged twice
with H2 (5 bar) and finally pressurized to 5 bar. The resulting mixture was stirred for 3 h at
50 °C. After cooling down to room temperature, the pressure was slowly released under
constant stirring at 300 rpm. The reaction mixture was filtered through celite and the filter cake
was washed with DCM (2 x 5 ml). The solvent was removed in vacuo and the residue was
dissolved in pentane (5 mL) and stored in the freezer until precipitation of the solid. The
Experimental section
150
precipitate was filtered and washed with cold pentane (2 x 5 ml), yielding the product 3 as
colorless solid (120 mg, 76 %).
Elemental analysis calc. for C20H32O3: C, 74.9; H, 10.1. Found C, 74.8; H, 9.8. 1H-NMR (300
MHz, CDCl3): = 10.98 (s, 1 H), 7.38 (dd, J = 8.3, 7.6 Hz, 1 H), 6.89 (dd, J = 8.3, 1.2 Hz, 1
H), 6.79 (dd, J = 7.5, 1.1 Hz, 1 H), 2.92 - 3.06 (m, 2 H), 1.54 - 1.70 (m, 2 H), 1.21 - 1.44 (m,
20 H), 0.84 - 0.93 (m, 3 H) ppm. 13C-NMR (75 MHz, CDCl3): = 176.1, 163.6, 147.9, 135.5,
130.3, 122.8, 115.9, 110.4, 36.5, 32.0, 31.9, 29.8, 29.69, 29.68, 29.65, 29.6, 29.5, 29.4, 29.3,
22.7, 22.2, 14.1 ppm.
The analytical data matched those reported in the literature.82
8.4 Catalytic, waste-free alkoxycarboxylation of terminal alkynes
8.4.1 GP: General procedure for the alkoxycarbonylation/hydrogenation of terminal
alkynes with K3PO4 as base
Two 10 mL headspace vials equipped with Teflon-coated stir bars were each charged with
anhydrous potassium phosphate (212 mg, 1.00 mmol) inside a glovebox and capped.
Afterwards, a solution of copper(I) bromide (146 µg, 1.00 µmol) in NMP (0.10 mL) and the
corresponding alkyne (1a–r, 0.50 mmol) were added via syringe. A spirally bent needle was
punched in the vials, which were placed in an autoclave. The atmosphere was exchanged twice
with CO2 (5 bar), and the autoclave was finally pressurised with CO2 (10 bar). The reaction was
stirred at 600 rpm and 80 °C for 12 h. After cooling down to room temperature, the pressure
was slowly released under stirring.
Palladium on alumina (21.3 mg, 5%, 10.0 µmol) was added as a slurry in the corresponding
alcohol (2a–d, 5 mL) and the autoclave was sealed again. The atmosphere was exchanged with
hydrogen (5 bar) twice and the autoclave was pressurised to a final hydrogen pressure of 5 bar.
After stirring the mixture at room temperature for 3 h, the atmosphere was exchanged with CO2
(2 × 10 bar) and the autoclave was finally pressurised with CO2 (45 bar). The mixture was
stirred at 180 °C for 20 h.
After cooling down, the contents of the reaction vessels and of the autoclave were diluted with
ethyl acetate (100 mL) and combined. The organic phase was washed with water (3 × 20 mL)
and aq. sat. NaHCO3 (2 × 20 mL). The aqueous phases were extracted with ethyl acetate (2 ×
15 mL) and the combined organic phases were washed with brine (30 mL), dried over MgSO4,
Experimental section
151
filtered, and the volatiles were removed under reduced pressure. The residue was purified by
column chromatography (SiO2, cyclohexane/ethyl acetate gradient) yielding the corresponding
esters.
8.4.2 Procedure for the alkoxycarboxylation of 1-heptyne with Cs2CO3 as base and
recovery of the base
Two 10 mL headspace vials equipped with Teflon-coated stir bars were each charged with
anhydrous caesium carbonate (329 mg, 1.00 mmol) inside a glovebox and capped. Afterwards,
a solution of copper(I) bromide (146 µg, 1.00 µmol) in NMP (0.15 mL) and 1-heptyne (1a,
0.50 mmol) were added via syringe. A spirally bent needle was punched in the vials, which
were placed in an autoclave. The atmosphere was exchanged twice with CO2 (5 bar), and the
autoclave was finally pressurised with CO2 (10 bar). The reaction was stirred at 600 rpm and
60 °C for 12 h. After cooling down to room temperature, the pressure was slowly released under
stirring.
Palladium on alumina (21.3 mg, 5%, 10.0 µmol) and methanol (2 mL) were added in the vials
and the autoclave was sealed again. The atmosphere was exchanged with hydrogen (5 bar)
twice and the autoclave was pressurised to a final hydrogen pressure of 5 bar. After stirring the
mixture at room temperature for 3 h, the content of the vials was transferred in the 50 mL vessel
of the Parr 4590, with additional 11 mL of methanol. The vessel was fixed to the upper part of
the autoclave by the split-ring. The atmosphere was exchanged with CO2 (3 × 10 bar) and the
weight of the autoclave was taken as tare. CO2 was added to the autoclave four times under
stirring (600 rpm), with intervals of 10 minutes between the additions, to give time to the CO2
to dissolve into the mixture. The load of inserted CO2 was determined by weighing, and
adjusted by venting excess CO2 until the desired amount was reached (15 g). The mixture was
stirred at 200 °C for 20 h.
After cooling down, the content of the vessel and of the autoclave were diluted with ethyl
acetate (100 mL) and water (70 mL). The organic phase was washed other two times with water
(2 × 30 mL) and mesitylen was added as internal standard (100 L, 0.72 mmol). The organic
phase was filtered through Mg2SO4 and analysed in GC. The aqueous phases were extracted
with ethyl acetate (2 × 15 mL) and dried under reduced pressure (65 °C, 10 mbar). The residual
salts were centrifuged three times with toluene and dried under vacuum (180 °C, 2 h). 1H-NMR
Experimental section
152
of the salts is measured with 1,3,5-trimethoxybenzene as internal standard to calculate the
amount of residual Cs-octanoate.
A new alkoxycarboxylation sequence of 1-heptyne was run and the amount of caesium
octanoate already presentin the base was deducted from the yield of Me-octanoate.
8.4.3 Synthesis and characterisation of the corresponding products
8.4.3.1 Synthesis of 2-(2-methoxyethoxy)ethyl 3-(2-pyridyl)propanoate (3qa)
2
Compound 3qa was synthesised following procedure GP1 starting from 2-ethynylpyridine (1q)
(105.2 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a, 10.3 g, 10.0 mL, 85.8 mmol) and
isolated as yellow oil (173 mg, 68%).
1H NMR (300 MHz, CDCl3): = 8.46 (ddd, J=4.9, 1.6, 0.9 Hz, 1 H), 7.53 (td, J=7.6, 1.8 Hz,
1 H), 7.13 (d, J=7.9 Hz, 1 H), 7.05 (ddd, J=7.5, 4.9, 1.2 Hz, 1 H), 4.15 - 4.22 (m, 2 H), 3.59 -
3.65 (m, 2 H), 3.58 (dd, J=4.0, 0.9 Hz, 1 H), 3.55 (t, J=2.4 Hz, 1 H), 3.49 (t, J=2.4 Hz, 1 H),
3.47 (dd, J=4.0, 0.9 Hz, 1 H), 3.32 (s, 3 H), 3.06 (t, J=7.4 Hz, 2 H), 2.78 (t, J=7.4 Hz, 2 H) ppm.
13C NMR (101 MHz, CDCl3): = 173.0, 160.0, 149.3, 136.3, 123.0, 121.3, 71.9, 70.5, 69.1,
63.6, 59.0, 33.3, 32.8 ppm. IR (neat): 𝜈 = 2878 (w), 1732 (s), 1593 (w), 1569 (w), 1475 (w),
1437 (m), 1244 (m), 1108 (s), 1050 (m), 920 (w), 852 (w), 754 (m), 730 (s) cm–1. MS (EI-
TOF): m/z (%): 238 (1), [(M–CH3)+], 165 (24), 134 (82), 107 (34), 106 (100), 78 (29), 59 (37),
45 (52). HRMS (EI-TOF) calcd. for C13H20NO4 ([M+H]+): 254.1392; found: 254.1394.
8.4.3.2 Synthesis of 2-(2-methoxyethoxy)ethyl octanoate (3aa)
2 (CAS: 581784-63-6)
Compound 3aa was synthesised following procedure GP1 starting from 1-heptyne (1a)
(98.2 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a, 10.3 g, 10.0 mL, 85.8 mmol) and
isolated as pale yellow oil (200 mg, 81%).
Experimental section
153
1H NMR (300 MHz, CDCl3): = 4.22-4.27 (m, 2 H), 3.68-3.74 (m, 2 H), 3.62-3.68 (m, 2 H),
3.53-3.60 (m, 2 H), 3.40 (s, 3 H), 2.34 (t, J=7.5 Hz, 2 H), 1.58-1.66 (m, 2 H), 1.25-1.34 (m, 8
H), 0.85-0.92 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): = 173.9, 71.9, 70.5, 69.2, 63.3,
59.1, 34.2, 31.6, 29.1, 28.9, 24.9, 22.6, 14.0 ppm. IR (neat): 𝜈 = 2926 (w), 2857 (w), 1735 (m),
1456 (w), 1253 (w), 1168 (w), 1106 (m), 915 (w), 730 (m) cm–1. MS (EI-TOF): m/z (%): 246
(1) [M+], 171 (55), 127 (72), 102 (16), 89 (18), 58 (100). HRMS (EI-TOF) calcd. for C13H27O4
([M+H]+): 247.1909; found: 247.1904.
8.4.3.3 Synthesis of 2-(2-methoxyethoxy)ethyl nonanoate (3ba)
2
Compound 3ba was synthesised following procedure GP1 starting from 1-octyne (1b) (114 mg,
1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a, 10.3 g, 10.0 mL, 85.8 mmol) and isolated as
pale yellow oil (180 mg, 69%).
1H NMR (300 MHz, CDCl3): = 4.20-4.29 (m, 2 H), 3.68-3.74 (m, 2 H), 3.62-3.68 (m, 2 H),
3.53-3.60 (m, 2 H), 3.39 (s, 3 H), 2.33 (t, J=7.6 Hz, 2 H), 1.58-1.67 (m, 2 H), 1.29 (br. s., 10
H), 0.85-0.92 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): = 173.9, 71.9, 70.5, 69.2, 63.3,
59.1, 34.2, 31.8, 29.2, 29.1 (2C), 24.9, 22.6, 14.1 ppm. IR (neat): 𝜈 = 2924 (m), 2856 (m), 1736
(s), 1456 (w), 1167 (m), 1107 (s), 916 (s), 731 (m) cm–1. MS (EI-TOF): m/z (%): 260 (0.1)
[M+], 185 (47), 141 (59), 102 (16), 89 (17), 71 (27), 58 (100). HRMS (EI-TOF) calcd. for
C14H29O4 ([M+H]+): 261.2066; found: 261.2061.
8.4.3.4 Synthesis of 2-(2-methoxyethoxy)ethyl 4-cyclohexylbutanoate (3ca)
2
Compound 3ca was synthesised following procedure GP1 starting from 3-cyclohexylpropyne
(1c) (126 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a, 10.3 g, 10.0 mL, 85.8 mmol)
and isolated as pale yellow oil (176 mg, 65%).
1H NMR (300 MHz, CDCl3): = 4.13 - 4.27 (m, 2 H), 3.63 - 3.72 (m, 2 H), 3.56 - 3.63 (m, 2
H), 3.46 - 3.56 (m, 2 H), 3.35 (s, 3 H), 2.27 (t, J=7.5 Hz, 2 H), 1.51 - 1.77 (m, 7 H), 1.02 - 1.30
Experimental section
154
(m, 6 H), 0.73 - 0.94 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): = 173.9, 71.9, 70.5, 69.2,
63.3, 59.1, 37.4, 36.9, 34.5, 33.2, 26.6, 26.3, 22.3 ppm. IR (neat): 𝜈 = 2921 (m), 2850 (m), 1734
(s), 1449 (w), 1175 (m), 1110 (s), 914 (m), 730 (vs) cm–1. MS (EI-TOF): m/z (%): 197 (17),
152 (23), 135 (83), 102 (2), 87 (20), 67 (27), 58 (100), 55 (36). HRMS (EI-TOF) calcd. for
C15H29O4 ([M+H]+): 273.2066; found: 273.2061.
8.4.3.5 Synthesis of 2-(2-methoxyethoxy)ethyl 4-phenylbutanoate (3fa)
2
Compound 3fa was synthesised following procedure GP1 starting from 3-phenylpropyne (1f)
(120 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a, 10.3 g, 10.0 mL, 85.8 mmol) and
isolated as yellow oil (108 mg, 41%).
1H NMR (400 MHz, CDCl3): = 7.12 - 7.37 (m, 5 H), 4.20 - 4.36 (m, 2 H), 3.61 - 3.77 (m, 4
H), 3.50 - 3.60 (m, 2 H), 3.36 (s, 3 H), 2.65 (t, J=7.7 Hz, 2 H), 2.35 (t, J=7.6 Hz, 2 H), 1.95
(quin, J=7.5 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): = 173.6, 141.5, 128.6, 128.5, 126.1,
72.0, 70.6, 69.4, 63.5, 59.2, 35.2, 33.7, 26.6 ppm. IR (neat): 𝜈 = 3027 (m), 2875 (m), 1732 (s),
1603 (w), 1497 (w), 1454 (m), 1244 (m), 1198 (m), 1109 (vs), 851 (w), 746 (m) cm–1. MS (EI-
TOF): m/z (%): 266 (2) [M+], 162 (14), 147 (31), 104 (100), 91 (71), 86 (23), 59 (39). HRMS
(EI-TOF) calcd. for C15H23O4 ([M+H]+): 267.1596; found: 267.1591.
8.4.3.6 Synthesis of 2-(2-methoxyethoxy)ethyl 3-phenylpropanoate (3ga)
2
Compound 3ga was synthesised following procedure GP1 starting from phenylacetylene (1g)
(104.2 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a, 10.3 g, 10.0 mL, 85.8 mmol) and
isolated as pale yellow oil (131 mg, 52%).
1H NMR (300 MHz, CDCl3): = 7.21 - 7.30 (m, 2 H), 7.07 - 7.20 (m, 3 H), 4.06 - 4.37 (m, 2
H), 3.61 - 3.70 (m, 2 H), 3.55 - 3.62 (m, 2 H), 3.46 - 3.54 (m, 2 H), 2.93 (t, J=7.8 Hz, 2 H), 2.56
- 2.70 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): = 172.7, 140.4, 128.4, 128.2, 126.2, 71.8,
70.4, 69.1, 63.5, 58.9, 35.7, 30.8 ppm. IR (neat): ν ̃ = 2877 (w), 1732 (s), 1454 (m), 1108 (s),
Experimental section
155
852 (m), 751 (m), 699 (s) cm–1. MS (EI-TOF): m/z (%): 252 (3) [M+], 176 (10), 133 (10), 104
(100), 91 (53), 59 (25), 45 (13). HRMS (EI-TOF) calcd. for C14H21O4 ([M+H]+): 253.1440;
found: 253.1434.
8.4.3.7 Synthesis of 2-(2-methoxyethoxy)ethyl 4-methoxybutanoate (3da)
2
Compound 3da was synthesised following procedure GP1 starting from methyl propargyl ether
(1d) (72.2 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a, 10.3 g, 10.0 mL, 85.8 mmol)
and isolated as pale yellow oil (52.8 mg, 24%).
1H NMR (300 MHz, CDCl3): = 4.16 - 4.26 (m, 2 H), 3.64 - 3.71 (m, 2 H), 3.57 - 3.64 (m, 2
H), 3.49 - 3.55 (m, 2 H), 3.37 (t, J=6.2 Hz, 2 H), 3.35 (s, 3 H), 3.29 (s, 3 H), 2.39 (t, J=7.4 Hz,
2 H), 1.86 (tt, J=7.4, 6.3 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): = 173.5, 72.0, 71.6,
70.5, 69.2, 63.5, 59.1, 58.6, 30.9, 25.0 ppm. IR (neat): 𝜈 = 2928 (w), 2875 (w), 2829 (w), 1733
(s), 1451 (w), 1379 (w), 1251 (w), 1172 (m), 1110 (s), 1026 (m), 963 (w), 852 (w) cm–1. MS
(EI-TOF): m/z (%): 207 (1) [M+−CH3], 145 (9), 113 (24), 101 (98), 86 (16), 69 (68), 58 (100),
45 (84). HRMS (EI-TOF) calcd. for C10H21O5 ([M+H]+): 221.1389; found: 221.1387.
8.4.3.8 Synthesis of n-octyl 4-methoxybutanoate (3db)
Compound 3db was synthesised following procedure GP1 starting from methyl propargyl ether
(1d) (72.2 mg, 1.00 mmol) and 1-octanol (2b, 8.24 g, 10.0 mL, 62.6 mmol) and isolated as pale
yellow oil (105 mg, 47%).
1H NMR (300 MHz, CDCl3): = 4.01 (t, J=6.7 Hz, 2 H), 3.35 (t, J=6.3 Hz, 2 H), 3.27 (s, 3 H),
2.33 (t, J=7.5 Hz, 2 H), 1.84 (quin, J=6.8 Hz, 1 H), 1.57 (quin, J=6.9 Hz, 1 H), 1.15 - 1.34 (m,
10 H), 0.83 (t, J=6.9 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): = 173.5, 71.7, 64.5, 58.5,
31.8, 31.0, 29.2, 29.3, 28.7, 26.0, 25.1, 22.7, 14.1 ppm. IR (neat): 𝜈 = 2926 (s), 2856 (s), 1735
(s), 1460 (w), 1388 (w), 1250 (m), 1168 (s), 1119 (s), 1084 (m), 1026 (m), 891 (w), 723 (w)
cm–1. MS (EI-TOF): m/z (%): 230 (1), [M+], 215 (1), 157 (1), 119 (12), 101 (100), 85 (15), 69
Experimental section
156
(37), 59 (80), 45 (42). HRMS (EI-TOF) calcd. for C13H27O3 ([M+H]+): 231.195; found:
231.195.
8.4.3.9 Synthesis of 2-(2-methoxyethoxy)ethyl 3-(2-methylphenyl)propanoate (3ha)
2
Compound 3ha was synthesised following procedure GP1 starting from 2-
methylphenylacetylene (1h) (120 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a, 10.3 g,
10.0 mL, 85.8 mmol) and isolated as yellow oil (167 mg, 63%).
1H NMR (300 MHz, CDCl3): = 6.97 - 7.19 (m, 4 H), 4.20 - 4.29 (m, 2 H), 3.65 - 3.71 (m, 2
H), 3.58 - 3.64 (m, 2 H), 3.50 - 3.56 (m, 2 H), 3.37 (s, 3 H), 2.87 - 3.02 (m, 2 H), 2.54 - 2.69
(m, 2 H), 2.31 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): = 172.9, 138.5, 135.9, 130.2, 128.4,
126.3, 126.0, 71.8, 70.4, 69.1, 63.5, 59.0, 34.4, 28.2, 19.2 ppm. IR (neat): 𝜈 = 2877 (m), 1732
(s), 1605 (w), 1493 (w), 1455 (m), 1284 (m), 1198 (m), 1106 (vs), 1054 (m), 851 (w), 747 (m)
cm–1. MS (EI-TOF): m/z (%): 266 (2) [M+], 146 (39), 118 (100), 105 (81), 91 (8), 77 (10), 59
(33). HRMS (EI-TOF) calcd. for C15H23O4 ([M+H]+): 267.1596; found: 267.1590.
8.4.3.10 Synthesis of 2-(2-methoxyethoxy)ethyl 3-(4-(trifluoromethyl)phenyl)propanoate
(3ma)
2
Compound 3ma was synthesised following procedure GP1 starting from 4-
(trifluoromethyl)phenylacetylene (1m) (175 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol
(2a, 10.3 g, 10.0 mL, 85.8 mmol) and isolated as pale yellow oil (75.0 mg, 24%).
1H NMR (300 MHz, CDCl3): = 7.51 (d, J=8.1 Hz, 2 H), 7.30 (d, J=8.1 Hz, 1 H), 4.16 - 4.25
(m, 2 H), 3.62 - 3.69 (m, 2 H), 3.55 - 3.62 (m, 2 H), 3.47 - 3.54 (m, 2 H), 3.32 - 3.37 (m, 3 H),
2.99 (t, J=7.6 Hz, 2 H), 2.66 (t, J=7.6 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): = 172.4,
144.7, 128.8, 128.7 (q, J=32.1 Hz), 125.4 (q, J=3.9 Hz), 124.3 (q, J=272.0 Hz), 71.9, 70.5, 69.1,
63.7, 59.0, 35.3, 30.6 ppm. 19F NMR (235 MHz, CDCl3, C6F6): = –62.3 ppm. IR (neat): 𝜈 =
Experimental section
157
2880 (w), 1733 (m), 1619 (w), 1324 (s), 1161 (m), 1106 (s), 1066 (s), 1018 (m), 832 (m) cm–1.
MS (EI-TOF): m/z (%): 245 (45), 173 (90), 159 (57), 153 (18), 102 (20), 89 (26), 58 (100).
HRMS (EI-TOF) calcd. for C15H20F3O4 ([M+H]+): 321.1314; found: 321.1309.
8.4.3.11 Synthesis of 2-(2-methoxyethoxy)ethyl 3-(4-methoxyphenyl)propanoate (3pa)
2
Compound 3pa was synthesised following procedure GP1 starting from 4-
methoxyphenylacetylene (1p) (136 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a,
10.3 g, 10.0 mL, 85.8 mmol) and isolated as pale yellow oil (155 mg, 55%).
1H NMR (300 MHz, CDCl3): = 6.96 - 7.13 (m, 2 H), 6.67 - 6.85 (m, 2 H), 4.10 - 4.23 (m, 2
H), 3.71 (s, 3 H), 3.58 - 3.65 (m, 2 H), 3.51 - 3.58 (m, 2 H), 3.40 - 3.51 (m, 2 H), 3.32 (s, 3 H),
2.84 (t, J=7.7 Hz, 2 H), 2.49 - 2.63 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): = 172.6,
157.9, 132.4, 129.1, 113.7, 71.7, 70.3, 69.0, 63.3, 58.8, 55.0, 35.9, 29.9 ppm. IR (neat): 𝜈 =
2878 (w), 1732 (s), 1612 (w), 1513 (s), 1454 (m), 1299 (m), 1244 (s), 1106 (s), 1033 (s), 826
(m), 730 (m) cm–1. MS (EI-TOF): m/z (%): 282 (4) [M+], 134 (100), 121 (69), 91 (8), 77 (5),
59 (9). HRMS (EI-TOF) calcd. for C15H23O5 ([M+H]+): 283.1546; found: 283.1541.
8.4.3.12 Synthesis of 2-(2-methoxyethoxy)ethyl 3-(4-aminophenyl)propanoate (3ka)
2
Compound 3ka was synthesised following procedure GP1 starting from (4-
nitrophenyl)acetylene (1k) (147 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a, 10.3 g,
10.0 mL, 85.8 mmol) and isolated as yellow oil (164 mg, 62%).
1H NMR (400 MHz, CDCl3): = 6.96 (d, J=8.3 Hz, 2 H), 6.58 (d, J=8.1 Hz, 2 H), 4.14 - 4.28
(m, 2 H), 3.45 - 3.75 (m, 8 H), 3.36 (s, 3 H), 2.82 (t, J=7.8 Hz, 2 H), 2.58 (t, J=7.8 Hz, 2 H)
ppm. 13C NMR (101 MHz, CDCl3): = 173.1, 144.8, 130.4, 129.1, 115.2, 71.9, 70.5, 69.2,
63.5, 59.0, 36.2, 30.1 ppm. IR (neat): 𝜈 = 3448 (w), 3362 (w), 3320 (w), 2878 (m), 1727 (s),
1626 (m), 1518 (s), 1451 (w), 1284 (m), 1178 (m), 1105 (vs), 1049 (m), 824 (s) cm–1. MS (EI-
Experimental section
158
TOF): m/z (%): 267 (6) [M+], 207 (4), 119 (30), 106 (100), 91 (1), 77 (2), 59 (7). HRMS (EI-
TOF) calcd. for C14H22NO4 ([M+H]+): 268.1549; found: 268.1545.
8.4.3.13 Synthesis of 2-(2-methoxyethoxy)ethyl 3-(4-(N,N-dimethyl)aminophenyl)propanoate
(3la)
2
Compound 3la was synthesised following procedure GP1 starting from (4-(N,N-
dimethyl)aminophenyl)acetylene (1l) (150 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol
(2a, 10.3 g, 10.0 mL, 85.8 mmol) and isolated as yellow oil (230 mg, 78%).
1H NMR (400 MHz, CDCl3): = 7.03 - 7.14 (m, 2 H), 6.64 - 6.76 (m, 2 H), 4.19 - 4.29 (m, 2
H), 3.68 (m, J=4.0 Hz, 2 H), 3.60 - 3.66 (m, 2 H), 3.52 - 3.58 (m, 2 H), 3.38 (s, 3 H), 2.91 (s, 6
H), 2.86 (t, J=7.8 Hz, 2 H), 2.61 (t, J=7.8 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3):
= 173.3, 149.4, 129.1, 128.7, 113.1, 72.0, 70.6, 69.4, 63.6, 59.2, 41.0, 36.4, 30.1 ppm. IR (neat):
𝜈 = cm–1. MS (EI-TOF): m/z (%): 295 (14) [M+], 147 (8), 134 (100), 118 (5), 91 (2), 59 (3), 44
(7). HRMS (EI-TOF) calcd. for C16H26NO4 ([M+H]+): 296.1856; found: 296.1865.
8.4.3.14 Synthesis of 2-(2-methoxyethoxy)ethyl 3-(3-aminophenyl)propanoate (3ja)
2
Compound 3ja was synthesised following procedure GP1 starting from (3-
aminophenyl)acetylene (1j) (122 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a, 10.3 g,
10.0 mL, 85.8 mmol) and isolated as yellow oil (70.0 mg, 26%).
1H NMR (400 MHz, CDCl3): = 7.06 (t, J=7.5 Hz, 1 H), 6.59 (d, J=7.3 Hz, 1 H), 6.46 - 6.55
(m, 2 H), 4.24 (m, 2 H), 3.58 - 3.73 (m, 4 H), 3.64 (br. s, 2 H), 3.51 - 3.58 (m, 2 H), 3.38 (s, 3
H), 2.86 (t, J=7.8 Hz, 2 H), 2.63 (t, J=7.8 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3):
= 173.1, 146.7, 141.8, 129.5, 118.6, 115.2, 113.2, 72.0, 70.6, 69.3, 63.6, 59.2, 35.8, 31.0 ppm.
IR (neat): 𝜈 = 3452 (w), 3364 (w), 2878 (w), 1728 (s), 1623 (m), 1460 (m), 1105 (s), 861 (m),
781 (m), 696 (m) cm–1. MS (EI-TOF): m/z (%): 267 (24) [M+], 209 (18), 165 (16), 148 (23),
Experimental section
159
120 (98), 106 (100), 59 (32). HRMS (EI-TOF) calcd. for C14H22NO4 ([M+H]+): 268.1549;
found: 268.1545.
8.4.3.15 Synthesis of 2-(2-methoxyethoxy)ethyl 3-(2-fluorophenyl)propanoate (3ia)
2
Compound 3ia was synthesised following procedure GP1 starting from 2-
fluorophenylacetylene (1i) (124 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a, 10.3 g,
10.0 mL, 85.8 mmol) and isolated as yellow oil (175 mg, 65%).
1H NMR (300 MHz, CDCl3): = 7.06 - 7.20 (m, 2 H), 6.87 - 7.03 (m, 2 H), 4.08 - 4.24 (m, 2
H), 3.58 - 3.67 (m, 2 H), 3.52 - 3.58 (m, 2 H), 3.42 - 3.51 (m, 2 H), 3.31 (s, 3 H), 2.92 (t, J=7.8
Hz, 2 H), 2.53 - 2.65 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): = 172.4, 161.0 (d, J=245.5
Hz), 130.5 (d, J=5.0 Hz), 127.9 (d, J=6.6 Hz), 127.1 (d, J=16.6 Hz), 123.9 (d, J=3.3 Hz), 115.1
(d, J=21.6 Hz), 71.7, 70.3, 69.0, 63.4, 58.8, 34.1, 24.3 (d, J=3.3 Hz) ppm. 19F NMR (235 MHz,
CDCl3, C6F6): = –118.4 ppm. IR (neat): 𝜈 = 2878 (w), 1733 (s), 1585 (m), 1455 (m), 1229
(m), 1179 (m), 1138 (m), 1100 (s), 851 (m), 756 (s) cm–1. MS (EI-TOF): m/z (%): 270 (1) [M+],
195 (21), 151 (24), 122 (100), 109 (95), 103 (26), 59 (63). HRMS (EI-TOF) calcd. for
C14H20FO4 ([M+H]+): 271.1346; found: 271.1341
8.4.3.16 Synthesis of 2-(2-methoxyethoxy)ethyl 3-(2-methoxyphenyl)propanoate (3na)
2
Compound 3na was synthesised following procedure GP1 starting from 2-
methoxyphenylacetylene (1n) (136 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a,
10.3 g, 10.0 mL, 85.8 mmol) and isolated as colourless oil (278 mg, 99%).
1H NMR (300 MHz, CDCl3): = 7.09 - 7.21 (m, 2 H), 6.77 - 6.90 (m, 2 H), 4.17 - 4.26 (m, 2
H), 3.79 (s, 3 H), 3.63 - 3.70 (m, 2 H), 3.57 - 3.63 (m, 2 H), 3.48 - 3.55 (m, 2 H), 3.36 (s, 3 H),
2.87 - 2.98 (m, 2 H), 2.58 - 2.68 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): = 173.2, 157.4,
129.9, 128.7, 127.5, 120.3, 110.1, 71.8, 70.4, 69.1, 63.4, 58.9, 55.1, 34.0, 26.0 ppm. IR (neat):
Experimental section
160
𝜈 = 2880 (w), 1732 (s), 1602 (w), 1588 (w), 1494 (m), 1461 (m), 1242 (s), 1108 (s), 1028 (s),
753 (s) cm–1. MS (EI-TOF): m/z (%): 282 (6) [M+], 134 (100), 121 (59), 119 (26), 91 (41), 77
(11), 59 (23). HRMS (EI-TOF) calcd. for C15H23O5 ([M+H]+): 283.1546; found: 283.1539.
8.4.3.17 Synthesis of methyl 3-(2-methoxyphenyl)propanoate (3nd)
(CAS: 55001-09-7)
Compound 3nd was synthesised following procedure GP1 starting from 2-
methoxyphenylacetylene (1n) (136 mg, 1.00 mmol) and methanol (2d, 7.91 g, 10.0 mL,
246 mmol) and isolated as colourless oil (184 mg, 95%). The product contained small amounts
of dimethyldimethoxysilane (3.3 % (m/m) as determined by 1H NMR) due to instability of the
silicone septum caps towards methanol. The yield has been adjusted accordingly.
1H NMR (400 MHz, CDCl3): = 7.21 (td, J=7.8, 1.8 Hz, 1 H), 7.13 - 7.18 (m, 1 H), 6.89 (t,
J=7.6 Hz, 1 H), 6.85 (d, J=8.3 Hz, 1 H), 3.83 (s, 3 H), 3.68 (s, 3 H), 2.96 (t, J=8.0 Hz, 2 H),
2.57 - 2.75 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): = 173.9, 157.6, 130.0, 128.9, 127.7,
120.5, 110.3, 55.2, 51.5, 34.1, 26.2 ppm. IR (neat): 𝜈 = 295 (w), 2938 (w), 1734 (s), 1602 (w),
1494 (s), 1437 (m), 1361 (w), 1241 (vs), 1156 (m), 1111 (m), 1028 (m), 853 (w), 751 (s) cm–1.
MS (EI-TOF): m/z (%): 194 (56) [M+], 134 (63), 121 (100), 119 (35), 91 (98), 77 (20), 65 (14).
HRMS (EI-TOF) calcd. for C11H15O3 ([M+H]+): 195.1015; found: 195.1015.
8.4.3.18 Synthesis of isopropyl 3-(2-methoxyphenyl)propanoate (3nc)
(CAS: 1480246-75-0)
Two 10 mL headspace vials equipped with a Teflon-coated stir bar were each charged with
anhydrous potassium phosphate (217 mg, 1.00 mmol) in a glovebox and capped. Afterwards, a
solution of copper(I) bromide (146 µg, 1.00 µmol) in NMP (0.10 mL) and 2-ethynylanisole
(1n, 0.50 mmol, 68.1 mg, 66.8 µL) were added via syringe. The vials were placed in an
autoclave, the atmosphere was exchanged twice with CO2 (10 bar) and the autoclave was finally
pressurised with CO2 (10 bar). The reaction was stirred at 600 rpm and 80 °C for 12 h. After
Experimental section
161
cooling down to room temperature, the pressure was slowly released under stirring. The
contents of the reaction vessels were rinsed into a stainless steel reaction vessel for Parr 4590
series using 2-propanol (2c, 10 mL). Palladium on alumina (42.6 mg, 5%, 10.0 µmol) was
added. The autoclave was sealed, the atmosphere was exchanged with hydrogen (10 bar) twice
and the autoclave was pressurised to a final pressure of 5 bar hydrogen. After stirring the
mixture at room temperature for 2 h, the atmosphere was exchanged with CO2 (2 × 10 bar) and
the autoclave was pressurised with CO2 (50 bar). The mixture was stirred at 180 °C for 20 h.
After cooling down, autoclave was rinsed thoroughly with ethyl acetate (100 mL) and water
(20 mL). The organic phase was washed with water (3 x 50 mL) and aq. sat. NaHCO3 (3 x 50
mL). The aqueous phases were extracted with ethyl acetate (2 x 50 mL) and the combined
organic phases were washed with brine (30 mL), dried over MgSO4, filtered, and the volatiles
were removed under reduced pressure. The residue was purified by column chromatography
(SiO2, cyclohexane/ethyl acetate gradient) yielding 3nc as pale yellow oil (28.0 mg, 13%).
1H NMR (400 MHz, CDCl3): = 7.19 (td, J=7.8, 1.5 Hz, 1 H), 7.15 (d, J=7.3 Hz, 1 H), 6.87
(t, J=7.3 Hz, 1 H), 6.84 (d, J=8.6 Hz, 1 H), 5.01 (spt, J=6.2 Hz, 1 H), 3.83 (s, 3 H), 2.94 (t,
J=7.8 Hz, 2 H), 2.58 (t, J=7.7 Hz, 2 H), 1.21 (d, J=6.3 Hz, 6 H) ppm. 13C NMR (101 MHz,
CDCl3): = 173.0, 157.6, 130.1, 129.1, 127.6, 120.5, 110.3, 67.6, 55.3, 34.6, 26.2, 22.0 ppm.
IR (neat): 𝜈 = 2979 (w), 2937 (w), 1726 (s), 1602 (w), 1588 (w), 1494 (m), 1465 (m), 1373
(m), 1286 (w), 1242 (s), 1176 (m), 1106 (vs), 1031 (m), 930 (w), 751 (s) cm–1. MS (EI-TOF):
m/z (%): 222 (35) [M+], 180 (22), 163 (21), 137 (38), 134 (32), 121 (100), 91 (55), 77 (18).
HRMS (EI-TOF) calcd. for C13H19O3 ([M+H]+): 223.1329; found: 223.1333.
8.4.3.19 Synthesis of 2-(2-methoxyethoxy)ethyl 5-phenylpentanoate (3ea)
2
Compound 3ea was synthesised following procedure GP1 starting from 4-phenylbut-1-yne (1e)
(136 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a, 10.3 g, 10.0 mL, 85.8 mmol) and
isolated colourless oil (191 mg, 68%).
1H NMR (300 MHz, CDCl3): = 7.22 - 7.32 (m, 2 H), 7.10 - 7.21 (m, 3 H), 4.15 - 4.30 (m, 2
H), 3.68 (m, J=4.8 Hz, 2 H), 3.62 (s, 2 H), 3.48 - 3.57 (m, 2 H), 3.36 (s, 3 H), 2.62 (t, J=7.2 Hz,
2 H), 2.35 (t, J=7.1 Hz, 2 H), 1.57 - 1.76 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): = 173.6,
Experimental section
162
142.1, 128.4, 128.3, 125.7, 71.9, 70.5, 69.2, 63.4, 59.1, 35.6, 34.0, 30.9, 24.5. ppm. IR (neat):
𝜈 = 2928 (w), 2865 (w), 1732 (s), 1453 (s), 1108 (s), 911 (m), 729 (vs), 699 (s) cm–1. MS (EI-
TOF): m/z (%): 205 (4) [M+], 160 (100), 117 (31), 104 (55), 91 (77), 59 (29). HRMS (EI-TOF)
calcd. for C16H25O4 ([M+H]+): 281.1753; found: 281.1749.
8.4.3.20 Synthesis of 2-(2-methoxyethoxy)ethyl 3-(3-methoxyphenyl)propanoate (3oa)
2
Compound 3oa was synthesised following procedure GP1 starting from 3-
methoxyphenylacetylene (1o) (138 mg, 1.00 mmol) and 2-(2-methoxyehoxy)ethanol (2a,
10.3 g, 10.0 mL, 85.8 mmol) and isolated pale yellow oil (246 mg, 87%).
1H NMR (300 MHz, CDCl3): = 7.10 - 7.19 (m, 1 H), 6.65 - 6.79 (m, 3 H), 4.15 - 4.24 (m, 2
H), 3.73 (s, 3 H), 3.60 - 3.66 (m, 2 H), 3.53 - 3.60 (m, 2 H), 3.44 - 3.52 (m, 2 H), 3.33 (s, 3 H),
2.89 (t, J=7.8 Hz, 2 H), 2.53 - 2.67 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): = 172.6,
159.6, 142.0, 129.3, 120.5, 113.9, 111.5, 71.7, 70.3, 69.0, 63.4, 58.9, 54.9, 35.5, 30.8 ppm. IR
(neat): 𝜈 = 2878 (w), 1732 (s), 1602 (m), 1585 (m), 1490 (m), 1454 (m), 1257 (s), 1138 (s),
1108 (s), 1043 (s), 863 (m), 781 (m), 695 (m) cm–1. MS (EI-TOF): m/z (%): 282 (6) [M+], 180
(14), 134 (100), 121 (47), 91 (14), 59 (22), 45 (15). HRMS (EI-TOF) calcd. for C15H23O5
([M+H]+): 283.1546; found: 283.1538.
8.4.4 Synthesis of dimethyl succinate (3rd)
(CAS: 581784-63-6)
8.4.4.1 From potassium propiolate
A stainless steel reaction vessel for Parr 4590 was kept in the freezer of a glovebox for 3 h.
Potassium propiolate (216 mg, 2.00 mmol), anhydrous potassium phosphate (1.27 g, 6.00
mmol) and a solution of copper(I) bromide (586 µg, 4.00 µmol) in NMP (4 mL) were added to
the vessel. The autoclave was sealed and flushed with CO2 (2 × 10 bar) and finally pressurized
with CO2 (10 bar). The mixture was stirred at 80 °C for 16 h.
Experimental section
163
The autoclave was cooled down and the pressure was released. Palladium on alumina (85.1 mg,
5%, 40.0 µmol) and methanol (1d, 20 mL) were added and the autoclave was flushed (2 × 10
bar) and pressurised with H2 (5 bar). After stirring two hours at room temperature, the
atmosphere was exchanged with CO2 (2 × 10 bar) and a final CO2 pressure of 50 bar was
applied. The mixture was stirred at 180 °C for 48 h.
After cooling down, the autoclave was rinsed with Et2O (50 mL) and water (50 mL). The
organic phase was additionally washed with water (2 × 20 mL) and 1 M HCl (2 × 20 mL) and
the aqueous phases were extracted with Et2O (2 × 20mL). The combined organic phases were
neutralised with aq. sat. NaHCO3, washed with brine (20 mL), dried over MgSO4 and filtered.
The solvent was carefully removed under reduced pressure (850 mbar, 45 °C) with a Vigreux
column. 3rd was obtained as colourless oil (165 mg, 1.13 mmol, 57%). The analytical data
matched the literature.377
8.4.4.2 From acetylene
Anhydrous potassium phosphate (1.56 g, 7.35 mmol) and a solution of copper(I) bromide
(717 µg, 4.90 µmol) in NMP (8 mL) were added to a stainless steel reaction vessel for Parr
4590 series inside a glovebox. The autoclave was sealed and flushed with CO2 (2 × 10 bar).
After releasing the pressure, the autoclave was pressurised with acetylene (60 mL, 2.45 mmol,
1 bar, 23 °C) and subsequently with CO2 (10 bar). The mixture was stirred at 80 °C until no
further decrease in pressure was observed (40 h).
The autoclave was cooled down and the pressure was released. Palladium on alumina (104 mg,
5%, 49.0 µmol) and methanol (30 mL) were added and the autoclave was flushed (2 × 10 bar)
and pressurised with hydrogen (5 bar). After stirring two hours at room temperature, the
atmosphere was exchanged with CO2 (2 × 10 bar) and a final CO2 pressure of 50 bar was
applied. The mixture was stirred at 180 °C for 48 h.
After cooling down, the autoclave was rinsed with Et2O (50 mL) and water (50 mL). The
organic phase was additionally washed with water (2 × 20 mL) and 1 M HCl (2 × 20 mL) and
the aqueous phases were extracted with Et2O (2 × 20mL). The combined organic phases were
neutralised with aq. sat. NaHCO3, washed with brine (30 mL), dried over MgSO4 and filtered.
The solvent was carefully removed under reduced pressure (850 mbar, 45 °C) with a Vigreux
column. 3ra was obtained as colourless oil (190 mg, 1.13 mmol, 53%). The analytical data
matched the literature.377
Experimental section
164
1H NMR (300 MHz, CDCl3): = 3.70 (s, 6 H), 2.64 (s, 4 H) ppm.
13C NMR (75 MHz, CDCl3): = 172.9, 52.0, 29.1 ppm.
8.4.5 Synthesis and distillation of dipropyl succinate
(CAS: 925-15-5)
8.4.5.1 Synthesis of dipropyl succinate
A stainless steel reaction vessel for Parr 4590 was kept in the freezer of a glovebox for 3 h.
Potassium propiolate (216 mg, 2.00 mmol), anhydrous potassium phosphate (1.30 g,
6.00 mmol) and a solution of copper(I) bromide (590 µg, 4.00 µmol) in NMP (4mL) were
added to the vessel. The autoclave was sealed and flushed with CO2 (2 × 10 bar) and finally
pressurized with CO2 (10 bar). The mixture was stirred at 80 °C for 16 h.
The autoclave was cooled down and the pressure was released. Palladium on alumina (85.1 mg,
5%, 40.0 µmol) and n-propanol (20 mL) were added and the autoclave was flushed (2 × 10 bar)
and pressurised with H2 (5 bar). After stirring two hours at room temperature, the atmosphere
was exchanged with CO2 (2 × 10 bar) and a final CO2 pressure of 50 bar was applied. The
mixture was stirred at 180 °C for 48 h.
After cooling down, the reaction mixture was filtered through celite. The celite was washed
with n-propanol (50 mL) and the alcohol was removed from the filtrate under reduced pressure.
The residue was diluted with Et2O (50 mL), the organic phase was washed with water (20 mL)
and 1 M HCl (2 × 20 mL) and the aqueous phases were extracted with Et2O (2 × 20 mL). The
combined organic phases were neutralised with aq. sat. NaHCO3, washed with brine (30 mL),
dried over MgSO4 and filtered. The solvent was removed under reduced pressure leading to a
mixture containing dipropyl succinate in 16% (67.5 mg).
8.4.5.2 Distillation of dipropyl succinate
A mixture consisting of dipropyl succinate (6.01 g) and NMP (360mL), being the equivalent
amount of 90 reactions, was separated by distillation. Dipropyl succinate was recovered as
colourless oil (4.82 g, 80%).
Experimental section
165
1H NMR (300 MHz, CDCl3): = 3.94 (t, J=6.8 Hz, 2 H), 2.51 (s, 2 H), 1.54 (sxt, J=7.1 Hz, 3
H), 0.83 ppm (t, J=7.5 Hz, 5 H). 13C NMR (75 MHz, CDCl3): = 172.2, 66.1, 29.0, 21.9, 10.2
ppm. IR (neat): 𝜈 = 2969 (m), 2882 (m), 1731 (vs), 1463 (w), 1414 (w), 1355 (m), 1318 (w),
1266 (m), 1209 (m), 1154 (s), 1060 (m), 986 (m), 911 (m) cm–1. MS (EI-TOF): m/z (%): 203
(1) [M+], 187 (1), 161 (4), 143 (42), 116 (2), 101 (100), 84 (1), 73 (7), 55 (6). HRMS (EI-TOF)
calcd. for C10H18NaO4 ([M+H]+): 225.11103; found: 225.1097.
8.4.6 Calculation of the amount of acetylene
To calculate the amount of acetylene, the the Van der Waals equation for non-ideal gases was
used:
𝑝 =𝑛𝑅𝑇
𝑉 − 𝑛𝑏−
𝑛2𝑎
𝑉2
with378
p pressure of the gas set or to be determined
R ideal gas constant 83.1446 L mbar·K–1·mol–1
T temperature of the gas 23 °C =296.15 K
V volume of the container 6.07 cm3 = 0.0607 L
n number of moles set or to be determined
a, b Van der Waals constants a = 4.516 L2·bar·mol–2 b = 0.0522 L·mol1
The inner volume of the autoclave was determined by filling a liquid into the holes and
measuring the needed volume and by conversely immersing the protruding parts in a liquid,
measuring the volume increase. The volume of the reaction vessel was adopted from its
manufacturer. The total available inner volume of the autoclave was determined to be 69.2 cm3.
The amount of solvent (8 mL) and of base were subtracted from this value, thus resulting in a
volume of 6.07 cm3. This is valid because the acetylene supply was shut off before the gas could
dissolve.
With the volume of 60.7 cm3 and a set pressure of 1 bar, the amount of acetylene in the reaction
of K3PO4 was calculated. Because of its cubic nature, the equation was solved numerically
using an online tool,379 which determined the number of moles to be n = 2.48 mmol.
For the reaction with Cs2CO3, the number of moles was set to be n = 1 mmol. With a volume
of 0.0607 L, the pressure was calculated to be 0.4 bar.
References
166
9 References
(1) Ritchie, H.; Roser, M. Fossil Fuels. Our World in Data 2017.
(2) Farman, J. C.; Gardiner, B. G.; Shanklin, J. D. Large Losses of Total Ozone in Antarctica
Reveal Seasonal ClOx/NOx Interaction. Nature 1985, 315 (6016), 207–210.
https://doi.org/10.1038/315207a0.
(3) NOAA ESRL CSD: WMO/UNEP Scientific Assessments of Ozone Depletion
https://www.esrl.noaa.gov/csd/assessments/ozone/ (accessed Apr 29, 2019).
(4) US Department of Commerce, N. Scientific Assessment of Ozone Depletion 2010
https://www.esrl.noaa.gov/csd/assessments/ozone/2010/report.html (accessed Apr 29,
2019).
(5) Jackson, R. The Effects of Climate Change https://climate.nasa.gov/effects (accessed Apr
24, 2019).
(6) Predictions of Future Global Climate | UCAR Center for Science Education
https://scied.ucar.edu/longcontent/predictions-future-global-climate (accessed Apr 24,
2019).
(7) Fifth Assessment Report - Impacts, Adaptation and Vulnerability_Chap.18
https://web.archive.org/web/20181223122504/https://archive.ipcc.ch/report/ar5/wg2/
(accessed Apr 29, 2019).
(8) Fifth Assessment Report - Mitigation of Climate Change
https://web.archive.org/web/20181223120913/https://archive.ipcc.ch/report/ar5/wg3/
(accessed Apr 29, 2019).
(9) Feely, R. A. Impact of Anthropogenic CO2 on the CaCO3 System in the Oceans. Science
2004, 305 (5682), 362–366. https://doi.org/10.1126/science.1097329.
(10) Millero, F. J. Thermodynamics of the Carbon Dioxide System in the Oceans. Geochimica
et Cosmochimica Acta 1995, 59 (4), 661–677. https://doi.org/10.1016/0016-
7037(94)00354-O.
(11) Causes, Effects and Solutions of Acid Rain - Conserve Energy Future
https://www.conserve-energy-future.com/causes-and-effects-of-acid-rain.php (accessed
Apr 29, 2019).
(12) Causes of Acid Rain
http://www2.gsu.edu/~mstnrhx/EnviroBio%20Projects/AcidRain/causes.html (accessed
Apr 29, 2019).
(13) Sariatli, F. Linear Economy Versus Circular Economy: A Comparative and Analyzer
Study for Optimization of Economy for Sustainability. Visegrad Journal on Bioeconomy
and Sustainable Development 2017, 6 (1), 31–34. https://doi.org/10.1515/vjbsd-2017-
0005.
(14) Waterstaat, M. van I. en. From a linear to a circular economy - Circular economy -
Government.nl https://www.government.nl/topics/circular-economy/from-a-linear-to-a-
circular-economy (accessed Apr 29, 2019).
References
167
(15) Geissdoerfer, M.; Savaget, P.; Bocken, N. M. P.; Hultink, E. J. The Circular Economy –
A New Sustainability Paradigm? Journal of Cleaner Production 2017, 143, 757–768.
https://doi.org/10.1016/j.jclepro.2016.12.048.
(16) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University
Press, 1998.
(17) 12 Principles of Green Chemistry
https://www.acs.org/content/acs/en/greenchemistry/principles/12-principles-of-green-
chemistry.html (accessed Apr 8, 2019).
(18) Anastas, P.; Eghbali, N. Green Chemistry: Principles and Practice. Chem. Soc. Rev. 2010,
39 (1), 301–312. https://doi.org/10.1039/B918763B.
(19) Marion, P.; Bernela, B.; Piccirilli, A.; Estrine, B.; Patouillard, N.; Guilbot, J.; Jérôme, F.
Sustainable Chemistry: How to Produce Better and More from Less? Green Chem. 2017,
19 (21), 4973–4989. https://doi.org/10.1039/C7GC02006F.
(20) Trost, B. The Atom Economy--a Search for Synthetic Efficiency. Science 1991, 254
(5037), 1471–1477. https://doi.org/10.1126/science.1962206.
(21) Sheldon, R. A. The E Factor: Fifteen Years On. Green Chemistry 2007, 9 (12), 1273.
https://doi.org/10.1039/b713736m.
(22) Sheldon, R. A. Metrics of Green Chemistry and Sustainability: Past, Present, and Future.
ACS Sustainable Chemistry & Engineering 2018, 6 (1), 32–48.
https://doi.org/10.1021/acssuschemeng.7b03505.
(23) Watson, W. J. W. How Do the Fine Chemical, Pharmaceutical, and Related Industries
Approach Green Chemistry and Sustainability? Green Chem. 2012, 14 (2), 251–259.
https://doi.org/10.1039/C1GC15904F.
(24) Roschangar, F.; Sheldon, R. A.; Senanayake, C. H. Overcoming Barriers to Green
Chemistry in the Pharmaceutical Industry – the Green Aspiration LevelTM Concept. Green
Chemistry 2015, 17 (2), 752–768. https://doi.org/10.1039/C4GC01563K.
(25) What Are Various Alternative Energy Sources. Conserve Energy Future, 2013.
(26) Where Wind Power Is Harnessed - Energy Explained, Your Guide To Understanding
Energy - Energy Information Administration
https://www.eia.gov/energyexplained/index.php?page=wind_where (accessed Apr 29,
2019).
(27) Where Solar Is Found - Energy Explained, Your Guide To Understanding Energy - Energy
Information Administration
https://www.eia.gov/energyexplained/index.php?page=solar_where (accessed Apr 29,
2019).
(28) Gallezot, P. Conversion of Biomass to Selected Chemical Products. Chem. Soc. Rev. 2012,
41 (4), 1538–1558. https://doi.org/10.1039/C1CS15147A.
(29) Brun, N.; Hesemann, P.; Esposito, D. Expanding the Biomass Derived Chemical Space.
Chemical Science 2017, 8 (7), 4724–4738. https://doi.org/10.1039/C7SC00936D.
(30) Renewable energy statistics - Statistics Explained https://ec.europa.eu/eurostat/statistics-
explained/index.php/Renewable_energy_statistics (accessed May 2, 2019).
(31) Ritchie, H.; Roser, M. Renewable Energy. Our World in Data 2017.
References
168
(32) Biofuels production in Europe, by country 2018
https://www.statista.com/statistics/332510/biofuels-production-in-selected-countries-in-
europe/ (accessed Jul 22, 2019).
(33) Girl, E. Renewable Energy Germany | German Energy Transition /strom-
report/renewable-energy-germany/ (accessed Apr 24, 2019).
(34) Girl, E. Recent Facts about Solar Power in Germany [Energy Graphics] /solar-power-
germany/ (accessed May 2, 2019).
(35) Biomass - Energy Explained, Your Guide To Understanding Energy - Energy Information
Administration https://www.eia.gov/energyexplained/?page=biomass_home (accessed
Apr 10, 2019).
(36) Lalak, J.; Martyniak, D.; Kasprzycka, A.; Żurek, G.; Moroń, W.; Chmielewska, M.;
Wiącek, D.; Tys, J. Comparison of Selected Parameters of Biomass and Coal.
International Agrophysics 2016, 30 (4), 475–482. https://doi.org/10.1515/intag-2016-
0021.
(37) Calorific value of biomass compared with other fuels http://www.biodiesel-
machine.com/news/calorific-value-of-biomass.html (accessed Apr 10, 2019).
(38) Hasan, M.; Haseli, Y.; Karadogan, E. Correlations to Predict Elemental Compositions and
Heating Value of Torrefied Biomass. Energies 2018, 11 (9), 2443.
https://doi.org/10.3390/en11092443.
(39) Fuel analysis http://bisyplan.bioenarea.eu/fuel_appendix.html (accessed Apr 10, 2019).
(40) Vassilev, S. V.; Baxter, D.; Andersen, L. K.; Vassileva, C. G. An Overview of the
Chemical Composition of Biomass. Fuel 2010, 89 (5), 913–933.
https://doi.org/10.1016/j.fuel.2009.10.022.
(41) Biomass Co-Combustion – European Biomass Industry Association.
(42) Nussbaumer, T. Combustion and Co-Combustion of Biomass: Fundamentals,
Technologies, and Primary Measures for Emission Reduction. Energy & Fuels 2003, 17
(6), 1510–1521. https://doi.org/10.1021/ef030031q.
(43) Alliance for Global Sustainability; Pathways to Sustainable European Energy Systems
(projekt); Nordic energy perspectives (projekt). The Complexity of Climate Change
Mechanisms: Aspects to Be Considered in Abatement Strategy Planning : AGS Pathways
Report 2010:EU2.; Alliance for Global Sustainability (AGS): Göteborg, 2010.
(44) Donate, P. M. Green Synthesis from Biomass. Chemical and Biological Technologies in
Agriculture 2014, 1 (1), 4. https://doi.org/10.1186/s40538-014-0004-2.
(45) Chatterjee, C.; Pong, F.; Sen, A. Chemical Conversion Pathways for Carbohydrates.
Green Chemistry 2015, 17 (1), 40–71. https://doi.org/10.1039/C4GC01062K.
(46) Mika, L. T.; Cséfalvay, E.; Németh, Á. Catalytic Conversion of Carbohydrates to Initial
Platform Chemicals: Chemistry and Sustainability. Chem. Rev. 2018, 118 (2), 505–613.
https://doi.org/10.1021/acs.chemrev.7b00395.
(47) Bozell, J. J. Chemicals and Materials from Renewable Resources. 9.
(48) Dusselier, M.; Mascal, M.; Sels, B. F. Top Chemical Opportunities from Carbohydrate
Biomass: A Chemist’s View of the Biorefinery. In Selective Catalysis for Renewable
References
169
Feedstocks and Chemicals; Nicholas, K. M., Ed.; Springer International Publishing:
Cham, 2014; Vol. 353, pp 1–40. https://doi.org/10.1007/128_2014_544.
(49) Williams, C.; Hillmyer, M. Polymers from Renewable Resources: A Perspective for a
Special Issue of Polymer Reviews. Polymer Reviews 2008, 48 (1), 1–10.
https://doi.org/10.1080/15583720701834133.
(50) Catalysis for the Conversion of Biomass and Its Derivatives; Behrens, M., Datye, A. K.,
Eds.; 2017.
(51) Quirino, R. L.; Garrison, T. F.; Kessler, M. R. Matrices from Vegetable Oils, Cashew Nut
Shell Liquid, and Other Relevant Systems for Biocomposite Applications. Green Chem.
2014, 16 (4), 1700–1715. https://doi.org/10.1039/C3GC41811A.
(52) Biermann, U.; Bornscheuer, U.; Meier, M. A. R.; Metzger, J. O.; Schäfer, H. J. Oils and
Fats as Renewable Raw Materials in Chemistry. Angewandte Chemie International
Edition 2011, 50 (17), 3854–3871. https://doi.org/10.1002/anie.201002767.
(53) Xia, Y.; Larock, R. C. Vegetable Oil-Based Polymeric Materials: Synthesis, Properties,
and Applications. Green Chemistry 2010, 12 (11), 1893.
https://doi.org/10.1039/c0gc00264j.
(54) Lligadas, G.; Ronda, J. C.; Galià, M.; Cádiz, V. Renewable Polymeric Materials from
Vegetable Oils: A Perspective. Materials Today 2013, 16 (9), 337–343.
https://doi.org/10.1016/j.mattod.2013.08.016.
(55) Trita, A. S.; Over, L. C.; Pollini, J.; Baader, S.; Riegsinger, S.; Meier, M. A. R.; Gooßen,
L. J. Synthesis of Potential Bisphenol A Substitutes by Isomerising Metathesis of
Renewable Raw Materials. Green Chem. 2017, 19 (13), 3051–3060.
https://doi.org/10.1039/C7GC00553A.
(56) Kosswig, K. Surfactants. In Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH
Verlag GmbH & Co. KGaA, Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,
Germany, 2000. https://doi.org/10.1002/14356007.a25_747.
(57) Bragoni, V.; Rit, R. K.; Kirchmann, R.; Trita, A. S.; Gooßen, L. J. Synthesis of Bio-Based
Surfactants from Cashew Nutshell Liquid in Water. Green Chemistry 2018, 20 (14), 3210–
3213. https://doi.org/10.1039/C8GC01686K.
(58) Zoller, U.; Sosis, P. Handbook of Detergents, Part F: Production; CRC Press, 2008.
(59) Kjellin, M.; Johansson, I. Surfactants from Renewable Resources; John Wiley & Sons,
2010.
(60) Worldwide production major vegetable oils, 2012-2019 | Statistic
https://www.statista.com/statistics/263933/production-of-vegetable-oils-worldwide-
since-2000/ (accessed Apr 18, 2019).
(61) Anneken, D. J.; Both, S.; Christoph, R.; Fieg, G.; Steinberner, U.; Westfechtel, A. Fatty
Acids. In Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH Verlag GmbH &
Co. KGaA, Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2006; p
a10_245.pub2. https://doi.org/10.1002/14356007.a10_245.pub2.
(62) Free Images : cooking, ingredient, culinary, produce, kitchen, cuisine, food preparation,
cook, nutrition, vegan, vegetarian, olive oil, diet, gastronomy, healthy eating, organic,
flowering plant, health conscious, vegetable oil, salad dressing, land plant, extra virgin oil
References
170
5472x3648 - - 853081 - Free stock photos - PxHere /en/photo/853081 (accessed Apr 18,
2019).
(63) Andjelkovic, D. D.; Valverde, M.; Henna, P.; Li, F.; Larock, R. C. Novel Thermosets
Prepared by Cationic Copolymerization of Various Vegetable Oils—Synthesis and Their
Structure–Property Relationships. Polymer 2005, 46 (23), 9674–9685.
https://doi.org/10.1016/j.polymer.2005.08.022.
(64) Valverde, M.; Andjelkovic, D.; Kundu, P. P.; Larock, R. C. Conjugated Low-Saturation
Soybean Oil Thermosets: Free-Radical Copolymerization with Dicyclopentadiene and
Divinylbenzene. Journal of Applied Polymer Science 2008, 107 (1), 423–430.
https://doi.org/10.1002/app.27080.
(65) Zhang, C.; Garrison, T. F.; Madbouly, S. A.; Kessler, M. R. Recent Advances in Vegetable
Oil-Based Polymers and Their Composites. Progress in Polymer Science 2017, 71, 91–
143. https://doi.org/10.1016/j.progpolymsci.2016.12.009.
(66) Karak, N. Fundamentals of Polymers. In Vegetable Oil-Based Polymers; Elsevier, 2012;
pp 1–30. https://doi.org/10.1533/9780857097149.1.
(67) Lamb, H. H.; Iv, W. L. R.; Stikeleather, L. F.; Turner, T. L. Process for Conversion of
Biomass to Fuel. EP2097496B1, December 29, 2010.
(68) Manzanera, M.; Molina-Munoz, M.; Gonzalez-Lopez, J. Biodiesel: An Alternative Fuel.
Recent Patents on Biotechnology 2008, 2 (1), 25–34.
https://doi.org/10.2174/187220808783330929.
(69) Marchetti, J. M.; Miguel, V. U.; Errazu, A. F. Possible Methods for Biodiesel Production.
Renewable and Sustainable Energy Reviews 2007, 11 (6), 1300–1311.
https://doi.org/10.1016/j.rser.2005.08.006.
(70) Cashew Nut Shell Liquid; Anilkumar, P., Ed.; Springer International Publishing: Cham,
2017. https://doi.org/10.1007/978-3-319-47455-7.
(71) Balachandran, V. S.; Jadhav, S. R.; Vemula, P. K.; John, G. Recent Advances in Cardanol
Chemistry in a Nutshell: From a Nut to Nanomaterials. Chem. Soc. Rev. 2013, 42 (2), 427–
438. https://doi.org/10.1039/C2CS35344J.
(72) FAOSTAT http://www.fao.org/faostat/en/#data/QC/visualize (accessed Apr 16, 2019).
(73) Free photo India Fruit Ripe Nut Cashew Fruit Red - Max Pixel
https://www.maxpixel.net/India-Fruit-Ripe-Nut-Cashew-Fruit-Red-317298 (accessed
Apr 16, 2019).
(74) Immagine: Why are Cashews Not Sold to Consumers in Their Shells! how are ...
https://www.google.com/imgres?imgurl=https%3A%2F%2Fi.ytimg.com%2Fvi%2FKR
XGd7wOUXI%2Fmaxresdefault.jpg&imgrefurl=https%3A%2F%2Fwww.youtube.com
%2Fwatch%3Fv%3DKRXGd7wOUXI&docid=U6bn60fhMp_AMM&tbnid=QmxS4qq
nXbjmkM%3A&vet=10ahUKEwja_pKq6NThAhVFr6QKHf5sDoQQMwh2KCowKg..i
&w=1280&h=720&client=firefox-b-
d&bih=1104&biw=1920&q=cashew%20nut%20apple%20opened%20shells&ved=0ahU
KEwja_pKq6NThAhVFr6QKHf5sDoQQMwh2KCowKg&iact=mrc&uact=8 (accessed
Apr 16, 2019).
(75) Paramashivappa, R.; Kumar, P. P.; Vithayathil, P. J.; Rao, A. S. Novel Method for
Isolation of Major Phenolic Constituents from Cashew ( Anacardium Occidentale L.) Nut
References
171
Shell Liquid. Journal of Agricultural and Food Chemistry 2001, 49 (5), 2548–2551.
https://doi.org/10.1021/jf001222j.
(76) Phani Kumar, P.; Paramashivappa, R.; Vithayathil, P. J.; Subba Rao, P. V.; Srinivasa Rao,
A. Process for Isolation of Cardanol from Technical Cashew ( Anacardium Occidentale
L.) Nut Shell Liquid. Journal of Agricultural and Food Chemistry 2002, 50 (16), 4705–
4708. https://doi.org/10.1021/jf020224w.
(77) Lubi, M. C.; Thachil, E. T. Cashew Nut Shell Liquid (CNSL) - a Versatile Monomer for
Polymer Synthesis. Designed Monomers & Polymers 2000, 3 (2), 123–153.
https://doi.org/10.1163/156855500300142834.
(78) Grazzini, R.; Hesk, D.; Heininger, E.; Hildenbrandt, G.; Reddy, C. C.; Cox-Foster, D.;
Medford, J.; Craig, R.; Mumma, R. O. Inhibition of Lipoxygenase and Prostaglandin
Endoperoxide Synthase by Anacardic Acids. Biochemical and Biophysical Research
Communications 1991, 176 (2), 775–780. https://doi.org/10.1016/S0006-291X(05)80252-
9.
(79) Kubo, I.; Kinst-Hori, I.; Yokokawa, Y. Tyrosinase Inhibitors from Anacardium
Occidentale Fruits. Journal of Natural Products 1994, 57 (4), 545–551.
https://doi.org/10.1021/np50106a021.
(80) Shobha, S. V.; Ramadoss, C. S.; Ravindranath, B. Inhibition of Soybean Lipoxygenase-1
by Anacardic Acids, Cardols, and Cardanols. Journal of Natural Products 1994, 57 (12),
1755–1757. https://doi.org/10.1021/np50114a025.
(81) Kubo, Isao.; Ochi, Masamitsu.; Vieira, P. C.; Komatsu, Sakae. Antitumor Agents from the
Cashew (Anacardium Occidentale) Apple Juice. Journal of Agricultural and Food
Chemistry 1993, 41 (6), 1012–1015. https://doi.org/10.1021/jf00030a035.
(82) Itokawa, H.; Totsuka, N.; Nakahara, K.; Takeya, K.; Lepoittevin, J.-P.; Asakawa, Y.
Antitumor Principles from Ginkgo Biloba L. CHEMICAL & PHARMACEUTICAL
BULLETIN 1987, 35 (7), 3016–3020. https://doi.org/10.1248/cpb.35.3016.
(83) Rambabu, N.; Dubey, P. K.; Ram, B.; Balram, B. Synthesis, Characterization and
Antimicrobial Evaluation of (E)-N’-[(1-(2-Methoxy-6-Pentadecylbenzyl)-1H-1,2,3-
Triazol-4-Yl]- Methylene)Benzohydrazide Derivatives. Asian Journal of Chemistry 2016,
28 (1), 175–180. https://doi.org/10.14233/ajchem.2016.19310.
(84) Kubo, Isao.; Muroi, Hisae.; Himejima, Masaki.; Yamagiwa, Yoshiro.; Mera, Hiroyuki.;
Tokushima, Kimihiro.; Ohta, Shigeo.; Kamikawa, Tadao. Structure-Antibacterial Activity
Relationships of Anacardic Acids. Journal of Agricultural and Food Chemistry 1993, 41
(6), 1016–1019. https://doi.org/10.1021/jf00030a036.
(85) Swamy, B. N.; Suma, T. K.; Rao, G. V.; Reddy, G. C. Synthesis of
Isonicotinoylhydrazones from Anacardic Acid and Their in Vitro Activity against
Mycobacterium Smegmatis. European Journal of Medicinal Chemistry 2007, 42 (3), 420–
424. https://doi.org/10.1016/j.ejmech.2006.09.009.
(86) Mgaya, J. E.; Mubofu, E. B.; Mgani, Q. A.; Cordes, D. B.; Slawin, A. M.; Cole-Hamilton,
D. J. Isomerization of Anacardic Acid: A Possible Route to the Synthesis of an
Unsaturated Benzolactone and a Kairomone: Chemicals from Cashew Nut Shell Liquid.
European Journal of Lipid Science and Technology 2015, 117 (2), 190–199.
https://doi.org/10.1002/ejlt.201400268.
References
172
(87) Logrado, L. P. L.; Santos, C. O.; Romeiro, L. A. S.; Costa, A. M.; Ferreira, J. R. O.;
Cavalcanti, B. C.; Manoel de Moraes, O.; Costa-Lotufo, L. V.; Pessoa, C.; dos Santos, M.
L. Synthesis and Cytotoxicity Screening of Substituted Isobenzofuranones Designed from
Anacardic Acids. European Journal of Medicinal Chemistry 2010, 45 (8), 3480–3489.
https://doi.org/10.1016/j.ejmech.2010.05.015.
(88) Logrado, L. P. L.; Silveira, D.; Romeiro, L. A. S.; Moraes, M. O. de; Cavalcanti, B. C.;
Costa-Lotufo, L. V.; Pessoa, C. do Ó.; Santos, M. L. dos. Synthesis and Biological
Evaluation of New Salicylate Macrolactones from Anacardic Acids. Journal of the
Brazilian Chemical Society 2005, 16 (6a), 1217–1225. https://doi.org/10.1590/S0103-
50532005000700020.
(89) Reddy, N. S.; Rao, A. S.; Chari, M. A.; Kumar, V. R.; Jyothy, V.; Himabindu, V. Synthesis
and Antibacterial Activity of Sulfonamide Derivatives at C-8 Alkyl Chain of Anacardic
Acid Mixture Isolated from a Natural Product Cashew Nut Shell Liquid (CNSL). J Chem
Sci 2012, 124 (3), 723–730. https://doi.org/10.1007/s12039-012-0253-1.
(90) Baader, S.; Podsiadly, P. E.; Cole-Hamilton, D. J.; Goossen, L. J. Synthesis of Tsetse Fly
Attractants from a Cashew Nut Shell Extract by Isomerising Metathesis. Green Chem.
2014, 16 (12), 4885–4890. https://doi.org/10.1039/C4GC01269K.
(91) Kubo, Isao.; Muroi, Hisae.; Kubo, Aya. Antibacterial Activity of Long-Chain Alcohols
against Streptococcus Mutans. Journal of Agricultural and Food Chemistry 1993, 41 (12),
2447–2450. https://doi.org/10.1021/jf00036a045.
(92) Nguyen, T. K. L.; Livi, S.; Soares, B. G.; Barra, G. M. O.; Gérard, J.-F.; Duchet-Rumeau,
J. Development of Sustainable Thermosets from Cardanol-Based Epoxy Prepolymer and
Ionic Liquids. ACS Sustainable Chemistry & Engineering 2017.
https://doi.org/10.1021/acssuschemeng.7b02292.
(93) Wang, X.; Zhou, S.; Guo, W.-W.; Wang, P.-L.; Xing, W.; Song, L.; Hu, Y. Renewable
Cardanol-Based Phosphate as a Flame Retardant Toughening Agent for Epoxy Resins.
ACS Sustainable Chemistry & Engineering 2017, 5 (4), 3409–3416.
https://doi.org/10.1021/acssuschemeng.7b00062.
(94) Mohapatra, S.; Nando, G. B. Cardanol: A Green Substitute for Aromatic Oil as a
Plasticizer in Natural Rubber. RSC Adv. 2014, 4 (30), 15406–15418.
https://doi.org/10.1039/C3RA46061D.
(95) Froidevaux, V.; Negrell, C.; Caillol, S.; Pascault, J.-P.; Boutevin, B. Biobased Amines:
From Synthesis to Polymers; Present and Future. Chemical Reviews 2016.
https://doi.org/10.1021/acs.chemrev.6b00486.
(96) Darroman, E.; Bonnot, L.; Auvergne, R.; Boutevin, B.; Caillol, S. New Aromatic Amine
Based on Cardanol Giving New Biobased Epoxy Networks with Cardanol: Amine
Functionalized Cardanol for Epoxy Resins. European Journal of Lipid Science and
Technology 2015, 117 (2), 178–189. https://doi.org/10.1002/ejlt.201400248.
(97) Voirin, C.; Caillol, S.; Sadavarte, N. V.; Tawade, B. V.; Boutevin, B.; Wadgaonkar, P. P.
Functionalization of Cardanol: Towards Biobased Polymers and Additives. Polym. Chem.
2014, 5 (9), 3142–3162. https://doi.org/10.1039/C3PY01194A.
(98) Bruce, I. E.; Mehta, L.; Porter, M. J.; Stein, B. K.; Tyman, J. H. P. Anionic Surfactants
Synthesised from Replenishable Phenolic Lipids. Journal of Surfactants and Detergents
2009, 12 (4), 337–344. https://doi.org/10.1007/s11743-009-1116-8.
References
173
(99) Tyman, J. H. P.; Bruce, I. E. Surfactant Properties and Biodegradation of Polyethoxylates
from Phenolic Lipids. Journal of Surfactants and Detergents 2004, 7 (2), 169–173.
https://doi.org/10.1007/s11743-004-0300-3.
(100) Tyman, J. H. P.; Bruce, I. E. Synthesis and Characterization of Polyethoxylate
Surfactants Derived from Phenolic Lipids. Journal of Surfactants and Detergents 2003, 6
(4), 291–297. https://doi.org/10.1007/s11743-003-0272-3.
(101) Shi, W.; Wang, P.; Li, C.; Li, J.; Li, H.; Zhang, Z.; Wu, S.; Wang, J. Synthesis of
Cardanol Sulfonate Gemini Surfactant and Enthalpy-Entropy Compensation of
Micellization in Aqueous Solutions. Open Journal of Applied Sciences 2014, 04 (06), 360.
https://doi.org/10.4236/ojapps.2014.46033.
(102) Abhijit, T.; Joseph, T. Cement Composition Containing a Substituted Ethoxylated
Phenol Surfactant for Use in an Oil-Contaminated Well. US8360150B2, July 27, 2010.
(103) Scorzza, C.; Nieves, J.; Vejar, F.; Bullón, J. Synthesis and Physicochemical
Characterization of Anionic Surfactants Derived from Cashew Nut Shell Oil. Journal of
Surfactants and Detergents 2010, 13 (1), 27–31. https://doi.org/10.1007/s11743-009-
1143-5.
(104) Lv, J.; Liu, Z.; Zhang, J.; Huo, J.; Yu, Y. Bio-Based Episulfide Composed of
Cardanol/Cardol for Anti-Corrosion Coating Applications. Polymer 2017, 121, 286–296.
https://doi.org/10.1016/j.polymer.2017.06.036.
(105) Barreto, A. C. H.; Maia, F. J. N.; Santiago, V. R.; Ribeiro, V. G. P.; Denardin, J. C.;
Mele, G.; Carbone, L.; Lomonaco, D.; Mazzetto, S. E.; Fechine, P. B. A. Novel Ferrofluids
Coated with a Renewable Material Obtained from Cashew Nut Shell Liquid. Microfluidics
and Nanofluidics 2012, 12 (5), 677–686. https://doi.org/10.1007/s10404-011-0910-6.
(106) Mgaya, J. E.; Shombe, G. B.; Masikane, S. C.; Mlowe, S.; Mubofu, E. B.; Revaprasadu,
N. Cashew Nut Shell: A Potential Bio-Resource for the Production of Green
Environmentally Friendly Chemicals, Materials and Fuels. Green Chemistry 2019.
https://doi.org/10.1039/C8GC02972E.
(107) Rahobinirina, A. I.; Rakotondramanga, M. F.; Berlioz-Barbier, A.; Métay, E.;
Ramanandraibe, V.; Lemaire, M. Valorization of Madagascar’s CNSL via the Synthesis
of One Advanced Intermediate (3-Pentadecylcyclohexanone). Tetrahedron Letters 2017,
58 (23), 2284–2289. https://doi.org/10.1016/j.tetlet.2017.04.093.
(108) Santos, M. L. dos; Magalhães, G. C. de. Utilisation of Cashew Nut Shell Liquid from
Anacardium Occidentale as Starting Material for Organic Synthesis: A Novel Route to
Lasiodiplodin from Cardols. Journal of the Brazilian Chemical Society 1999, 10 (1), 13–
20. https://doi.org/10.1590/S0103-50531999000100003.
(109) Maia, F. J. N.; Ribeiro, V. G. P.; Lomonaco, D.; Luna, F. M. T.; Mazzetto, S. E.
Synthesis of a New Thiophosphorylated Compound Derived from Cashew Nut Shell
Liquid and Study of Its Antioxidant Activity. Industrial Crops and Products 2012, 36 (1),
271–275. https://doi.org/10.1016/j.indcrop.2011.10.019.
(110) US Department of Commerce, N. ESRL Global Monitoring Division - Global
Greenhouse Gas Reference Network https://www.esrl.noaa.gov/gmd/ccgg/trends/
(accessed Apr 24, 2019).
References
174
(111) Global carbon dioxide growth in 2018 reached 4th highest on record | National Oceanic
and Atmospheric Administration https://www.noaa.gov/news/global-carbon-dioxide-
growth-in-2018-reached-4th-highest-on-record (accessed Apr 24, 2019).
(112) Carbon Cycle. Wikipedia; 2019.
(113) WEO https://www.iea.org/weo/ (accessed Apr 24, 2019).
(114) The Carbon Capture & Storage Association (CCSA) http://www.ccsassociation.org/
(accessed Apr 25, 2019).
(115) Spigarelli, B. P.; Kawatra, S. K. Opportunities and Challenges in Carbon Dioxide
Capture. Journal of CO2 Utilization 2013, 1, 69–87.
https://doi.org/10.1016/j.jcou.2013.03.002.
(116) Markewitz, P.; Kuckshinrichs, W.; Leitner, W.; Linssen, J.; Zapp, P.; Bongartz, R.;
Schreiber, A.; Müller, T. E. Worldwide Innovations in the Development of Carbon
Capture Technologies and the Utilization of CO2. Energy Environ. Sci. 2012, 5 (6), 7281–
7305. https://doi.org/10.1039/C2EE03403D.
(117) Understanding CCS https://www.globalccsinstitute.com/why-ccs/what-is-ccs/
(accessed May 8, 2019).
(118) Carbon capture, utilisation and storage https://www.iea.org/topics/carbon-capture-and-
storage/ (accessed Apr 25, 2019).
(119) Peters, M.; Köhler, B.; Kuckshinrichs, W.; Leitner, W.; Markewitz, P.; Müller, T. E.
Chemical Technologies for Exploiting and Recycling Carbon Dioxide into the Value
Chain. ChemSusChem 2011, 4 (9), 1216–1240. https://doi.org/10.1002/cssc.201000447.
(120) CCU in the Green Economy Report.Pdf.
(121) Cuéllar-Franca, R. M.; Azapagic, A. Carbon Capture, Storage and Utilisation
Technologies: A Critical Analysis and Comparison of Their Life Cycle Environmental
Impacts. Journal of CO2 Utilization 2015, 9, 82–102.
https://doi.org/10.1016/j.jcou.2014.12.001.
(122) Aresta, M.; Dibenedetto, A.; Angelini, A. Catalysis for the Valorization of Exhaust
Carbon: From CO2 to Chemicals, Materials, and Fuels. Technological Use of CO2.
Chemical Reviews 2014, 114 (3), 1709–1742. https://doi.org/10.1021/cr4002758.
(123) The Use Of Carbon Dioxide In Fire Suppression Systems
https://www.fireline.com/blog/the-use-of-carbon-dioxide-in-fire-suppression-systems/
(accessed Apr 25, 2019).
(124) American Airguns - Three Basic Types of Airguns
http://www.airguns.net/general_airgun_types.php (accessed Apr 25, 2019).
(125) Arrighi, M. ENVIRONMENTAL IMPACTS OF CARBON DIOXIDE AND DRY ICE
PRODUCTION. 2010, 13.
(126) Carbon Dioxide - Product Stewardship Summary. 3.
(127) CRC Handbook Of Chemistry And Physics (86th Edition) Pdf | Al-Zaytoonah
University.
(128) Aresta, M.; Dibenedetto, A. Utilisation of CO2 as a Chemical Feedstock: Opportunities
and Challenges. Dalton Transactions 2007, No. 28, 2975.
https://doi.org/10.1039/b700658f.
References
175
(129) Riduan, S. N.; Zhang, Y. Recent Developments in Carbon Dioxide Utilization under
Mild Conditions. Dalton Trans. 2010, 39 (14), 3347. https://doi.org/10.1039/b920163g.
(130) Alper, E.; Yuksel Orhan, O. CO 2 Utilization: Developments in Conversion Processes.
Petroleum 2017, 3 (1), 109–126. https://doi.org/10.1016/j.petlm.2016.11.003.
(131) von der Assen, N.; Jung, J.; Bardow, A. Life-Cycle Assessment of Carbon Dioxide
Capture and Utilization: Avoiding the Pitfalls. Energy Environ. Sci. 2013, 6 (9), 2721.
https://doi.org/10.1039/c3ee41151f.
(132) Carl, B.; Wilhelm, M. Process of Manufacturing Urea. US1429483A, September 19,
1922.
(133) Fromm, D.; Lützow, D. Moderne Verfahren Der Großchemie: Harnstoff. Chemie in
unserer Zeit 1979, 13 (3), 78–81. https://doi.org/10.1002/ciuz.19790130303.
(134) Kolbe, H. Ueber Synthese der Salicylsäure. Ann. Chem. Pharm. 1860, 113 (1), 125–
127. https://doi.org/10.1002/jlac.18601130120.
(135) Schmitt, R. Beitrag Zur Kenntniss Der Kolbe’schen Salicylsäure Synthese. J. Prakt.
Chem. 1885, 31 (1), 397–411. https://doi.org/10.1002/prac.18850310130.
(136) Lindsey, A. S.; Jeskey, H. The Kolbe-Schmitt Reaction. Chem. Rev. 1957, 57 (4), 583–
620. https://doi.org/10.1021/cr50016a001.
(137) Urea production by countries, 2018 - knoema.com
https://knoema.com//atlas/topics/Agriculture/Fertilizers-Production-Quantity-in-
Nutrients/Urea-production (accessed May 8, 2019).
(138) Dadas, D. Thermodynamics of the Urea Process.
(139) Production of Chemicals. NZ Institute of Chemistry.
(140) Beller, M.; Bornscheuer, U. T. CO2 Fixation through Hydrogenation by Chemical or
Enzymatic Methods. Angew. Chem. Int. Ed. 2014, 53 (18), 4527–4528.
https://doi.org/10.1002/anie.201402963.
(141) Darensbourg, D. J. Making Plastics from Carbon Dioxide: Salen Metal Complexes as
Catalysts for the Production of Polycarbonates from Epoxides and CO2. Chem. Rev. 2007,
107 (6), 2388–2410. https://doi.org/10.1021/cr068363q.
(142) Coates, G. W.; Moore, D. R. Discrete Metal-Based Catalysts for the Copolymerization
of CO2 and Epoxides: Discovery, Reactivity, Optimization, and Mechanism. Angew.
Chem. Int. Ed. 2004, 43 (48), 6618–6639. https://doi.org/10.1002/anie.200460442.
(143) Sakakura, T.; Kohno, K. The Synthesis of Organic Carbonates from Carbon Dioxide.
Chem. Commun. 2009, No. 11, 1312. https://doi.org/10.1039/b819997c.
(144) Takahashi, T.; Watahiki, T.; Kitazume, S.; Yasuda, H.; Sakakura, T. Synergistic Hybrid
Catalyst for Cyclic Carbonate Synthesis: Remarkable Acceleration Caused by
Immobilization of Homogeneous Catalyst on Silica. Chem. Commun. 2006, No. 15, 1664.
https://doi.org/10.1039/b517140g.
(145) Liang, S.; Liu, H.; Jiang, T.; Song, J.; Yang, G.; Han, B. Highly Efficient Synthesis of
Cyclic Carbonates from CO2 and Epoxides over Cellulose/KI. Chem. Commun. 2011, 47
(7), 2131–2133. https://doi.org/10.1039/C0CC04829A.
References
176
(146) Dengler, J. E.; Lehenmeier, M. W.; Klaus, S.; Anderson, C. E.; Herdtweck, E.; Rieger,
B. A One-Component Iron Catalyst for Cyclic Propylene Carbonate Synthesis. Eur. J.
Inorg. Chem. 2011, 2011 (3), 336–343. https://doi.org/10.1002/ejic.201000861.
(147) Warner, T. D.; Mitchell, J. A. Cyclooxygenase-3 (COX-3): Filling in the Gaps toward
a COX Continuum? Proceedings of the National Academy of Sciences 2002, 99 (21),
13371–13373. https://doi.org/10.1073/pnas.222543099.
(148) cycles, T. text provides general information S. assumes no liability for the information
given being complete or correct D. to varying update; Text, S. C. D. M. up-to-D. D. T. R.
in the. Topic: Bayer AG https://www.statista.com/topics/4292/bayer-ag/ (accessed May 9,
2019).
(149) WHO Model List of Essential Medicines.
(150) R. Schmitt. MANUFACTURE of SALICYLIC ACID. US334290 (A), January 12,
1886.
(151) Hunt, S. E.; Jones, J. I.; Lindsey, A. S.; Killoh, D. C.; Turner, H. S. Mechanism of the
Kolbe–Schmitt Reaction. Part II. Influence of the Alkali Metal. J. Chem. Soc. 1958, 0 (0),
3152–3160. https://doi.org/10.1039/JR9580003152.
(152) Marković, Z.; Marković, S.; Manojlović, N.; Predojević-Simović, J. Mechanism of the
Kolbe−Schmitt Reaction. Structure of the Intermediate Potassium Phenoxide−CO2
Complex. J. Chem. Inf. Model. 2007, 47 (4), 1520–1525.
https://doi.org/10.1021/ci700068b.
(153) What is Methanol, its uses, energies https://www.methanol.org/ (accessed May 13,
2019).
(154) Ogden, J. M. PROSPECTS FOR BUILDING A HYDROGEN ENERGY
INFRASTRUCTURE. Annu. Rev. Energy. Environ. 1999, 24 (1), 227–279.
https://doi.org/10.1146/annurev.energy.24.1.227.
(155) Hydrogen Production: Electrolysis https://www.energy.gov/eere/fuelcells/hydrogen-
production-electrolysis (accessed May 13, 2019).
(156) Methanol: The Basic Chemical and Energy Feedstock of the Future: Asinger’s Vision
Today ; Based on “Methanol - Chemie- Und Energierohstoff: Die Mobilisation Der
Kohle” by Friedrich Asinger Published in 1986; Bertau, M., Offermanns, H., Plass, L.,
Schmidt, F., Wernicke, H.-J., Asinger, F., Eds.; Springer: Berlin, 2014.
(157) Eberle, U.; Felderhoff, M.; Schüth, F. Chemical and Physical Solutions for Hydrogen
Storage. Angew. Chem. Int. Ed. 2009, 48 (36), 6608–6630.
https://doi.org/10.1002/anie.200806293.
(158) Tadros, T. F. Applied Surfactants: Principles and Applications, 2. repr.; Wiley-VCH:
Weinheim, 2008.
(159) Levey, M. The Early History of Detergent Substances: A Chapter in Babylonian
Chemistry. Journal of Chemical Education 1954, 31 (10), 521.
https://doi.org/10.1021/ed031p521.
(160) Schumann, K.; Siekmann, K. Soaps. In Ullmann’s Encyclopedia of Industrial
Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA, Ed.; Wiley-VCH Verlag GmbH &
Co. KGaA: Weinheim, Germany, 2000. https://doi.org/10.1002/14356007.a24_247.
References
177
(161) Surfactants Market by Type (Cationic, Anionic, Non-ionic, Amphoteric) and
Application (Household detergents, Personal Care, Industrial & Institutional Cleaners,
Emulsion Polymerization, Food Processing, Oilfield Chemicals) - Global Opportunity
Analysis and Industry Forecast, 2014 - 2020
https://www.alliedmarketresearch.com/surfactant-market (accessed Apr 20, 2018).
(162) Conrad, S.; Max, W. Assistants for the Textile and Related Industries. US1970578A,
August 21, 1934.
(163) Schrauth, W.; Schenck, O.; Stickdorn, K. Über Die Herstellung von
Kohlenwasserstoffen Und Alkoholen Durch Hochdruck-Reduktion von Fettstoffen.
Berichte der deutschen chemischen Gesellschaft (A and B Series) 1931, 64 (6), 1314–
1318. https://doi.org/10.1002/cber.19310640616.
(164) Heinrich, B. Process for the Sulphonation of Fatty Materials. US1801189A, April 14,
1931.
(165) Heinrich, B. Process for Obtaining Sulphonation Products from Polymerized Fats or
Oils or the Acids Thereof. US1749463A, March 4, 1930.
(166) Domagk, G. Eine neue Klasse von Desinfektionsmitteln. DMW - Deutsche Medizinische
Wochenschrift 1935, 61 (21), 829–832. https://doi.org/10.1055/s-0028-1129654.
(167) Puchta, R. Cationic Surfactants in Laundry Detergents and Laundry Aftertreatment
Aids. Journal of the American Oil Chemists’ Society 1984, 61 (2), 367–376.
https://doi.org/10.1007/BF02678796.
(168) Surfactants Market Report: Global Industry Analysis, 2024
https://www.ceresana.com/en/market-studies/chemicals/surfactants (accessed Jun 27,
2019).
(169) Bajpai, D.; Tyagi, V. K. Laundry Detergents: An Overview. Journal of Oleo Science
2007, 56 (7), 327–340. https://doi.org/10.5650/jos.56.327.
(170) Anionic Surfactants Market: Global Industry Trend Analysis 2013 to 2017 and Forecast
2018 - 2028 https://www.persistencemarketresearch.com/market-research/anionic-
surfactants-market.asp (accessed Jun 26, 2019).
(171) Holmberg, K.; Jönsson, B.; Kronberg, B.; Lindman, B. Surfactants and Polymers in
Aqueous Solution; John Wiley & Sons, Ltd: Chichester, UK, 2002.
https://doi.org/10.1002/0470856424.
(172) Surfactants Market Size | Global Industry Trend Analysis 2018-2025
https://www.alliedmarketresearch.com/surfactant-market (accessed Jun 26, 2019).
(173) Bernier, D.; Wefelscheid, U. K.; Woodward, S. Properties, Preparation and Synthetic
Uses of Amine N-Oxides. An Update. Organic Preparations and Procedures
International 2009, 41 (3), 173–210. https://doi.org/10.1080/00304940902955756.
(174) Amine Oxide Market - Global Industry Analysis, Size, Share, Growth, Trends, and
Forecast 2018 - 2026 https://www.transparencymarketresearch.com/amine-oxide-
market.html (accessed Jun 28, 2019).
(175) Steber, J.; Wiebel, F. Laundry Detergents, 4. Ecology and Toxicology. In Ullmann’s
Encyclopedia of Industrial Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA, Ed.;
Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2011.
https://doi.org/10.1002/14356007.o15_o15.
References
178
(176) Gesetz Über Detergentien in Wasch- Und Reinigungsmitteln. Bundesgesetzblatt Teil I
1961, No. 72, 1653.
(177) Scott, M. J.; Jones, M. N. The Biodegradation of Surfactants in the Environment.
Biochimica et Biophysica Acta (BBA) - Biomembranes 2000, 1508 (1), 235–251.
https://doi.org/10.1016/S0304-4157(00)00013-7.
(178) Hashim, M. A.; Kulandai, J.; Hassan, R. S. Biodegradability of Branched Alkylbenzene
Sulphonates. Journal of Chemical Technology & Biotechnology 1992, 54 (3), 207–214.
https://doi.org/10.1002/jctb.280540302.
(179) Toxic substance profile: Surfactants http://www.ukmarinesac.org.uk/activities/water-
quality/wq8_46.htm (accessed Apr 20, 2018).
(180) SERVOS, M.; BENNIE, D.; BURNISON, K.; CURETON, P.; DAVIDSON, N.;
RAWN, T. Uncertainties Associated with Assessing the Risk of an Endocrine Active
Substance in the Canadian Environment. 12.
(181) Review of the Persistence of Nonylphenol and Nonylphenol Ethoxylates in Aquatic
Environments.
(182) Review of the Aquatic Toxicity, Estrogenic Responses and Bioaccumulation of
Alkylphenols and Alkylphenol Polyethoxylates.
(183) Toxicological Evaluation and Limit Values for Nonylphenol, Nonylphenol
Ethoxylates.Pdf.
(184) Soares, A.; Guieysse, B.; Jefferson, B.; Cartmell, E.; Lester, J. N. Nonylphenol in the
Environment: A Critical Review on Occurrence, Fate, Toxicity and Treatment in
Wastewaters. Environment International 2008, 34 (7), 1033–1049.
https://doi.org/10.1016/j.envint.2008.01.004.
(185) Nonylphenol and Nonylphenol Ethoxylates - Toxipedia
http://www.toxipedia.org/display/toxipedia/Nonylphenol+and+Nonylphenol+Ethoxylate
s (accessed Apr 23, 2018).
(186) Restrictions on the Marketing and Use of Certain Dangerous Substances and
Preparations (Nonylphenol, Nonylphenol Ethoxylate and Cement).Pdf.
(187) Foley, P.; Kermanshahi pour, A.; Beach, E. S.; Zimmerman, J. B. Derivation and
Synthesis of Renewable Surfactants. Chem. Soc. Rev. 2012, 41 (4), 1499–1518.
https://doi.org/10.1039/C1CS15217C.
(188) Tobori, N.; Kakui, T. Methyl Ester Sulfonate. In Biobased Surfactants; Elsevier, 2019;
pp 303–324. https://doi.org/10.1016/B978-0-12-812705-6.00009-5.
(189) Benvegnu, T.; Plusquellec, D.; Lemiègre, L. Surfactants from Renewable Sources:
Synthesis and Applications. In Monomers, Polymers and Composites from Renewable
Resources; Elsevier, 2008; pp 153–178. https://doi.org/10.1016/B978-0-08-045316-
3.00007-7.
(190) del Marmol, V.; Beermann, F. Tyrosinase and Related Proteins in Mammalian
Pigmentation. FEBS Letters 1996, 381 (3), 165–168. https://doi.org/10.1016/0014-
5793(96)00109-3.
(191) Chang, T.-S. An Updated Review of Tyrosinase Inhibitors. Int J Mol Sci 2009, 10 (6),
2440–2475. https://doi.org/10.3390/ijms10062440.
References
179
(192) Zolghadri, S.; Bahrami, A.; Hassan Khan, M. T.; Munoz-Munoz, J.; Garcia-Molina, F.;
Garcia-Canovas, F.; Saboury, A. A. A Comprehensive Review on Tyrosinase Inhibitors.
Journal of Enzyme Inhibition and Medicinal Chemistry 2019, 34 (1), 279–309.
https://doi.org/10.1080/14756366.2018.1545767.
(193) Solano, F.; Briganti, S.; Picardo, M.; Ghanem, G. Hypopigmenting Agents: An Updated
Review on Biological, Chemical and Clinical Aspects. Pigment Cell Research 2006, 19
(6), 550–571. https://doi.org/10.1111/j.1600-0749.2006.00334.x.
(194) Ando, H.; Kondoh, H.; Ichihashi, M.; Hearing, V. J. Approaches to Identify Inhibitors
of Melanin Biosynthesis via the Quality Control of Tyrosinase. Journal of Investigative
Dermatology 2007, 127 (4), 751–761. https://doi.org/10.1038/sj.jid.5700683.
(195) Kim, Y.-J.; Uyama, H. Tyrosinase Inhibitors from Natural and Synthetic Sources:
Structure, Inhibition Mechanism and Perspective for the Future. Cellular and Molecular
Life Sciences 2005, 62 (15), 1707–1723. https://doi.org/10.1007/s00018-005-5054-y.
(196) Shi Shun, A. L. K.; Tykwinski, R. R. Synthesis of Naturally Occurring Polyynes.
Angewandte Chemie International Edition 2006, 45 (7), 1034–1057.
https://doi.org/10.1002/anie.200502071.
(197) Bohlmann, F.; Burkhardt, T.; Zdero, C. Naturally Occurring Acetylenes; Academic
Press: London, New York, 1973.
(198) PHENYLACETYLENE. Organic Syntheses 1950, 30, 72.
https://doi.org/10.15227/orgsyn.030.0072.
(199) Gilbert, J. C.; Weerasooriya, U. Diazoethenes: Their Attempted Synthesis from
Aldehydes and Aromatic Ketones by Way of the Horner-Emmons Modification of the
Wittig Reaction. A Facile Synthesis of Alkynes. The Journal of Organic Chemistry 1982,
47 (10), 1837–1845. https://doi.org/10.1021/jo00349a007.
(200) Seyferth, D.; Marmor, R. S.; Hilbert, P. Reactions of Dimethylphosphono-Substituted
Diazoalkanes. (MeO)2P(O)CR Transfer to Olefins and 1,3-Dipolar Additions of
(MeO)2P(O)C(N2)R. The Journal of Organic Chemistry 1971, 36 (10), 1379–1386.
https://doi.org/10.1021/jo00809a014.
(201) Ohira, S. Methanolysis of Dimethyl (1-Diazo-2-Oxopropyl) Phosphonate: Generation
of Dimethyl (Diazomethyl) Phosphonate and Reaction with Carbonyl Compounds.
Synthetic Communications 1989, 19 (3–4), 561–564.
https://doi.org/10.1080/00397918908050700.
(202) Roth, G.; Liepold, B.; Müller, S.; Bestmann, H. Further Improvements of the Synthesis
of Alkynes from Aldehydes. Synthesis 2003, 2004 (01), 59–62. https://doi.org/10.1055/s-
2003-44346.
(203) Acetylene.JPG (JPEG Image, 816 × 586 pixels)
https://upload.wikimedia.org/wikipedia/commons/1/1d/Acetylene.JPG (accessed Aug 6,
2019).
(204) Table Of Bond Dissociation Energies 2018.Pdf.
(205) Lindlar, H. Ein Neuer Katalysator Für Selektive Hydrierungen. Helvetica Chimica Acta
1952, 35 (2), 446–450. https://doi.org/10.1002/hlca.19520350205.
(206) Pässler, P.; Hefner, W.; Buckl, K.; Meinass, H.; Meiswinkel, A.; Wernicke, H.-J.;
Ebersberg, G.; Müller, R.; Bässler, J.; Behringer, H.; et al. Acetylene. In Ullmann’s
References
180
Encyclopedia of Industrial Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA, Ed.;
Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2008.
https://doi.org/10.1002/14356007.a01_097.pub3.
(207) Howard, W. B. Production of Acetylene by the Partial Combustion Process.
US3234300A, February 8, 1966.
(208) Global and China 1, 4-butanediol (BDO) Industry Report, 2019-2025 - MarketWatch
https://www.marketwatch.com/press-release/global-and-china-1-4-butanediol-bdo-
industry-report-2019-2025-2019-06-12 (accessed Feb 7, 2020).
(209) 1, 4 Butanediol Market 2019 Global Share, Growth, Size, Opportunities, Trends,
Regional Overview, Leading Company Analysis, And Key Country Forecast To 2025 -
MarketWatch https://www.marketwatch.com/press-release/1-4-butanediol-market-2019-
global-share-growth-size-opportunities-trends-regional-overview-leading-company-
analysis-and-key-country-forecast-to-2025-2019-03-18 (accessed Feb 7, 2020).
(210) Burk, M. J.; Burgard, A. P.; Osterhout, R. E.; Sun, J. Microorganisms for the Production
of 1,4-Butanediol. US20130109069A1, May 2, 2013.
(211) BASF und Genomatica erweitern Lizenzvereinbarung für 1,4-Butandiol (BDO) aus
nachwachsenden Rohstoffen https://www.basf.com/global/de/media/news-
releases/2015/09/p-15-347.html (accessed Feb 7, 2020).
(212) Gunardson, H. H. Industrial Gases in Petrochemical Processing : Chemical Industries;
CRC Press, 1997. https://doi.org/10.1201/9781420001150.
(213) M. Beller, Catalysis - a Key to Sustainability, in Leibniz Perspectives, 2007.
(214) Catalyst: Sustainable Catalysis | Elsevier Enhanced Reader
https://reader.elsevier.com/reader/sd/pii/S2451929417300839?token=5D99BCBFE0AC
F5EC5C90FE8C359DD2130236F9482EFDD69A977FC7B7BDF5C84C15F8AFF0FF3
438E75AC45033F741232B (accessed Apr 29, 2019).
https://doi.org/10.1016/j.chempr.2017.02.014.
(215) Chemistry, I. U. of P. and A. IUPAC Gold Book - catalyst
http://goldbook.iupac.org/html/C/C00876.html (accessed Apr 29, 2019).
https://doi.org/10.1351/goldbook.C00876.
(216) Rothenberg, G. Catalysis-Concepts and Green Applications; Wiley-VCH Verlag GmbH
& Co. KGaA: Weinheim, Germany, 2008. https://doi.org/10.1002/9783527621866.
(217) Chorkendorff, I.; Niemantsverdriet, J. W. Concepts of Modern Catalysis and Kinetics;
Wiley-VCH: Weinheim [Germany], 2003.
(218) Rylander, P. N. Hydrogenation Methods; Best synthetic methods; Academic Press:
London ; Orlando [Fla.], 1985.
(219) Dub, P. A.; Ikariya, T. Catalytic Reductive Transformations of Carboxylic and Carbonic
Acid Derivatives Using Molecular Hydrogen. ACS Catalysis 2012, 2 (8), 1718–1741.
https://doi.org/10.1021/cs300341g.
(220) Navarro, R. M.; Guil, R.; Fierro, J. L. G. Introduction to Hydrogen Production. In
Compendium of Hydrogen Energy; Elsevier, 2015; pp 21–61.
https://doi.org/10.1016/B978-1-78242-361-4.00002-9.
References
181
(221) Global Hydrogen Generation Market Size | Industry Report, 2018-2025
https://www.grandviewresearch.com/industry-analysis/hydrogen-generation-market
(accessed Jun 13, 2019).
(222) Catalytic Hydrogenation of Alkenes
https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemental_Modules_(O
rganic_Chemistry)/Alkenes/Reactivity_of_Alkenes/Catalytic_Hydrogenation (accessed
Jun 17, 2019).
(223) Horiuti, I.; Polanyi, M. Exchange Reactions of Hydrogen on Metallic Catalysts.
Transactions of the Faraday Society 1934, 30, 1164.
https://doi.org/10.1039/tf9343001164.
(224) Smith, M. B.; March, J. March’s Advanced Organic Chemistry; John Wiley & Sons,
Inc.: Hoboken, NJ, USA, 2006. https://doi.org/10.1002/0470084960.
(225) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D.
Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride.
Studies on Direct and Indirect Reductive Amination Procedures 1. The Journal of Organic
Chemistry 1996, 61 (11), 3849–3862. https://doi.org/10.1021/jo960057x.
(226) Zhou, P.; Zhang, Z. One-Pot Reductive Amination of Carbonyl Compounds with Nitro
Compounds by Transfer Hydrogenation over Co-Nx as Catalyst. ChemSusChem 2017, 10
(9), 1892–1897. https://doi.org/10.1002/cssc.201700348.
(227) Zhang, Y.; Yan, Q.; Zi, G.; Hou, G. Enantioselective Direct Synthesis of Free Cyclic
Amines via Intramolecular Reductive Amination. Organic Letters 2017.
https://doi.org/10.1021/acs.orglett.7b01828.
(228) Ono, Y.; Ishida, H. Amination of Phenols with Ammonia over Palladium Supported on
Alumina. Journal of Catalysis 1981, 72 (1), 121–128. https://doi.org/10.1016/0021-
9517(81)90083-X.
(229) Rice, R. G.; Kohn, E. J.; Daasch, L. W. Alkylation of Amines with Alcohols Catalyzed
by Raney Nickel. II. Aliphatic Amines. The Journal of Organic Chemistry 1958, 23 (9),
1352–1354. https://doi.org/10.1021/jo01103a032.
(230) Podyacheva, E.; Afanasyev, O. I.; Tsygankov, A. A.; Makarova, M.; Chusov, D.
Hitchhiker’s Guide to Reductive Amination. Synthesis 2019, 51 (13), 2667–2677.
https://doi.org/10.1055/s-0037-1611788.
(231) Olefin Metathesis: Theory and Practice; Grela, K., Ed.; Wiley: Hoboken, New Jersey,
2014.
(232) Calderon, N. Olefin Metathesis Reaction. Accounts of Chemical Research 1972, 5 (4),
127–132. https://doi.org/10.1021/ar50052a002.
(233) Banks, R. L.; Bailey, G. C. Olefin Disproportionation. A New Catalytic Process.
Industrial & Engineering Chemistry Product Research and Development 1964, 3 (3),
170–173. https://doi.org/10.1021/i360011a002.
(234) Bradshaw, C. Olefin Dismutation: Reactions of Olefins on Cobalt Oxide-Molybdenum
Oxide-Alumina. Journal of Catalysis 1967, 7 (3), 269–276. https://doi.org/10.1016/0021-
9517(67)90105-4.
References
182
(235) Calderon, Nissim.; Ofstead, E. A.; Ward, J. P.; Judy, W. Allen.; Scott, K. W. Olefin
Metathesis. I. Acyclic Vinylenic Hydrocarbons. Journal of the American Chemical
Society 1968, 90 (15), 4133–4140. https://doi.org/10.1021/ja01017a039.
(236) Jolly, P. W.; Pettit, R. Evidence for a Novel Metal-Carbene System. Journal of the
American Chemical Society 1966, 88 (21), 5044–5045.
https://doi.org/10.1021/ja00973a062.
(237) Grubbs, R. H.; Brunck, T. K. Possible Intermediate in the Tungsten-Catalyzed Olefin
Metathesis Reaction. Journal of the American Chemical Society 1972, 94 (7), 2538–2540.
https://doi.org/10.1021/ja00762a073.
(238) Biefeld, C. G.; Eick, H. A.; Grubbs, R. H. Crystal Structure of
Bis(Triphenylphosphine)Tetramethyleneplatinum(II). Inorganic Chemistry 1973, 12 (9),
2166–2170. https://doi.org/10.1021/ic50127a046.
(239) Hérisson, P. J.-L.; Chauvin, Y. Catalyse de transformation des oléfines par les
complexes du tungstène. II. Télomérisation des oléfines cycliques en présence d’oléfines
acycliques. Die Makromolekulare Chemie 1971, 141 (1), 161–176.
https://doi.org/10.1002/macp.1971.021410112.
(240) Astruc, D. The Metathesis Reactions: From a Historical Perspective to Recent
Developments. New Journal of Chemistry 2005, 29 (1), 42.
https://doi.org/10.1039/b412198h.
(241) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. A Series of Well-Defined
Metathesis Catalysts–Synthesis of[RuCl2( CHR′)(PR3)2] and Its Reactions.
Angewandte Chemie International Edition in English 1995, 34 (18), 2039–2041.
https://doi.org/10.1002/anie.199520391.
(242) Schwab, P.; Grubbs, R. H.; Ziller, J. W. Synthesis and Applications of
RuCl2(CHR‘)(PR3)2: The Influence of the Alkylidene Moiety on Metathesis Activity.
Journal of the American Chemical Society 1996, 118 (1), 100–110.
https://doi.org/10.1021/ja952676d.
(243) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Increased Ring Closing
Metathesis Activity of Ruthenium-Based Olefin Metathesis Catalysts Coordinated with
Imidazolin-2-Ylidene Ligands. Tetrahedron Letters 1999, 40 (12), 2247–2250.
https://doi.org/10.1016/S0040-4039(99)00217-8.
(244) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Synthesis and Activity of a New
Generation of Ruthenium-Based Olefin Metathesis Catalysts Coordinated with 1,3-
Dimesityl-4,5-Dihydroimidazol-2-Ylidene Ligands §. Organic Letters 1999, 1 (6), 953–
956. https://doi.org/10.1021/ol990909q.
(245) Weskamp, T.; Schattenmann, W. C.; Spiegler, M.; Herrmann, W. A. A Novel Class of
Ruthenium Catalysts for Olefin Metathesis. Angewandte Chemie International Edition
1998, 37 (18), 2490–2493. https://doi.org/10.1002/(SICI)1521-
3773(19981002)37:18<2490::AID-ANIE2490>3.0.CO;2-X.
(246) Vougioukalakis, G. C.; Grubbs, R. H. Ruthenium-Based Heterocyclic Carbene-
Coordinated Olefin Metathesis Catalysts†. Chemical Reviews 2010, 110 (3), 1746–1787.
https://doi.org/10.1021/cr9002424.
References
183
(247) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. Efficient and Recyclable
Monomeric and Dendritic Ru-Based Metathesis Catalysts. Journal of the American
Chemical Society 2000, 122 (34), 8168–8179. https://doi.org/10.1021/ja001179g.
(248) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. A Recyclable Ru-
Based Metathesis Catalyst. Journal of the American Chemical Society 1999, 121 (4), 791–
799. https://doi.org/10.1021/ja983222u.
(249) Grela, K.; Harutyunyan, S.; Michrowska, A. A Highly Efficient Ruthenium Catalyst for
Metathesis Reactions. Angewandte Chemie International Edition 2002, 41 (21), 4038–
4040. https://doi.org/10.1002/1521-3773(20021104)41:21<4038::AID-
ANIE4038>3.0.CO;2-0.
(250) Blechert, S. Novel Transition Metal Complexes and Their Use in Transition Metal-
Catalysed Reactions. US20030220512A1, November 27, 2003.
(251) Zhan, Z.-Y. Recyclable Ruthenium Catalysts for Metathesis Reactions.
US20070043180A1, February 22, 2007.
(252) Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. A Practical and Highly Active
Ruthenium-Based Catalyst That Effects the Cross Metathesis of Acrylonitrile.
Angewandte Chemie International Edition 2002, 41 (21), 4035–4037.
https://doi.org/10.1002/1521-3773(20021104)41:21<4035::AID-ANIE4035>3.0.CO;2-I.
(253) Love, J. A.; Sanford, M. S.; Day, M. W.; Grubbs, R. H. Synthesis, Structure, and
Activity of Enhanced Initiators for Olefin Metathesis. Journal of the American Chemical
Society 2003, 125 (33), 10103–10109. https://doi.org/10.1021/ja027472t.
(254) Leitgeb, A.; Wappel, J.; Slugovc, C. The ROMP Toolbox Upgraded. Polymer 2010, 51
(14), 2927–2946. https://doi.org/10.1016/j.polymer.2010.05.002.
(255) Mol, J. Industrial Applications of Olefin Metathesis. Journal of Molecular Catalysis A:
Chemical 2004, 213 (1), 39–45. https://doi.org/10.1016/j.molcata.2003.10.049.
(256) Reuben, B.; Wittcoff, H. The SHOP Process: An Example of Industrial Creativity.
Journal of Chemical Education 1988, 65 (7), 605. https://doi.org/10.1021/ed065p605.
(257) Keim, W. Oligomerization of Ethylene to α-Olefins: Discovery and Development of the
Shell Higher Olefin Process (SHOP). Angewandte Chemie International Edition 2013, 52
(48), 12492–12496. https://doi.org/10.1002/anie.201305308.
(258) Vol’pin, M. E.; Kolomnikov, I. S. Reactions of Carbon Dioxide with Transition Metal
Compounds. Pure and Applied Chemistry 1973, 33 (4), 567–582.
https://doi.org/10.1351/pac197333040567.
(259) Normant, J. F.; Cahiez, G.; Chuit, C.; Villieras, J. Stereospecific Synthesis of Di- and
Tri-Substituted Acids by Carbonation of Vinyl-Copper Reagents. Journal of
Organometallic Chemistry 1973, 54, C53–C56. https://doi.org/10.1016/S0022-
328X(00)84981-5.
(260) Kobayashi, K.; Kondo, Y. Transition-Metal-Free Carboxylation of Organozinc
Reagents Using CO2 in DMF Solvent. Org. Lett. 2009, 11 (9), 2035–2037.
https://doi.org/10.1021/ol900528h.
(261) Correa, A.; Martín, R. Metal-Catalyzed Carboxylation of Organometallic Reagents with
Carbon Dioxide. Angewandte Chemie International Edition 2009, 48 (34), 6201–6204.
https://doi.org/10.1002/anie.200900667.
References
184
(262) Shi, M.; Nicholas, K. M. Palladium-Catalyzed Carboxylation of Allyl Stannanes. J. Am.
Chem. Soc. 1997, 119 (21), 5057–5058. https://doi.org/10.1021/ja9639832.
(263) Takaya, J.; Tadami, S.; Ukai, K.; Iwasawa, N. Copper(I)-Catalyzed Carboxylation of
Aryl- and Alkenylboronic Esters. Org. Lett. 2008, 10 (13), 2697–2700.
https://doi.org/10.1021/ol800829q.
(264) Ukai, K.; Aoki, M.; Takaya, J.; Iwasawa, N. Rhodium(I)-Catalyzed Carboxylation of
Aryl- and Alkenylboronic Esters with CO2. J. Am. Chem. Soc. 2006, 128 (27), 8706–
8707. https://doi.org/10.1021/ja061232m.
(265) Ohishi, T.; Nishiura, M.; Hou, Z. Carboxylation of Organoboronic Esters Catalyzed by
N‐Heterocyclic Carbene Copper(I) Complexes. Angew. Chem. Int. Ed. 2008, 47 (31),
5792–5795. https://doi.org/10.1002/anie.200801857.
(266) Osakada, K.; Sato, R.; Yamamoto, T. Nickel-Complex-Promoted Carboxylation of
Haloarenes Involving Insertion of CO2 into NiII-C Bonds. Organometallics 1994, 13 (11),
4645–4647. https://doi.org/10.1021/om00023a078.
(267) Correa, A.; Martín, R. Palladium-Catalyzed Direct Carboxylation of Aryl Bromides
with Carbon Dioxide. J. Am. Chem. Soc. 2009, 131 (44), 15974–15975.
https://doi.org/10.1021/ja905264a.
(268) Fujihara, T.; Nogi, K.; Xu, T.; Terao, J.; Tsuji, Y. Nickel-Catalyzed Carboxylation of
Aryl and Vinyl Chlorides Employing Carbon Dioxide. J. Am. Chem. Soc. 2012, 134 (22),
9106–9109. https://doi.org/10.1021/ja303514b.
(269) Nogi, K.; Fujihara, T.; Terao, J.; Tsuji, Y. Cobalt- and Nickel-Catalyzed Carboxylation
of Alkenyl and Sterically Hindered Aryl Triflates Utilizing CO2. J. Org. Chem. 2015, 80
(22), 11618–11623. https://doi.org/10.1021/acs.joc.5b02307.
(270) Rebih, F.; Andreini, M.; Moncomble, A.; Harrison-Marchand, A.; Maddaluno, J.;
Durandetti, M. Direct Carboxylation of Aryl Tosylates by CO2 Catalyzed by In Situ-
Generated Ni(0). Chem. Eur. J. 2016, 22 (11), 3758–3763.
https://doi.org/10.1002/chem.201503926.
(271) Liu, Y.; Cornella, J.; Martin, R. Ni-Catalyzed Carboxylation of Unactivated Primary
Alkyl Bromides and Sulfonates with CO2. J. Am. Chem. Soc. 2014, 136 (32), 11212–
11215. https://doi.org/10.1021/ja5064586.
(272) Zhang, S.; Chen, W.-Q.; Yu, A.; He, L.-N. Palladium-Catalyzed Carboxylation of
Benzyl Chlorides with Atmospheric Carbon Dioxide in Combination with
Manganese/Magnesium Chloride. ChemCatChem 2015, 7 (23), 3972–3977.
https://doi.org/10.1002/cctc.201500724.
(273) Correa, A.; León, T.; Martin, R. Ni-Catalyzed Carboxylation of C(Sp2)– and C(Sp3)–
O Bonds with CO2. J. Am. Chem. Soc. 2014, 136 (3), 1062–1069.
https://doi.org/10.1021/ja410883p.
(274) Nogi, K.; Fujihara, T.; Terao, J.; Tsuji, Y. Cobalt-Catalyzed Carboxylation of Propargyl
Acetates with Carbon Dioxide. Chem. Commun. 2014, 50 (86), 13052–13055.
https://doi.org/10.1039/C4CC03644A.
(275) Moragas, T.; Cornella, J.; Martin, R. Ligand-Controlled Regiodivergent Ni-Catalyzed
Reductive Carboxylation of Allyl Esters with CO2. J. Am. Chem. Soc. 2014, 136 (51),
17702–17705. https://doi.org/10.1021/ja509077a.
References
185
(276) Mita, T.; Higuchi, Y.; Sato, Y. Highly Regioselective Palladium-Catalyzed
Carboxylation of Allylic Alcohols with CO2. Chem. Eur. J. 2015, 21 (46), 16391–16394.
https://doi.org/10.1002/chem.201503359.
(277) Moragas, T.; Gaydou, M.; Martin, R. Nickel-Catalyzed Carboxylation of Benzylic C−N
Bonds with CO2. Angew. Chem. Int. Ed. 2016, 55 (16), 5053–5057.
https://doi.org/10.1002/anie.201600697.
(278) Aresta, M.; Nobile, C. F.; Albano, V. G.; Forni, E.; Manassero, M. New Nickel–Carbon
Dioxide Complex: Synthesis, Properties, and Crystallographic Characterization of
(Carbon Dioxide)-Bis(Tricyclohexylphosphine)Nickel. J. Chem. Soc., Chem. Commun.
1975, 0 (15), 636–637. https://doi.org/10.1039/C39750000636.
(279) Burkhart, G.; Hoberg, H. Oxanickelacyclopentene Derivatives from Nickel(0), Carbon
Dioxide, and Alkynes. Angew. Chem. Int. Ed. Engl. 1982, 21 (1), 76–76.
https://doi.org/10.1002/anie.198200762.
(280) Hoberg, H.; Peres, Y.; Krüger, C.; Tsay, Y.-H. A 1-Oxa-2-Nickela-5-Cyclopentanone
from Ethene and Carbon Dioxide: Preparation, Structure, and Reactivity. Angew. Chem.
Int. Ed. Engl. 1987, 26 (8), 771–773. https://doi.org/10.1002/anie.198707711.
(281) Takimoto, M.; Shimizu, K.; Mori, M. Nickel-Promoted Alkylative or Arylative
Carboxylation of Alkynes. Org. Lett. 2001, 3 (21), 3345–3347.
https://doi.org/10.1021/ol016585z.
(282) Takimoto, M.; Mori, M. Cross-Coupling Reaction of Oxo-π-Allylnickel Complex
Generated from 1,3-Diene under an Atmosphere of Carbon Dioxide. J. Am. Chem. Soc.
2001, 123 (12), 2895–2896. https://doi.org/10.1021/ja004004f.
(283) Saito, S.; Nakagawa, S.; Koizumi, T.; Hirayama, K.; Yamamoto, Y. Nickel-Mediated
Regio- and Chemoselective Carboxylation of Alkynes in the Presence of Carbon Dioxide.
J. Org. Chem. 1999, 64 (11), 3975–3978. https://doi.org/10.1021/jo982443f.
(284) Aoki, M.; Kaneko, M.; Izumi, S.; Ukai, K.; Iwasawa, N. Bidentate Amidine Ligands for
Nickel(0)-Mediated Coupling of Carbon Dioxide with Unsaturated Hydrocarbons. Chem.
Commun. 2004, No. 22, 2568. https://doi.org/10.1039/b411802b.
(285) Yu, D.; Teong, S. P.; Zhang, Y. Transition Metal Complex Catalyzed Carboxylation
Reactions with CO2. Coordination Chemistry Reviews 2015, 293–294, 279–291.
https://doi.org/10.1016/j.ccr.2014.09.002.
(286) Inoue, Y.; Itoh, Y.; Hashimoto, H. INCORPORATION OF CARBON DIOXIDE IN
ALKYNE OLIGOMERIZATION CATALYZED BY NICKEL(0) COMPLEXES.
FORMATION OF SUBSTITUTED 2-PYRONES. Chem. Lett. 1977, 6 (8), 855–856.
https://doi.org/10.1246/cl.1977.855.
(287) Tsuda, T.; Morikawa, S.; Sumiya, R.; Saegusa, T. Nickel(0)-Catalyzed Cycloaddition
of Diynes and Carbon Dioxide to Give Bicyclic .Alpha.-Pyrones. J. Org. Chem. 1988, 53
(14), 3140–3145. https://doi.org/10.1021/jo00249a003.
(288) Louie, J.; Gibby, J. E.; Farnworth, M. V.; Tekavec, T. N. Efficient Nickel-Catalyzed [2
+ 2 + 2] Cycloaddition of CO2 and Diynes. J. Am. Chem. Soc. 2002, 124 (51), 15188–
15189. https://doi.org/10.1021/ja027438e.
(289) Li, S.; Yuan, W.; Ma, S. Highly Regio- and Stereoselective Three-Component Nickel-
Catalyzed Syn-Hydrocarboxylation of Alkynes with Diethyl Zinc and Carbon Dioxide.
References
186
Angew. Chem. Int. Ed. 2011, 50 (11), 2578–2582.
https://doi.org/10.1002/anie.201007128.
(290) Fujihara, T.; Xu, T.; Semba, K.; Terao, J.; Tsuji, Y. Copper-Catalyzed
Hydrocarboxylation of Alkynes Using Carbon Dioxide and Hydrosilanes. Angew. Chem.
Int. Ed. 2011, 50 (2), 523–527. https://doi.org/10.1002/anie.201006292.
(291) Zhang, Y.; Riduan, S. N. Catalytic Hydrocarboxylation of Alkenes and Alkynes with
CO2. Angew. Chem. Int. Ed. 2011, 50 (28), 6210–6212.
https://doi.org/10.1002/anie.201101341.
(292) Fujihara, T.; Tani, Y.; Semba, K.; Terao, J.; Tsuji, Y. Copper-Catalyzed
Silacarboxylation of Internal Alkynes by Employing Carbon Dioxide and Silylboranes.
Angew. Chem. Int. Ed. 2012, 51 (46), 11487–11490.
https://doi.org/10.1002/anie.201207148.
(293) Dinjus, E.; Leitner, W. New Insights into the Palladium-Catalysed Synthesis of ?-
Lactones from 1,3-Dienes and Carbon Dioxide. Appl. Organomet. Chem. 1995, 9 (1), 43–
50. https://doi.org/10.1002/aoc.590090108.
(294) Behr, A.; Juszak, K.-D. Palladium-Catalyzed Reaction of Butadiene and Carbon
Dioxide. Journal of Organometallic Chemistry 1983, 255 (2), 263–268.
https://doi.org/10.1016/0022-328X(83)87028-4.
(295) Inoue, Y.; Hibi, T.; Satake, M.; Hashimoto, H. Reaction of Methylenecyclopropanes
with Carbon Dioxide Catalysed by Palladium(0) Complexes. Synthesis of Five-Membered
Lactones. J. Chem. Soc., Chem. Commun. 1979, No. 22, 982.
https://doi.org/10.1039/c39790000982.
(296) Sasaki, Y.; Inoue, Y.; Hashimoto, H. Reaction of Carbon Dioxide with Butadiene
Catalysed by Palladium Complexes. Synthesis of 2-Ethylidenehept-5-En-4-Olide. J.
Chem. Soc., Chem. Commun. 1976, No. 15, 605. https://doi.org/10.1039/c39760000605.
(297) Takaya, J.; Iwasawa, N. Hydrocarboxylation of Allenes with CO2 Catalyzed by Silyl
Pincer-Type Palladium Complex. J. Am. Chem. Soc. 2008, 130 (46), 15254–15255.
https://doi.org/10.1021/ja806677w.
(298) Takaya, J.; Sasano, K.; Iwasawa, N. Efficient One-to-One Coupling of Easily Available
1,3-Dienes with Carbon Dioxide. Org. Lett. 2011, 13 (7), 1698–1701.
https://doi.org/10.1021/ol2002094.
(299) Takimoto, M.; Mori, M. Novel Catalytic CO2 Incorporation Reaction: Nickel-
Catalyzed Regio- and Stereoselective Ring-Closing Carboxylation of Bis-1,3-Dienes. J.
Am. Chem. Soc. 2002, 124 (34), 10008–10009. https://doi.org/10.1021/ja026620c.
(300) Nakano, R.; Ito, S.; Nozaki, K. Copolymerization of Carbon Dioxide and Butadiene via
a Lactone Intermediate. Nature Chem 2014, 6 (4), 325–331.
https://doi.org/10.1038/nchem.1882.
(301) Williams, C. M.; Johnson, J. B.; Rovis, T. Nickel-Catalyzed Reductive Carboxylation
of Styrenes Using CO2. J. Am. Chem. Soc. 2008, 130 (45), 14936–14937.
https://doi.org/10.1021/ja8062925.
(302) Shirakawa, E.; Ikeda, D.; Masui, S.; Yoshida, M.; Hayashi, T. Iron–Copper Cooperative
Catalysis in the Reactions of Alkyl Grignard Reagents: Exchange Reaction with Alkenes
References
187
and Carbometalation of Alkynes. J. Am. Chem. Soc. 2012, 134 (1), 272–279.
https://doi.org/10.1021/ja206745w.
(303) Greenhalgh, M. D.; Thomas, S. P. Iron-Catalyzed, Highly Regioselective Synthesis of
α-Aryl Carboxylic Acids from Styrene Derivatives and CO2. J. Am. Chem. Soc. 2012, 134
(29), 11900–11903. https://doi.org/10.1021/ja3045053.
(304) Ostapowicz, T. G.; Schmitz, M.; Krystof, M.; Klankermayer, J.; Leitner, W. Carbon
Dioxide as a C1 Building Block for the Formation of Carboxylic Acids by Formal
Catalytic Hydrocarboxylation. Angew. Chem. Int. Ed. 2013, 52 (46), 12119–12123.
https://doi.org/10.1002/anie.201304529.
(305) Wu, L.; Liu, Q.; Fleischer, I.; Jackstell, R.; Beller, M. Ruthenium-Catalysed
Alkoxycarbonylation of Alkenes with Carbon Dioxide. Nat Commun 2014, 5 (1), 3091.
https://doi.org/10.1038/ncomms4091.
(306) Bertleff, W.; Roeper, M.; Sava, X. Carbonylation. In Ullmann’s Encyclopedia of
Industrial Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA, Ed.; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, Germany, 2007; p a05_217.pub2.
https://doi.org/10.1002/14356007.a05_217.pub2.
(307) Bierhals, J. Carbon Monoxide. In Ullmann’s Encyclopedia of Industrial Chemistry;
Wiley-VCH Verlag GmbH & Co. KGaA, Ed.; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, Germany, 2001; p a05_203. https://doi.org/10.1002/14356007.a05_203.
(308) Franke, R.; Selent, D.; Börner, A. Applied Hydroformylation. Chem. Rev. 2012, 112
(11), 5675–5732. https://doi.org/10.1021/cr3001803.
(309) Tominaga, K.; Sasaki, Y.; Kawai, M.; Watanabe, T.; Saito, M. Ruthenium Complex
Catalysed Hydrogenation of Carbon Dioxide to Carbon Monoxide, Methanol and
Methane. J. Chem. Soc., Chem. Commun. 1993, No. 7, 629.
https://doi.org/10.1039/c39930000629.
(310) Tominaga, K.; Sasaki, Y. Ruthenium Complex-Catalyzed Hydroformylation of Alkenes
with Carbon Dioxide. Catalysis Communications 2000, 1 (1–4), 1–3.
https://doi.org/10.1016/S1566-7367(00)00006-6.
(311) Liu, Q.; Wu, L.; Fleischer, I.; Selent, D.; Franke, R.; Jackstell, R.; Beller, M.
Development of a Ruthenium/Phosphite Catalyst System for Domino Hydroformylation-
Reduction of Olefins with Carbon Dioxide. Chem. Eur. J. 2014, 20 (23), 6888–6894.
https://doi.org/10.1002/chem.201400358.
(312) Sekine, K.; Takayanagi, A.; Kikuchi, S.; Yamada, T. Silver-Catalyzed C–C Bond
Formation with Carbon Dioxide: Significant Synthesis of Dihydroisobenzofurans. Chem.
Commun. 2013, 49 (96), 11320. https://doi.org/10.1039/c3cc47221c.
(313) Kikuchi, S.; Sekine, K.; Ishida, T.; Yamada, T. C-C Bond Formation with Carbon
Dioxide Promoted by a Silver Catalyst. Angew. Chem. Int. Ed. 2012, 51 (28), 6989–6992.
https://doi.org/10.1002/anie.201201399.
(314) Vechorkin, O.; Hirt, N.; Hu, X. Carbon Dioxide as the C1 Source for Direct C−H
Functionalization of Aromatic Heterocycles. Org. Lett. 2010, 12 (15), 3567–3569.
https://doi.org/10.1021/ol101450u.
(315) Fenner, S.; Ackermann, L. C–H Carboxylation of Heteroarenes with Ambient CO2.
Green Chem. 2016, 18 (13), 3804–3807. https://doi.org/10.1039/C6GC00200E.
References
188
(316) Yoo, W.-J.; Capdevila, M. G.; Du, X.; Kobayashi, S. Base-Mediated Carboxylation of
Unprotected Indole Derivatives with Carbon Dioxide. Org. Lett. 2012, 14 (20), 5326–
5329. https://doi.org/10.1021/ol3025082.
(317) Banerjee, A.; Dick, G. R.; Yoshino, T.; Kanan, M. W. Carbon Dioxide Utilization via
Carbonate-Promoted C–H Carboxylation. Nature 2016, 531 (7593), 215–219.
https://doi.org/10.1038/nature17185.
(318) Boogaerts, I. I. F.; Fortman, G. C.; Furst, M. R. L.; Cazin, C. S. J.; Nolan, S. P.
Carboxylation of N-H/C-H Bonds Using N-Heterocyclic Carbene Copper(I) Complexes.
Angewandte Chemie International Edition 2010, 49 (46), 8674–8677.
https://doi.org/10.1002/anie.201004153.
(319) Gaillard, S.; Cazin, C. S. J.; Nolan, S. P. N-Heterocyclic Carbene Gold(I) and Copper(I)
Complexes in C–H Bond Activation. Acc. Chem. Res. 2012, 45 (6), 778–787.
https://doi.org/10.1021/ar200188f.
(320) Zhang, L.; Cheng, J.; Ohishi, T.; Hou, Z. Copper-Catalyzed Direct Carboxylation of C-
H Bonds with Carbon Dioxide. Angewandte Chemie International Edition 2010, 49 (46),
8670–8673. https://doi.org/10.1002/anie.201003995.
(321) Inomata, H.; Ogata, K.; Fukuzawa, S.; Hou, Z. Direct C–H Carboxylation with Carbon
Dioxide Using 1,2,3-Triazol-5-Ylidene Copper(I) Complexes. Org. Lett. 2012, 14 (15),
3986–3989. https://doi.org/10.1021/ol301760n.
(322) Boogaerts, I. I. F.; Nolan, S. P. Carboxylation of C−H Bonds Using N-Heterocyclic
Carbene Gold(I) Complexes. J. Am. Chem. Soc. 2010, 132 (26), 8858–8859.
https://doi.org/10.1021/ja103429q.
(323) Sugimoto, H.; Kawata, I.; Taniguchi, H.; Fujiwara, Y. Preliminary Communication.
Journal of Organometallic Chemistry 1984, 266 (3), c44–c46.
https://doi.org/10.1016/0022-328X(84)80150-3.
(324) Sasano, K.; Takaya, J.; Iwasawa, N. Palladium(II)-Catalyzed Direct Carboxylation of
Alkenyl C–H Bonds with CO2. J. Am. Chem. Soc. 2013, 135 (30), 10954–10957.
https://doi.org/10.1021/ja405503y.
(325) Mizuno, H.; Takaya, J.; Iwasawa, N. Rhodium(I)-Catalyzed Direct Carboxylation of
Arenes with CO2 via Chelation-Assisted C−H Bond Activation. J. Am. Chem. Soc. 2011,
133 (5), 1251–1253. https://doi.org/10.1021/ja109097z.
(326) Lejkowski, M. L.; Lindner, R.; Kageyama, T.; Bódizs, G. É.; Plessow, P. N.; Müller, I.
B.; Schäfer, A.; Rominger, F.; Hofmann, P.; Futter, C.; et al. The First Catalytic Synthesis
of an Acrylate from CO2 and an Alkene-A Rational Approach. Chem. Eur. J. 2012, 18
(44), 14017–14025. https://doi.org/10.1002/chem.201201757.
(327) Huguet, N.; Jevtovikj, I.; Gordillo, A.; Lejkowski, M. L.; Lindner, R.; Bru, M.;
Khalimon, A. Y.; Rominger, F.; Schunk, S. A.; Hofmann, P.; et al. Nickel-Catalyzed
Direct Carboxylation of Olefins with CO2: One-Pot Synthesis of α,β-Unsaturated
Carboxylic Acid Salts. Chem. Eur. J. 2014, 20 (51), 16858–16862.
https://doi.org/10.1002/chem.201405528.
(328) Stieber, S. C. E.; Huguet, N.; Kageyama, T.; Jevtovikj, I.; Ariyananda, P.; Gordillo, A.;
Schunk, S. A.; Rominger, F.; Hofmann, P.; Limbach, M. Acrylate Formation from CO2
and Ethylene: Catalysis with Palladium and Mechanistic Insight. Chem. Commun. 2015,
51 (54), 10907–10909. https://doi.org/10.1039/C5CC01932J.
References
189
(329) Manzini, S.; Cadu, A.; Schmidt, A.-C.; Huguet, N.; Trapp, O.; Paciello, R.; Schaub, T.
Enhanced Activity and Recyclability of Palladium Complexes in the Catalytic Synthesis
of Sodium Acrylate from Carbon Dioxide and Ethylene. ChemCatChem 2017, 9 (12),
2269–2274. https://doi.org/10.1002/cctc.201601150.
(330) Manzini, S.; Huguet, N.; Trapp, O.; Paciello, R. A.; Schaub, T. Synthesis of Acrylates
from Olefins and CO2 Using Sodium Alkoxides as Bases. Catalysis Today 2017, 281,
379–386. https://doi.org/10.1016/j.cattod.2016.03.025.
(331) Tsuda, T.; Ueda, K.; Saegusa, T. Carbon Dioxide Insertion into Organocopper and
Organosilver Compounds. J. Chem. Soc., Chem. Commun. 1974, No. 10, 380.
https://doi.org/10.1039/c39740000380.
(332) Tsuda, T.; Chujo, Y.; Saegusa, T. Reversible Carbon Dioxide Fixation by Organocopper
Complexes. J. Chem. Soc., Chem. Commun. 1975, No. 24, 963.
https://doi.org/10.1039/c39750000963.
(333) Fukue, Y.; Oi, S.; Inoue, Y. Direct Synthesis of Alkyl 2-Alkynoates from Alk-1-Ynes,
CO2, and Bromoalkanes Catalysed by Copper(I) or Silver(I) Salt. J. Chem. Soc., Chem.
Commun. 1994, No. 18, 2091. https://doi.org/10.1039/c39940002091.
(334) Zhang, W.-Z.; Li, W.-J.; Zhang, X.; Zhou, H.; Lu, X.-B. Cu(I)-Catalyzed Carboxylative
Coupling of Terminal Alkynes, Allylic Chlorides, and CO2. Org. Lett. 2010, 12 (21),
4748–4751. https://doi.org/10.1021/ol102172v.
(335) Gooßen, L. J.; Rodríguez, N.; Manjolinho, F.; Lange, P. P. Synthesis of Propiolic Acids
via Copper-Catalyzed Insertion of Carbon Dioxide into the C-H Bond of Terminal
Alkynes. Adv. Synth. Catal. 2010, 352 (17), 2913–2917.
https://doi.org/10.1002/adsc.201000564.
(336) Yu, D.; Zhang, Y. Copper- and Copper-N-Heterocyclic Carbene-Catalyzed C-H
Activating Carboxylation of Terminal Alkynes with CO2 at Ambient Conditions.
Proceedings of the National Academy of Sciences 2010, 107 (47), 20184–20189.
https://doi.org/10.1073/pnas.1010962107.
(337) Inamoto, K.; Asano, N.; Kobayashi, K.; Yonemoto, M.; Kondo, Y. A Copper-Based
Catalytic System for Carboxylation of Terminal Alkynes: Synthesis of Alkyl 2-
Alkynoates. Org. Biomol. Chem. 2012, 10 (8), 1514. https://doi.org/10.1039/c2ob06884b.
(338) Zhang, X.; Zhang, W.-Z.; Ren, X.; Zhang, L.-L.; Lu, X.-B. Ligand-Free Ag(I)-
Catalyzed Carboxylation of Terminal Alkynes with CO2. Org. Lett. 2011, 13 (9), 2402–
2405. https://doi.org/10.1021/ol200638z.
(339) Arndt, M.; Risto, E.; Krause, T.; Gooßen, L. J. C-H Carboxylation of Terminal Alkynes
Catalyzed by Low Loadings of Silver(I)/DMSO at Ambient CO2 Pressure. ChemCatChem
2012, 4 (4), 484–487. https://doi.org/10.1002/cctc.201200047.
(340) Yu, D.; Tan, M. X.; Zhang, Y. Carboxylation of Terminal Alkynes with Carbon Dioxide
Catalyzed by Poly(N-Heterocyclic Carbene)-Supported Silver Nanoparticles. Adv. Synth.
Catal. 2012, 354 (6), 969–974. https://doi.org/10.1002/adsc.201100934.
(341) Dingyi, Y.; Yugen, Z. The Direct Carboxylation of Terminal Alkynes with Carbon
Dioxide. Green Chemistry 2011, 13 (5), 1275. https://doi.org/10.1039/c0gc00819b.
References
190
(342) Peungjitton, P.; Sangvanich, P.; Pornpakakul, S.; Petsom, A.; Roengsumran, S. Sodium
Cardanol Sulfonate Surfactant from Cashew Nut Shell Liquid. Journal of Surfactants and
Detergents 2009, 12 (2), 85–89. https://doi.org/10.1007/s11743-008-1082-6.
(343) Wang, J.; Wang, Y. W.; Li, C. Q.; Li, J. Synthesis and Surface Activity of Biomass
Cardanol Sulfonate Surfactant. Advanced Materials Research 2011, 183–185, 1534–1538.
https://doi.org/10.4028/www.scientific.net/AMR.183-185.1534.
(344) Castro Dantas, T. N.; Vale, T. Y. F.; Dantas Neto, A. A.; Scatena Jr., H.; Moura, M. C.
P. A. Micellization Study and Adsorption Properties of an Ionic Surfactant Synthesized
from Hydrogenated Cardanol in Air–Water and in Air–Brine Interfaces. Colloid and
Polymer Science 2009, 287 (1), 81–87. https://doi.org/10.1007/s00396-008-1956-1.
(345) Faye, I.; Besse, V.; David, G.; Caillol, S. Sustainable Cardanol-Based Ionic Surfactants.
Green Materials 2017, 5 (3), 144–152. https://doi.org/10.1680/jgrma.17.00018.
(346) Wang, R.; Luo, Y.; Cheng, C.-J.; Huang, Q.-H.; Huang, H.-S.; Qin, S.-L.; Tu, Y.-M.
Syntheses of Cardanol-Based Cationic Surfactants and Their Use in Emulsion
Polymerisation. Chemical Papers 2016, 70 (9). https://doi.org/10.1515/chempap-2016-
0052.
(347) Verge, P.; Fouquet, T.; Barrère, C.; Toniazzo, V.; Ruch, D.; Bomfim, J. A. S.
Organomodification of Sepiolite Clay Using Bio-Sourced Surfactants: Compatibilization
and Dispersion into Epoxy Thermosets for Properties Enhancement. Composites Science
and Technology 2013, 79, 126–132. https://doi.org/10.1016/j.compscitech.2013.02.019.
(348) Yan, L.; Liu, X.-X.; Fu, Y. N-Alkylation of Amines with Phenols over Highly Active
Heterogeneous Palladium Hydride Catalysts. RSC Advances 2016, 6 (111), 109702–
109705. https://doi.org/10.1039/C6RA22383D.
(349) Cui, X.; Junge, K.; Beller, M. Palladium-Catalyzed Synthesis of Alkylated Amines from
Aryl Ethers or Phenols. ACS Catalysis 2016, 6 (11), 7834–7838.
https://doi.org/10.1021/acscatal.6b01687.
(350) Chen, Z.; Zeng, H.; Gong, H.; Wang, H.; Li, C.-J. Palladium-Catalyzed Reductive
Coupling of Phenols with Anilines and Amines: Efficient Conversion of Phenolic Lignin
Model Monomers and Analogues to Cyclohexylamines. Chem. Sci. 2015, 6 (7), 4174–
4178. https://doi.org/10.1039/C5SC00941C.
(351) Jumde, V. R.; Petricci, E.; Petrucci, C.; Santillo, N.; Taddei, M.; Vaccaro, L. Domino
Hydrogenation–Reductive Amination of Phenols, a Simple Process To Access Substituted
Cyclohexylamines. Organic Letters 2015, 17 (16), 3990–3993.
https://doi.org/10.1021/acs.orglett.5b01842.
(352) Welcome to www.sheldon.nl http://www.sheldon.nl/bi/EFactor.aspx (accessed Mar 22,
2018).
(353) Sheldon, R. A. Fundamentals of Green Chemistry: Efficiency in Reaction Design.
Chem. Soc. Rev. 2012, 41 (4), 1437–1451. https://doi.org/10.1039/C1CS15219J.
(354) GmbH, K. Determining the Surface Tension of Liquids by Measurements on Pendant
Drops. 5.
(355) Fu, Y.; Hong, S.; Li, D.; Liu, S. Novel Chemical Synthesis of Ginkgolic Acid (13:0)
and Evaluation of Its Tyrosinase Inhibitory Activity. Journal of Agricultural and Food
Chemistry 2013, 61 (22), 5347–5352. https://doi.org/10.1021/jf4012642.
References
191
(356) Choi, Y. H.; Choi, H.-K.; Peltenburg-Looman, A. M. G.; Lefeber, A. W. M.; Verpoorte,
R. Quantitative Analysis of Ginkgolic Acids FromGinkgo Leaves and Products Using1H-
NMR. Phytochemical Analysis 2004, 15 (5), 325–330. https://doi.org/10.1002/pca.786.
(357) Li, R.; Shen, Y.; Zhang, X.; Ma, M.; Chen, B.; van Beek, T. A. Efficient Purification of
Ginkgolic Acids from Ginkgo Biloba Leaves by Selective Adsorption on Fe 3 O 4 Magnetic
Nanoparticles. Journal of Natural Products 2014, 77 (3), 571–575.
https://doi.org/10.1021/np400821r.
(358) van Beek, T. A. Chemical Analysis of Ginkgo Biloba Leaves and Extracts. Journal of
Chromatography A 2002, 967 (1), 21–55. https://doi.org/10.1016/S0021-9673(02)00172-
3.
(359) Durrani, A. A.; Tyman, J. H. P. Long Chain Phenols. Part 15. Synthesis of 6-n-
Alkylsalicylic Acids (and Isomeric Acids) from Fluoroanisoles with Alkyl-Lithium. J.
Chem. Soc., Perkin Trans. 1 1979, 0 (0), 2079–2087.
https://doi.org/10.1039/P19790002079.
(360) Fürstner, A.; Seidel, G. Shortcut Syntheses of Naturally Occurring 5-Alkylresorcinols
with DNA-Cleaving Properties. The Journal of Organic Chemistry 1997, 62 (8), 2332–
2336. https://doi.org/10.1021/jo962423i.
(361) Drouin, S. D.; Zamanian, F.; Fogg, D. E. Multiple Tandem Catalysis: Facile Cycling
between Hydrogenation and Metathesis Chemistry. Organometallics 2001, 20 (26), 5495–
5497. https://doi.org/10.1021/om010747d.
(362) Manjolinho, F.; Arndt, M.; Gooßen, K.; Gooßen, L. J. Catalytic C–H Carboxylation of
Terminal Alkynes with Carbon Dioxide. ACS Catalysis 2012, 2 (9), 2014–2021.
https://doi.org/10.1021/cs300448v.
(363) Wendling, T.; Risto, E.; Krause, T.; Gooßen, L. J. Salt-Free Strategy for the Insertion
of CO 2 into C−H Bonds: Catalytic Hydroxymethylation of Alkynes. Chemistry - A
European Journal 2018, 24 (23), 6019–6024. https://doi.org/10.1002/chem.201800526.
(364) Streitwieser, A.; Reuben, D. M. E. Acidity of Hydrocarbons. XXXV. Equilibrium
Acidities of Phenylacetylene and Tert-Butylacetylene in Cyclohexylamine. Journal of the
American Chemical Society 1971, 93 (7), 1794–1795.
https://doi.org/10.1021/ja00736a045.
(365) Wendling, Timo. Stoffliche Nutzung von Kohlenstoffdioxid Als C1-Baustein Und
Einsatz von Wasserstoff Als Umweltfreundliches Reduktionsmittel Für Carbonsäuren,
Technische Universität Kaiserslautern, 2018.
(366) Risto, Eugen. Entwicklung Effizienter Katalysatorsysteme C-H-Carboxylierung von
Acetylen Mit CO2 Und Anschließender Hydrierung Der Propiolsäure: Ein
Klimafreundlicher Zugang Zu C4-Grundchemikalien, Technische Universität
Kaiserlsautern, 2016.
(367) Krause, Thilo. Nachhaltige Synthese und Derivatisierung von Carbonsäuren,
Technische Universität Kaiserslautern, 2018.
(368) Pouilloux, Y. Selective Hydrogenation of Methyl Oleate into Unsaturated Alcohols
Relationships between Catalytic Properties and Composition of Cobalt–Tin Catalysts.
Catalysis Today 2000, 63 (1), 87–100. https://doi.org/10.1016/S0920-5861(00)00448-X.
References
192
(369) Barve, P. P.; Kamble, S. P.; Joshi, J. B.; Gupte, M. Y.; Kulkarni, B. D. Preparation of
Pure Methyl Esters from Corresponding Alkali Metal Salts of Carboxylic Acids Using
Carbon Dioxide and Methanol. Industrial & Engineering Chemistry Research 2012, 51
(4), 1498–1505. https://doi.org/10.1021/ie200632v.
(370) Barve, P. P.; Kulkarni, B. D.; Gupte, M. Y.; Nene, S. N.; Shinde, R. W. Process for
Preparation of Pure Alkyl Esters from Alkali Metal Salt of Carboxylic Acid.
US20120296110A1, November 22, 2012.
(371) Exner Benjamin. Emissionsvermeidung Und Chemische Nutzung Klimaschädlicher
Verbindungen, Ruhr-Universität Bochum, 2019.
(372) Goossen, L. J.; Risto, E.; Wendling, T. Verfahren Zur Herstellung von 1,4-Butandiol
Aus Acetylen Und Kohlenstoffdioxid. DE102017214043A1, February 22, 2018.
(373) Kuriyama, W.; Matsumoto, T.; Ogata, O.; Ino, Y.; Aoki, K.; Tanaka, S.; Ishida, K.;
Kobayashi, T.; Sayo, N.; Saito, T. Catalytic Hydrogenation of Esters. Development of an
Efficient Catalyst and Processes for Synthesising ( R )-1,2-Propanediol and 2-( l -
Menthoxy)Ethanol. Organic Process Research & Development 2012, 16 (1), 166–171.
https://doi.org/10.1021/op200234j.
(374) Mcdowell, R. W.; Stewart, I. Peak Assignments for Phosphorus-31 Nuclear Magnetic
Resonance Spectroscopy in PH Range 5–13 and Their Application in Environmental
Samples. Chemistry and Ecology 2005, 21 (4), 211–226.
https://doi.org/10.1080/02757540500211590.
(375) Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chemicals, 5th ed.;
Butterworth-Heinemann: Amsterdam ; Boston, 2003.
(376) Zehnter, R.; Gerlach, H. Synthesis of anacardic acids. Liebigs Annalen 1995, 1995 (12),
2209–2220. https://doi.org/10.1002/jlac.1995199512307.
(377) AIST:Spectral Database for Organic Compounds,SDBS
https://sdbs.db.aist.go.jp/sdbs/cgi-bin/direct_frame_top.cgi (accessed Jul 29, 2019).
(378) Lide, D. R.; Baysinger, G.; Chemistry, S.; Berger, L. I.; Goldberg, R. N.; Kehiaian, H.
V. CRC Handbook of Chemistry and Physics. 2661.
(379) arkajitmandal. Van Der Waals Equation Calculator
http://calistry.org/calculate/vanDerWaalsCalculator (accessed Jul 29, 2019).
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