connecting repositories · promoters prof. dr. ir. christian stevens department of sustainable...
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Promoters
Prof. Dr. ir. Christian Stevens
Department of Sustainable Organic
Chemistry and Technology,
Faculty of Bioscience Engineering,
Ghent University
Prof. Dr. ir. Geraldine Heynderickx
Laboratory for Chemical Technology,
Faculty of Engineering and
Architecture,
Ghent University
Chairman of the jury
Secretary of the jury
Prof. Dr. ir. Filip Tack
Laboratory of Analytical Chemistry
and Applied Ecochemistry,
Faculty of Bioscience Engineering,
Ghent University
Prof. Dr. ir. Wim Soetaert
Centre of Expertise for Industrial
Biotechnology and Biocatalysis,
Faculty of Bioscience Engineering,
Ghent University
Members of the jury
Prof. Dr. Timothy Noël
Micro Flow Chemistry and Process
Technology,
Eindhoven University of Technology,
The Netherlands
Dr. Bert Metten
Ajinomoto OmniChem,
Wetteren
Prof. Dr. ir. Kevin Van Geem
Laboratory for Chemical Technology,
Faculty of Engineering and
Architecture,
Ghent University
Em. Prof. Roland Verhé
Department of Sustainable Organic
Chemistry and Technology,
Faculty of Bioscience Engineering,
Ghent University
Dean of the Faculty
Rector of the University
Prof. Dr. ir. Guido Van Huylenbroeck Prof. Dr. Paul Van Cauwenberge
Ana Ćukalović
Use of microreactor technology and
renewable resources to develop green
chemical processes
Thesis submitted in fulfilment of the requirements for the degree of Doctor
(Ph.D.) in Applied Biological Sciences: Chemistry
Nederlandstalige titel: “Het gebruik van microreactor technologie en
hernieuwbare energiebronnen om groene chemische processen te
ontwikkelen”
Please cite as: Cukalovic, A. “Use of microreactor technology and
renewable resources to develop green chemical processes”, Ph.D. dissertation,
Ghent University, 2012.
This research was funded by the Long Term Structural Methusalem
Funding by the Flemish Government (M2dcR2).
The author and the promoters give the authorisation to consult and to
copy parts of this work for personal use only. Every other use is subject to
copyright laws. Permission to reproduce any material contained in this work
should be obtained from the author.
Author
Ana Ćukalović
Promoters
Prof Dr. ir. Christian Stevens
Prof. Dr. ir Geraldine Heynderickx
ISBN number: 978-90-5989-581-2
Printed by University Press, Zelzate
i
Acknowledgments
At the end of this work and the beginning of this book, I would first like to
thank professor Stevens for the chance to do this research and for the guidance
throughout these years. You are a great person, always positive and with a lot
of understanding for an enormous array of personal and professional
exigencies that a person can go through, and an excellent guide through the
academic world. I am certain that the jolly atmosphere at the department is
like that very much thanks to you. And I can only admire the way you
handled my straightforwardness and my temperament in a couple situations
(and kept the budget of the department safe).
Professor Heynderickx, dear Geraldine, you joined at just the right
moment to give a positive injection my PhD needed. You were always
available, and your door was always open for discussions over work or for
pep talks. Talking to you always had the feel of talking to a good friend
instead to a boss.
I would like to thank the members of my jury for reading this manuscript
and for sharing their useful suggestions and opinions. It was a real honour for
me to interact with such a fine selection of experts. Special gratitude I owe to
professor Verhé, who first made it possible to come to Ghent via a Tempus
project. Professor, I admire so much your versatility, your energy, your visions
and ideas; you make everything seem possible and are a source of great
inspiration.
I would, of course, like to thank all the nice colleagues, especially the
neighbours from the lab and from the office. You made the days at the
“boerekot” something to remember, and I hope we’ll stay in touch.
My friends, my mental floss, my connection to real life, I would not make
it without you. Living in this beautiful and exciting city I would not change for
any other life anywhere else; and you are the most important part of it. Thanks
for all the great talks, for all the great music that we share, for all the laughter
and all the fun.
ii
Mama i tata, znam da nije uvek bilo lako sa mnom, ali se nadam da bar
delimično razumete moju potrebu da živim onako kako hoću, a ne kako
”treba”... Miki, ti si moje sunce, zbog tebe sam bolji čovek nego što bih možda
bila, i na tome ti hvala.
Mijn schoonfamilie moet ik bedanken vooral voor de mooie tijden dat we
altijd met elkaar boorbrengen. Jullie zijn echt een superfamilie, vol met liefde
en steun voor elkaar, en vooral beste vrienden van elkaar... de Pet Shop boys.
Bert, baby, je hebt me zo veel gegeven, en van het meeste wist ik zelfs niet
dat ik het nodig had. Je bent een ongelooflijke man, zo vol met liefde, begrip
en geduld dat ik me snel en vaak ontwapend voel . Ik hoop dat ik nu kan
beginnen om beetje bij beetje terug te geven van wat je al die jaren, en vooral
de laatste maanden, gaf. ‘k Zie u gere.
Ana Ćukalović
Gentbrugge, 3.12.2012.
iii
Table of contents
List of abbreviations vi
1. Introduction 1
1.1. The concept of sustainability 1
1.2. Green chemistry 2
1.2.1. Renewable chemicals 5
1.2.2. Solid catalysts/biocatalysis 9
1.2.3. Organic solvents 10
1.2.4. Process intensification (PI) by the use of microreactor technology 14
1.3. Biofuels 17
1.4. Application of green chemistry principles in this work 18
2. Production and reductive amination of bio-based HMF 23
2.1. Introduction 23
2.1.1. HMF production 24
2.1.2. HMF derivatives 30
2.2. Results and discussion 33
2.2.1. HMF production from inulin 33
2.2.2. Production of HMF derivatives by reductive amination 40
2.3. Experimental part 47
2.3.1. Production of HMF 48
2.3.2. Reductive amination of HMF 49
2.4. Conclusions 55
3. The application of microreaction technology on the Kiliani reaction on ketoses 57
3.1. Introduction 57
3.1.1. Kiliani reaction 59
3.2. Results and discussion 61
3.2.1. Reaction setup 61
3.2.2. Experiments on dihydroxyacetone using alkaline cyanides as CN- source 68
iv
3.2.3. Experiments on erythrulose using alkaline cyanides as CN- source 68
3.2.4. Reactions under increased pressure 70
3.2.5. Acetone cyanohydrin as cyanide source 71
3.2.6. Experiments on D-fructose 73
3.3. Experimental part 74
3.3.1. General 74
3.3.2. Flow reactors 74
3.3.3. Example run with DHA (with an alkaline cyanide salt and acetic acid) 75
3.3.4. Example run with L-erythrulose (with dihydroxyacetone and the addition of
base) 75
3.4. Conclusions 76
4. Application of microreactor technology for amino acid coupling via α-
aminoacylbenzotriazoles 77
4.1. Introduction 77
4.2. Results and discussion 80
4.2.1. Production of starting materials, N-protected α-aminoacylbenzotriazoles 80
4.2.2. Production of α-aminoacylamino substituted heterocycles 81
4.3. Experimental part 86
4.3.1. Production of starting materials, N-protected α-aminoacylbenzotriazoles 87
4.3.2. Production of N-protected--aminoacyl)amino heterocycles 89
4.4. Conclusions 90
5. Optimization and scale-up of biodiesel production from crude palm oil and
effective use in developing countries 91
5.1. Introduction 91
5.1.1. Biodiesel as a transport fuel 94
5.1.2. Palm oil as biodiesel feedstock 99
5.2. Results and discussion 103
5.2.1. Use of potassium hydroxide as basic catalyst 104
5.2.2. Use of potassium methoxide as basic catalyst 109
v
5.2.3. Acid-catalysed esterification followed by base-catalysed transesterification112
5.2.4. One-step approach – transesterification 114
5.2.5. Scale-up to one ton 115
5.3. Experimental part 119
5.3.1. Reaction setup – lab scale 120
5.3.2. Reaction setup – pilot scale 122
5.4. Conclusions 122
6. Summary 125
7. Samenvatting 131
References 136
Curriculum vitae 154
vi
List of abbreviations
[BMIM]Cl – 1-bytyl-3-methylimidazolium chloride
[HMIM]Cl – 1-methylimidazolium chloride
[TMP]MS – 1,2,4-trimethylpyrazolium methylsulphate
2,5-DMF – 2,5-dimethylfuran
2-MeTHF – 2-methyltetrahydrofuran
AIChE/CWRT – American Institute of Chemical Engineers’ Center for
Waste Reduction Technologies
AOCS – American Oil Chemists’ Society
BHF – 2,5-bis(hydroxymethyl)furan
BrMF – 5-(bromomethyl)furfural
Bt – benzotriazole
BtH – 1H-benzotriazole
CCS – carbon capture and storage
CE – carbon efficiency
CLP – classification, labelling and packaging of chemicals
CMF – 5-(chloromethyl)furfural
CMR – carcinogen, mutagen, reprotoxic
CPME – cyclopentyl methyl ether
CPO – crude palm oil
DCM – dichloromethane
DFF – 2,5-diformylfuran
DG – diglycerols
DMF – dimethylformamide
ECB – European Chemicals Bureau
EINECS – European Inventory of Existing Commercial Chemical
Substances
EMY – effective mass yield
ETBE – ethyl tert-butyl ester
FAME – fatty acids methyl esters
FDCA – 2,5-furandicarboxylic acid
FFA – free fatty acids
FG – free glycerol
GC – gas chromatography
GHG – greenhouse gases
HMF – (5-hydroxymethyl)-2-furfural
IL – ionic liquid
IR – infrared
vii
ISC – inherently safe chemical
LCA – life cycle analysis
LC-MS – liquid chromatography-mass spectrometry
MG – monoglycerols
mp – melting point
mGlu2 – metabotropic glutamate receptor
NMR – nuclear magnetic resonance
NREL – The National Renewable Energy Laboratory
OECD – Organisation for Economic Cooperation and Development
OMBF – 5,5’-oxydimethylene-bis-(2-furfural)
p – pressure
PBT– persistent, accumulative, biotoxic
PI – process intensification
PLA – polylactic acid
PMI – process mass intensity
POP – persistent prganic pollutants
ppm – parts per million
PTFE – polytetrafluoroethylene, Teflon
Py – pyridine
QSAR – quantitative structure-activity relationship
RBD PO – refined, bleached, deodorized palm oil
REACh – registration, evaluation, authorisation (and restriction) of
chemicals
RME – reaction mass efficiency
TCA – total cost assessment
TG – triglycerols
TLC – thin layer chromatography
TMS – tetramethylsilane
VOC – volatile organic compound
vPvB – very persistent, very biotoxic
“In de jaren '60 had men ons voorgespiegeld dat de bomen tot in de hemel zouden
groeien. Niet dus.”
Ludo Mariman
“I can go with the flow.”
Joshua Homme
1
1. Introduction
1.1. The concept of sustainability
One of the manners to define sustainability is the performance of the
actions in a way that will not irreversibly change the environment. In the
United Nations’ World Commission on Environment and Development
report, “Our Common Future” (Brundtland report) from 1987, one of the first
action plans for sustainable development were defined.1 This strategy is being
continuously followed and evaluated, and several other important action
plans and reports, on global and regional levels, followed this report.2–9
Sustainability as a global term comprises social responsibility,
environmental protection and (the so-called PPP-criteria: people, planet,
profit). A special section of the proposed action plans is dedicated to the
sustainability of chemicals.10 The transition from the traditional to the more
sustainable practices in the business models of chemical companies is
encouraged.11,12 Chemical companies are actively improving sustainability of
their actions: BASF has, for example, developed analysis systems linked to
their chemical processes: Seebalance® and eco-efficiency analysis.13,14
Governmental support, legislative and guidelines are very important in the
shift to sustainable practices. In the US, the Biomass R&D Technical Advisory
Committee15 advised in their 2002 roadmap16 that by the year 2030, bio-based
organic carbon-based products will make up 25 % of the market, 20 % of the
transportation fuels market and 10 % of the total energy needs. An update of
this roadmap in 2007 contained promising results in the renewable fuels
section; the total volume of bio-power, however, is likely not to meet these
goals. Additionally, the actual volume of the bio-based products is difficult to
estimate, because of the lack of systematic publicly available data on the
subject.17
The trend of sustainability is illustrated by the constantly growing number
of research articles, patents, books, new journals and conferences. This is
Chapter 1
2
followed by a prompt media attention, influencing the consciousness of the
average consumer. Promotion and clustering are important parts of bringing
the sustainable processes closer to society. A European Technology Platform
SusChem was created to bring together academia and industry and is
supported by the European Commission.18
1.2. Green chemistry
The difference between the terms “sustainability” and “greenness” is
rather important in the chemical field. While the term “green” focuses on the
characteristics of the substance such as its harmlessness and renewability, the
sustainability criterion will also involve the ease and the cost of obtaining and
manipulating the substance (Figure 1). A target for the definition of a “green”
chemical substance can be a concept of inherently safe chemicals and
processes, which will not cause damage to human health or the environment
under any circumstances, even in case of accidents.
Figure 1: The simplified relation between green and sustainable practices in
chemistry
The term “green chemistry” was introduced by Paul Anastas.19 Green
chemistry is basically the design of chemical processes and products in which
the use and generation of hazardous substances are eliminated, the waste
production and energy requirements are reduced, and the use of inherently
safe and easily available materials (renewable resources) is encouraged (Figure
2).20 This is accompanied by process intensification (PI): optimisation of a
People Profit
Green practices
Planet
Sustainable practices
Introduction
3
chemical process is often possible by the modification of the existing
equipment and physical conditions of a reaction.11
Chemistry is from its beginnings traditionally sustainable and green: the
old chemists worked mainly with materials found in nature. With the boom of
the petrochemical industry, especially in the second half of the 20th century,
the chemical industry experienced an immense development, using
petrochemical, non-renewable resources. Massive production and use of
chemicals, along with the overall massive industrialization has led to a series
of questions regarding the environmental and toxicological impact of these
products. This resulted in a new trend: two decades ago, the environmental
and toxicological concerns began to enter the state policies. On the EU level,
following the demands defined in the “White Paper” issued by the European
Commission,21–23 the REACh regulation came into force in 2007.24,i The
regulation aims at systematizing the data on existing and new substances,
with special attention on chemicals’ safety by identifying their intrinsic
properties. The REACh regulation is complemented by the CLP/GHS
regulations (Globally Harmonised System of Classification and Labelling of
Chemicals.25
The production and use of chemicals in a way that minimizes the effects on
human health and the environment is achieved by risk assessment and risk
management techniques. Risk is defined as the product of hazard and
exposure.
Risk = Hazard x Exposure
A traditional approach to minimize the risk in processes is the reduction of
the exposure. On the contrary, the green chemistry principles are formulated
to avoid hazard by developing intrinsically safe processes, as a more efficient
concept. This concept involves the use of smaller quantities of materials
recognised as hazardous, the replacement of hazardous materials by
i REACh stands for registration, evaluation and authorisation (and substitution / restriction) of
chemicals.
Chapter 1
4
7. use of renewable materials
8. avoidance of unneccessary
derivatisation
9. using of catalystic instead of
stoichiometric reagents
10. biodegradability
11. in-line, real-time monitoring of
processes
12. minimization of potential for accidents
atom economy
safety
energy efficiency
waste minimization
alternative materials, and the use of alternative reaction routes or process
conditions.
Figure 2: 12 Principles of green chemistry can be simplified to four basic
guidelines
“The ideal synthesis,” described by Clark,10 has the following
characteristics: it is environmentally acceptable, safe, performed in one step,
using available reagents, with 100 % yield. Increasing reaction efficiency by
increasing its selectivity was proposed by Trost already in 1983.26 As a manner
of quantifying the “greenness” of a chemical process, he introduced the term
“atom economy”.27,28
Atom economy = (Mw desired product/ Mw of all products) × 100 %
The information on atom economy can be very valuable for the estimation
of the overall process applicability. “Atom efficiency” or “atom utilisation”29
1. prevention of waste instead of clean
up
2. maximise the incorporation of
starting materials in the final product
3. the use and the generation of
materials with little or no toxicity
4. preservation of efficiacy while
reducing toxicity
5. reducing the use of auxiliary materials
(solvents etc.)
6. minimization of energy requirements
Introduction
5
are equally valuable concepts, based on the ratio between the “input” and
“output” of a chemical reaction.
Another simple and efficient manner for this quantification is the
Environmental (E) factor, introduced by Sheldon.29–32 The E factor defines the
usefulness of a process by comparing the quantities of raw materials with the
actual product and the produced waste.
E = [mass raw materials - mass product]/[mass product]
or E = mass waste/mass product
A higher E factor is associated with more waste and a stronger negative
impact to the environment. Typically, processes of production of fine
chemicals and pharmaceuticals are associated with higher E factors, due to the
usually applied multistep syntheses and the use of stoichiometric reagents. On
the other hand, since these materials are produced on a smaller scale than bulk
chemicals, the total waste quantity is smaller as well.
Some alternative metrics for the quantification of the environmental
impact of the processes include process mass intensity (PMI),33,34 carbon
efficiency (CE) and reaction mass efficiency (RME),11,33 and effective mass yield
(EMY).35
To be able to completely evaluate the sustainability of a chemical process,
it is necessary to involve the LCA (life-cycle analysis) calculations, the TCA
(total cost assessment) methodology,11 as well as the whole socio-economic
influence of this process;36 this extensive analysis is rather difficult to perform
for a single process, from the point of view of a chemist.
Several aspects of green chemistry principles in practice are explored in
more detail further in the text.
1.2.1. Renewable chemicals
Bio-based chemicals are traditionally used as starting materials for the
conversions. Namely, the first chemists were bound to use the materials from
nature, simply because of their availability. With the development of the
Chapter 1
6
petrochemical industry in the 19th and 20th century, and especially from the
1950s on, chemical processes based on petrochemical based hydrocarbons
became dominant.37 Research in the bio-based area did not diminish, but it was
not the focus of a prevailing number of research groups. In the actual trend of
redefining chemistry by making it “greener”, we are witnessing the
“renaissance” of bio-based materials as starting feeds for chemical processes.
On top of the environmental issues in the frame of sustainability of
processes, another major reason for the increased interest in bio-based
chemicals is the simple fact that the petrochemical sources on Earth are
diminishing. The physical end of the supplies is accompanied by the
economical hurdles surrounding the availability of the sources. These are
mostly concerning the energy sources, as only about 5 % of the total volume of
the petrochemical sources are used for the production of chemicals. Even so,
the benefits of the introduction of bio-based chemicals are unquestionable.
Gross energy requirements (GER) are much higher for petrochemicals than for
bio-based chemicals;ii 38 even base petrochemicals, such as ethylene, have a
higher GER value than their counterpart basic bio-based resources. Intensive
research is being continuously performed in order to replace the
petrochemical sources with renewable ones where possible. Evaluation of the
methods is needed to make technological processes for these transformations
more economically acceptable.
A fine example of the application principles of sustainability in chemical
production is the biorefinery concept (Figure 3). It is seen as an alternative to
the petrochemical refinery – production of energy and materials from biomass
instead of fossil sources. According to Kamm and Kamm,39 a green biorefinery
is defined as a “fully integrated system of sustainable, environment - and
resource-friendly technologies for the comprehensive utilization and
exploitation of biological raw materials in the form of green and residue
biomass from targeted sustainable regional land utilization.”
ii GER indicates the total consumption of the primary energy used to deliver a certain product.
Introduction
7
Figure 3: Strategies of biomass conversion process.37
Carbohydrates represent the most abundant biomaterial on Earth – about
75 % of all plant material on Earth is of lignocellulosic composit ion. Simple
carbohydrates are the most favourable substrates for further processing.
However, simple sugars are rarely present in vast biomass and thus need to be
obtained by pre-treatment procedures from polysaccharide plant mass.12
The US Department of Energy, National Renewable Energy Laboratory
(DOE – NREL) report, compiled by Werpy and Petersen in 2004, singled out
the “top twelve” chemicals (or chemical groups) produced from carbohydrate
biomass with high industrial potential for further conversions.40 The materials
included glycerol37,40–45 and several other carbohydrate-based alcohols,42 four
carbon 1,4-diacids,46–49 3-hydroxypropanoic acid50,51 and several other
polyhydroxyacids, and furan dicarboxylic acid (FDCA).52–54 These molecules
are either obtained or potentially obtained from carbohydrate sources via
simple and economically acceptable chemical or biochemical routes, and were
estimated to have either an actual or a highly potential wide extent of use for
further conversions. This report was followed by its second part, focusing on
products potentially obtained from lignin.55 Subsequently, an update of the
initial list was published in 2010;42 some substances were here omitted, as the
amount of research on the subject and the production volumes did not justify
Biomass conversion
1.Platform molecules
conversion 2. Pool of molecules 3. Functional polymers
Chemicals: intermediates,
specialties, fine chemicals
Functional products: surfactants, lubricants,
foams, binders, plasticizers, etc.
Bio-catalytic
processes
Chemo-catalytic
processes
Chemical modification
of polymers
Chemo-catalytic
processes
Chapter 1
8
the expectations from 2004 (glutamic and glucaric acid, for example). On the
other hand, some new substances were included in the list, either because the
initial estimation of low potential for further conversions was found to be
incorrect (such as ethanol), or because the research on the chemical gave new
insights and possibilities for the improved routes of production and use (such
as furfural and 5-(hydroxymethyl)furfural, HMF).
There are several interesting examples of the actual use of nature-based
chemicals. Furfural was, for example, used as the original feedstock for the
production of Nylon 6.6 – the low prices of petrochemical feedstocks have
stopped this production route in the 1950s.39 Some interesting industrial
applications for HMF, furfural, levulinic acid, sorbitol and isosorbide, succinic
acid, lactic acid and triglycerides include their conversion to lubricants,
plasticizers or polymers.37,56–62 Classical examples of the use of renewable
chemicals include surfactants (emulgators) based on sorbitan (TWEEN,
SPAN), rhamno- and sophorolipids, biosurfactants produced on an industrial
scale by fermentations,63 and alkyl polyglucosides.64 Glycerol is, in simple
processes, converted not only to acrolein,65 an industrially extremely
important monomer, but also to epichlorohydrin,66,67 1,2- and 1,3-propanediol
(PDO).12,41 PDO is produced on a larger scale from glucose by industrial
fermentations68,69 and used as a starting material for Sorona® fibre –
poly(trimethylene terephthalate).40,70 Other diols are interesting platform
chemicals as well.71
Bio-based polylactic acid (PLA) is produced from bio-based lactic acid72,73
and successfully used for various kinds of packaging74,75 or in medicine.76
Lipids and lipid constituents are used as starting materials for biofuels and for
various types of polymers. Various lipids used in the cosmetic or food
industry are produced via biotechnological routes.77 Fatty acid derivatives are
often met in adhesives, surfactants, lubricants, paint dryers. Base chemicals
from fats and oils include propylene oxide (polyesters, glycol esters, higher
propylene glycols), acrylic acid, and linear diacids such as adipic acid.38
Middle to long-chain (6-20 C atoms) linear natural diacids are useful as
monomers for the production of polyesters, polyamides and polyuretanes.38
Biohydrocarbons can be produced by fermentations from biological
resources.42
Introduction
9
Generally speaking, the main hurdles in the actual use of the renewable
chemicals are the low selectivities and yields of the processes, interconnected
to purification problems, leading to the small production volumes and high
price of these chemicals in comparison to the petrochemically derived ones. In
some cases, the new technologies demand high investments; accordingly, the
transition from the petrochemical to the renewable resources will be directly
linked to the available resources, and in today’s context of high consumerism
and the recent economic crisis, governmental support is crucial in bridging the
gap between existing and novel technologies.
1.2.2. Solid catalysts/biocatalysis
By the efficient use of catalysts, it is possible to reach the desired product
in a much more elegant way with much less starting materials.28,78,79 Some
relevant examples include the ibuprofen production in a three-step instead of
the original six-step procedure,80 or the application of the Barbier reaction for
the production of alcohols from carbonyls and alkylhalides, as opposite to the
Grignard procedure,81 both resulting in massive reduction of waste.
Extensive research into the solid (heterogeneous) catalytic processes
instead of the use of stoichiometric reagents has led to the introduction of
numerous new catalysts. Some of the revolutionary new catalysts are made
from renewable resources. Starbons® are mesoporous catalysts made from
starch or other polysaccharide-based materials, in a procedure that involves a
minimum of chemicals – water and a catalytic amount of acid – under
determined temperature and pressure conditions. By variation of the active
sites, catalytic properties can be tuned for versatile applications; the catalysts
are reusable and environmentally friendly.82,83
Other types of solid, relatively innocuous catalysts include resins or
zeolites. Resins are made of synthetic polymers (for example, polystyrene or
its copolymers), carrying active sites. They are used in the form of beads with
various surface areas and pore sizes, and are characterised by the number of
active sites. These resins can be regenerated by simple washing, and
subsequently reused, which contributes to the reduction of waste.84–89
Chapter 1
10
Zeolites are crystalline silicates and aluminosilicates linked through
oxygen atoms, producing a three-dimensional network in the solid material
containing channels and cavities of molecular dimensions. They are found in
nature or synthesised in a laboratory environment. Their catalytic properties
can be modulated by incorporation of various active sites, control of pore size
and other manipulations.84,90–93
Biocatalysis – the use of the active principles from microorganisms,
enzymes – is above all characterised by high regio- and enantiomeric
selectivity and environmental friendliness. The downside of these processes is
their high cost. However, if the initial hurdles are bypassed and the process is
scaled up to an industrial level, the gain is high as the final products are
valuable. There are currently over a hundred enzymatic processes applied on
industrial scale and leading to industrially valuable materials.94–98 The largest
scale process (close to 15∙106 t/year99) is the formation of fructose from glucose,
catalysed by glucose isomerase, used in food industry. Some other interesting
examples of important chemicals produced on large scale include 1,3 -
propanediol,41 acrylamide, aspartic acid,94 chiral carboxylic acids and amines,94
vanillin,100–102 or amino acids.94,103 Enzymatic catalysis is especially convenient
for the synthesis of pharmaceuticals, for example 11α-hydroxyprogesterone32
or 6-aminopenicillanic acid (6-APA), a key raw material for penicillin and
cephalosporin antibiotics.104
1.2.3. Organic solvents
Much attention has been given to the role of organic solvents in chemical
processes. Organic solvents are extensively used in numerous industrial and
non-industrial applications. In the classical chemical synthesis, solvents are
extensively used as reaction media, to facilitate the mass transfer, i.e. enhance
reaction rate, yield, selectivity etc. Furthermore, solvents are used as
extraction, wash and dispersion media, and as “auxiliary” agents ( i.e. for
cleaning purposes).28 Their widespread use results in considerable spills, via
either evaporation or release to the environment. In the huge majority of cases,
this has detrimental consequences to the living world and to the planet.
Avoiding solvents completely would be a simple manner to circumvent
Introduction
11
problems related to the use of solvents; however, this is very often impossible,
and solventless reaction routes are mostly associated with microwave
synthesis. An interesting redefinition of a solvent in terms of green chemistry
stipulates that the ideal solvent will still facilitate the mass transfer but will not
dissolve.28 An ideal solvent has to be non-toxic and non-hazardous – non-
flammable and non-corrosive.105 These demands are incorporated in the
various guidelines and legislations.106–108 For example, the use of toxic solvents
such as benzene or carbon tetrachloride is strongly discouraged or even
banned.
Various manners of knowledge systematisation on solvent toxicity are
used to facilitate and enhance the choice of a proper solvent. Various
methodologies and software applications systematise solvent properties by
various parameters and suggest some “greener” substitutes.109–112 Chemical
companies follow the legislation and the trends in more sustainable
processing. Pfizer has, for example, developed a solvent selection guide for
medicinal chemistry.113 Solvents are divided in three groups of acceptability,
on account of their safety with regards to human health and to the process,
and to the environmental and regulatory considerations. Some preferred
solvents include water, ethanol and other short chain alcohol, ethyl acetate
etc.; usable solvents are, for example, cyclohexane, tetrahydrofurane or
dimethylsulfoxide. Solvents such as chlorinated solvents, ether or hexanes are
labelled as undesirable.113 Alternatively, at GSK, the total number of solvents is
reduced by developing a concept of “best-of-class” solvents: replacing of one
solvent by another one, with similar properties; additionally, the replacement
solvent will ideally be suitable for several types of reactions.11
Generally speaking, a transition from halogenated solvents to water,
alcohols or, in some cases, ethers is encouraged.105 Water, as the omnipresent
liquid on Earth, can be used as a chemical solvent, sometimes, surprisingly, in
processes that traditionally label water as undesirable.114–125 A concept of
performing reactions “on water”, i.e. using water as dispersing, and not
dissolving medium, a medium that carries hydrophobic molecules of starting
materials and products, is proven to be successful in a number of
applications.126–129 A critical point of using water as solvent is the complicated
and energy demanding purification of waste streams. Ethanol is an
Chapter 1
12
inexpensive, natural and biodegradable product. It is produced by
fermentation processes from carbohydrate containing materials, in high yields
and using economically accepted procedures. Its mass production is linked to
the use of bioethanol as fuel.130–132 Methanol can be produced from plant
sources via pyrolysis or fermentation; a lot of research is on the way to
upgrade these processes to a level where biomethanol would be economically
interesting.133–135 Ethyl lactate is a bio-based solvent suggested from many
instances – however, in water it hydrolyses to ethanol and lactic acids under
basic conditions and this can impede its range of use.136 2-
Methyltetrahydrofuran (2-MeTHF) is a promising alternative to
tetrahydrofuran (THF) for a range of applications, due to its positive chemical
and toxicological properties. It is produced from renewable resources (furfural
or levulinic acid).137 Another recently highlighted solvent is
cyclopentylmethylether (CPME), as a preferred replacement for a range of
other ethereal solvents, due to its range of positive features, such as chemical
stability, a relatively high boiling point, and the formation of azeotropes with
water.138
Higher boiling solvents are preferred in order to avoid the dangers of VOC
(volatile organic compounds) exposure and emissions when handling low
boiling solvents. However, the high boiling point is at the same time their
disadvantage, due to the high energy demands for their regeneration via
evaporation. Some interesting and friendly solvents include glycerol, side-
product of biodiesel production,139 and polymers - PEG and PPG
(polyethylene and polypropylene glycol, respectively). They are non-toxic
(approved for use in beverages), thermally robust, easily reusable and have
good solvating properties.140–142
The use of the supercritical solvents in synthesis or analysis is a very
elegant way to avoid the environmental, energy and toxicological issues – by
the increase of the temperature and pressure above the everyday limits, the
improved characteristics of the solvents are obtained.143–148 Superheated
water,149–153 acetone154–156 or methanol157–166 have been used for various
processes. Especially interesting is supercritical CO2, proven to be an adequate
replacement for the traditionally used chlorofluorocarbons (CFCs) and other
Introduction
13
solvents in an array of applications and processes; it is also renewable,
chemically inert and risk-free of organic solvent pollution.167–173
Fluorous solvents are especially interesting for biphasic systems with
heterogeneous catalysts.174–182 They are stable, reusable, inert and non-toxic,
however characterised by an extremely long lifetime, which can lead to
problems if they are released into the environment.105 The so-called
“switchable solvents” are able to change their physical characteristics and/or
polarity by a reversible process of controlled manipulation on a molecular
level by an internal stimulus, such as a change of temperature and the addition
or removal of gas.111,183–185
In one more class of solvents, the low volatility plays an important role in
the wide acceptance and the extensive research. Ionic liquids are an
interesting class of molecules. They are characterised with highly
asymmetrical ionic structures, relatively low melting temperatures (by the
rule, up to 100 °C), extremely high vapour pressures (i.e. practically non-
volatile), and are thermally stable up to 300 °C. Ionic liquids possess some
significant advantages as compared to “classical” solvents. They are highly
polar, immiscible with many organic solvents, and yet have the ability to
dissolve many different organic, inorganic and organometallic materials. Their
solvent properties can be tuned for a specific application by varying the anion
cation combinations (“designer solvents”). 105,186–191 Most recently, the
biological properties of ionic liquids have been mapped, and this might open
new routes in drug synthesis and delivery.192
On the negative side, similarly to fluorous solvents, the ILs are very
persistent in the environment, which can result in pollution, sometimes with
unforeseen consequences, as many of these chemicals are still not fully
tested.193,194 Bio-based and biodegradable ionic liquids are a possible solution
for this issue.195
In the chemical industry, BASF was a pioneer in use of the ILs: the BASIL
(Biphasic Acid Scavenging utilizing Ionic Liquids) process is used to
drastically improve the process of alkoxyphenylphosphines production.196
Chapter 1
14
1.2.4. Process intensification (PI) by the use of microreactor
technology
Miniaturisation of chemical reactors is a trend of the last two decennia. The
obvious advantages are the small reaction volume, linked to a sharp decrease
in the reagents and solvents use, and to the improved mixing linked to the
higher surface to volume ratio. Furthermore, the ease of control of reaction
conditions and the flexibility of a physically small setup are adjoined by the
enormous savings in energy and time, and by an improved reaction safety,
due to the smaller scale, closed systems that reduce the exposure, and the
improved mass and heat transfer.197,198 Miniaturisation, on the other hand,
demands adjusted apparatus and improved techniques to correctly set and
follow-up the reactions on such a small scale. Reactions can be performed in
batch; some examples include the droplet micro- or nanoreactors, reverse
micelles, microemulsions or template-based syntheses.199–204 However, in most
cases, the term “microreactor” is associated with continuous flow reactors. In
these set-ups, the advantages of the miniaturisation and of the flow processes
are combined: beside the savings in materials, energy and time, the improved
reaction control and the flexibility of the setup, the improved stoichiometry
and mixing in situ result in a reduced amount of side products and very often
to improved conversions and yields.
The main asset of continuous flow microreactor technology is its scalability,
which is of high industrial importance. The scale-up to an industrial level can
be facilitated, as the parameters of mixing and heat transfer are better
characterised in flow systems.205 Scale-out is another possibility of using the
microreactors for the industrial production.206
Primarily flash chemistry can benefit from the performance in flow
microreactors. It is often mentioned that the continuous microreactor
technology can be an efficient manner to scale-up reactions which benefit from
microwave technology; indeed, reaction efficiency and the ease of control is a
mutual property of these two technologies.207 On the other hand, reactions that
demand very long reaction times and cannot be accelerated by temperature
changes actually cannot benefit from the microreactor technology.205
Introduction
15
The relatively short fluidic paths are associated with a laminar type of flow in
the microreactors; this means that the mixing in the microflow depends on the
diffusion across the streams. In accordance to this, the reduction in the channel
diameter enhances the diffusion and leads to better mixing.205 The variations in
the velocity can be measured and assessed, to evaluate the influence of the
diffusion on the reaction and to use the results in the anticipation of the
behaviour in the scale up.
In the construction of the microreactors, various mixers are employed, the
simplest being T- or Y-mixers. In this type of mixers two flows get together
resulting in laminar flow behaviour, where the mixing occurs by diffusion.
These are the so-called passive mixers.
Figure 4: Mixing in laminar flow. Left: T- and Y-mixers.208 Right: Simplified
scheme of interdigital flow
Mixing improvement is achieved by construction of more advanced passive
mixers – adjusting the design, which influences the flow paths (for example
interdigital or injection mixers). Alternatively, the mixing is improved by the
use of active mixers, where external sources of energy are used.208–213 The use
of enhanced mixers is especially important with reactions where the
bottleneck is the transfer of reagents from one phase to another.
Heat exchange is more efficient in flow than in batch reactors (conductive vs.
convective heat transfer, respectively). This conductivity is dependent on the
microreactor construction material and can play a role with extremely
exothermic and fast reactions. The improved mixing also influences thermal
effects in the reaction – in the flow reactors, both reagents are mixed at the
same temperature, unlike with the batch reactors. The influence of reactants
temperature on the required reaction temperature is thus minimized.205
Chapter 1
16
Microwave heating can be used to intensify the microreactor conducted
processes by application of this more efficient type of heating; the relatively
low permeability of microwaves is rather insufficient for the large scale
applications in batch processes, however adequate for heating the low
diameter channels of the microreactors.214 The often encountered problem of
the slurries and solid particles, occurring as reactants, reagents, products or
side products of the reactions, and leading to clogging of the fine channels,215
is recently successfully handled by the use of ultrasound irradiation, via an
external ultrasonic baths or an integrated piezoelectric actuator.216–218
Microreactors can be used for heterogeneous catalytic reactions by using the
immobilized catalyst particles incorporated in the flow paths .219,220
Microreactors are valuable for the high-throughput screening of catalysts and
for a better control of the size distribution if the reactor is used for particle
synthesis. Fine chemistry, polymerisation and even material production is
performed in microreactors.206 Microreactors are especially suitable for
performing photochemical reactions, due to the improved exposure of the
liquid paths to the light emission.221–223
Microreactors are made from various materials, including glass, silicon,
stainless steel, ceramics or polymers; the choice of the reactor is made
according to the chemicals and of the process parameters.224 Pumps used in the
construction of microsystems are HPLC, syringe or peristaltic pumps. To
avoid problems with pressure, other types of pumps are used, such as
piezoelectric or electroosmotic driven pumps.225
For a fast analysis of the reaction products, which is important for the
evaluation of the reactions, microreactors are coupled with in-line detection
equipment: UV–VIS226,227 electrochemical,228 mass spectrometry (MS),229,230
HPLC,231 NMR232 or ATR.233
Practically, the only serious drawback of the microreactor technology is the
formation of solids during the reaction; insoluble particles can easily clog the
fine channels stopping the flow and creating difficulties in conducting the
reaction. Another problem can be the formation of gasses during the reaction,
which can cause instability of the flow thus demanding a strict control of the
Introduction
17
pressure in the device. The handling or the formation of viscous material can
be problematic due to the pressure drop that is created. However, when these
risks are avoided or controlled, the microreactor technology is considered very
advantageous for various applications in the fine chemicals and the
pharmaceutical industry.
1.3. Biofuels
The oil reserves on Earth are limited. We are facing the fact that that no
spectacular discoveries of oil fields were made since the 1970s, and German-
based Energy Watch group predicts that world oil production already peaked
in 2006 and will decline by half already by 2030.234 Along with the physical
decrease of the sources, a strong drive for the redefinition of the energy
sources is the threat of the global warming. Carbon dioxide (CO2) emissions
from the burned fossil fuels is an important factor contributing to the global
climate change. Burning of biobased fuels, on the other hand, in theory only
releases amount of CO2 captured by plants in photosynthesis process during
their growth. However, a precise LCA analysis of a biofuel has to take into
account all the manipulations during biomass and fuel production and
manipulation, generally on a regional level.235–238
Even with the intensive tendency to use renewable resources, the world
energy consumption still heavily relies on petrochemical sources – for
example, 79 % of the European energy consumption is of fossil origin.12 Many
goals were set on several global and national levels on the parts of the market
to be covered by bio-based instead of petrochemical products and energy. The
European Council brought an action plan aimed at increasing the share of
biofuels to 10 % of European transport fuel consumption by 2020.239 This target
was, however, recently reformulated to only 5 % in a recent proposal.240
A general problem with the use of renewable energy is the low energy
densityiii of this energy source, as compared to the petroleum fuel.12 Another
problem is the consistency of the supplies – biomass yields can vary and
iii Energy density is defined as the amount of energy stored in a given system per unit mass.
Chapter 1
18
depend on a range of factors. Vegetable oils were the first biofuels used for
engine drive. They were followed by the esters obtained from oils (biodiesel)
and by ethanol obtained by fermentations from starch-rich sources. These are
first generation biofuels – products made from the crops that otherwise serve
as food crops. The main problem with the use of these crops is the so -called
“fuel vs. food dilemma”:241,242 the danger of unfavourable economical and
environmental changes to the regions where a crop is cultivated and to the
planet as a whole. Another issue is the possible inconsistency in the supply of
these feedstocks, being related to the weather conditions. Relatively quickly,
this resulted in the introduction of second generation biofuels – fuels made
from the non-food crops (e.g. Jatropha or switchgrass) or from non-edible,
lignocellulosic plant parts. Second generation biofuels are nowadays the
preferred trend in research and development. Third generation biofuels are
produced by the genetic modification of crops, resulting in a higher biofuels
potential, and from the alternative sources such as algae.243,244
The first three generations of biofuels are (theoretically) carbon neutral fuels,
i.e. the amount of carbon captured by the biofeeds is equal to the amount that
is released to the atmosphere. Fourth generation biofuels are the fuels with the
negative carbon potential – the substrates used for the production of these
fuels have a large carbon storage capacity.
Additionally, geo- or biosequestration are techniques used to reduce the CO2
quantity in the atmosphere. Geosequestration (or carbon capture and storage,
CCS) is a process of shifting CO2 away from the surface of the Earth to make it
unavailable for a long period of time, to the deep ocean or the deep geological
formations, or in form of minerals.245 Basically, this is a dirty process and it is
coupled with several controversies: the risks of CO2 release and ocean
acidification, for example. Biosequestration, enhanced capture of CO2 by
plants, is a much more acceptable process.246
1.4. Application of green chemistry principles in this work
In this work (Figure 5), the postulates of green chemistry were approached
from several angles. Renewable resources were used as starting materials for
the studied reactions: simple carbohydrates, building blocks derived from
Introduction
19
carbohydrates in a straightforward way, amino acids and vegetable oils.
Several existing processes were performed in alternative manners, using either
alternative conditions of solvent and catalyst systems, or flow microreactor
technology as a tool for process intensification. The advantages of the
alternative technologies and resources in all the tested applications have been
proven, and produced building blocks were found to be useful either for
further chemical conversions, or as such (biofuel). In the first part of the work
(Chapter 2), the conversion of the fructose precursor inulin, an oligofructan
found in the rhizomes of several plants and not used in the primary human
diet, was converted to HMF, a molecule with a very interesting structure for
potential conversions and interesting uses in fine and polymer chemistry.
Some novel solid zeolites were used as catalysts for this process. Alternatively,
ionic liquids were tested and proved to be efficient as solvents and catalysts.
Some “green solvents” were tested as extraction media for the separation of
HMF product from the reaction mixture. As a continuation of this work, by a
simple process of reductive amination, HMF was converted to a range of
derivatives with potential use as starting materials for future conversions to
the pharmaceutically active derivatives. Reactions were conducted in water,
traditionally the most undesired compound in this reaction, being one of its
side products. Alternatively, methanol and ethanol were used as solvents and
performed better than water. Reactions were performed in the absence of
catalysts, and under mild conditions of temperature and pressure (Figure 5).
Chapter 1
20
In the second part (Chapter 3), the conversion of ketoses under microreactor
conditions to their respective cyanohydrins and to the products of their
hydrolysis (α-hydroxyacids) was explored. The latter have a potential use for
various future conversions to pharmaceutically interesting derivatives.
Microreactor conducted conversions to cyanohydrins and their hydrolysis
were shown to be completed in significantly reduced times and under lower
temperatures than in previously reported and self conducted batch processes.
Methanol was the main solvent of choice for the Kiliani conducted reactions in
flow. The possible dangers of the gaseous HCN formed in the mixture were
efficiently avoided by the use of the closed systems and careful in-line
neutralisation.
Figure 5: The use of green chemistry principles in this work
Chapter 2.
Production
and reductive
amination of
bio-based
HMF
Chapter 4.
Application of
microreactor
technology on
amino acid
coupling via
benzotriazol
chemistry
Non-catalytic processes/
heterogeneous catalysis/
alternative catalytic
systems
Chapter 3.
Application of
microreaction
technology for
the Kiliani
reaction
Chapter 5:
Biodiesel
production
from crude
palm oil
Use of renewable
starting materials
Process intensification,
increased safety
(micro channels, closed
systems)
Use of renewable/benign
reaction media
Reduction of the waste
by recuperation of the
side products
Introduction
21
In the third part of the work, L-amino acids were converted to heterocycles
(Chapter 4); the amide coupling was enabled by the use of benzotriazole
chemistry, in a continuous process, previously reported on a small scale and
under microwave heating. In case of the translation of microwave to
microreactor conducted processes and the heterocyclic amides production
from amino acids, the process was successfully scaled up and the conversions
were shown to be improved. In the amide coupling on amino acids we have
successfully replaced the potentially carcinogenic dimethylformamide (DMF)
by much less harmful dimethyl sulfoxide (DMSO).
In the final part of the work (Chapter 5), an unprocessed oil was used for the
production of a biofuel; the process is scaled-up from the lab to the pilot (one
ton) scale and is now in actual use, under technologically challenging
conditions at the production site of the oil self. Production of biodies el was
conducted in methanol, using the relatively cheap heterogeneous catalysis; the
side stream of this reaction, containing the salt side product of the reaction
catalysts (potassium sulphate, K2SO4), can be recuperated and used for
agricultural purposes.
Chapter 1
22
23
2. Production and reductive amination of bio-based
HMF
2.1. Introduction
Carbohydrates, as most abundant bio-based resource on the planet, are an
obvious choice of starting material for various chemical processes aimed at
obtaining useful structures.40,247 One of the many transformations of
monosaccharides is the acid-catalysed dehydration; in this manner, pentoses
and hexoses are converted into furanic structures: furfural (2-furaldehyde,
furan-2-carboxaldehyde, 1), and 5-(hydroxymethyl)furfural (5-hydroxymethyl-
2-formylfuran, HMF, 2) ( Scheme 1).248,249 Industrial production of furfural is
well developed, and at present, furfural is one of the few bio-based molecules
produced on a very large scale (280 000t/y). As an actual chemical commodity,
furfural is used as chemical solvent, as a starting material for conversions to
other structures with furan core, and has a potential for use as an energy
source.250
O
HO O
O
O
1 2
HO O
OH
OH
OH
O
HO
HO OH
OH H+
-3 H2OO
HO
HO OH
OH
OH
HOOH
O
OH
OH
OH
H+
-3 H2O
HH
Scheme 1: Obtaining furfural (1) and 5-hydroxymethylfurfural (2) from
monosaccharides
HMF is receiving a significant amount of attention in synthetic chemistry,
owing to its interesting structure: the furan ring, alcohol and aldehyde group
are chemical moieties with high potential for numerous conversions. Several
recent reviews comprise the HMF production, chemistry and
biochemistry.52,251–256 However, HMF is still obtained on a relatively small scale
as compared to furfural, and its price is, accordingly, rather high. The main
reasons for this are technological hurdles in HMF production and purification
Chapter 2
24
– primarily, low yields due to the side-reactions or catalysts poisoning. Under
the operating conditions for its production, HMF tends to degrade, most
notably into levulinic and formic acid. Another problem is the polymerisation
of HMF and other molecules present in the reaction mixture during its
production, to soluble and insoluble polymers (humins). These undesirable
side-reactions are observed primarily in aqueous media and in concentrated
solutions, and eventually cause problems of HMF purification, as well as its
handling and storage.257 The difficulties in isolating and in manipulating HMF
are thus the major obstacles in its large-scale production and conversion.
2.1.1. HMF production
As a product of the dehydration of hexoses in the presence of acid, HMF is
found in foodstuffs; it is one of the products of Maillard reaction (non-
enzymatic food browning during thermal operations). Due to its presence in
food, the daily intake was estimated to 30-150 mg.258 The mutagenic, genotoxic
and nephrotoxic properties of HMF and its metabolite SMF (5-
sulfooxymethylfurfural) were tested, with mixed results, showing non -
mutagenic, weakly mutagenic259–261 or even antimutagenic properties.262
First accounts of synthesis of furans and levulinic acid by acid-catalysed
dehydration from carbohydrates originate from the 19th century.263 Since then,
a lot of research has been done on these processes. Fructose is the most
suitable precursor for HMF production, due to its favourable structure in
solution – formation of the furanose form, which enables the desired
dehydration (Scheme 2). Several hypotheses were suggested for the
mechanism of HMF formation, and a cyclic route was recently proven by the
NMR identification of the intermediate 3 (Scheme 2), in a follow-up of the
reaction in DMSO by Amarasekara et al.264 and Antal et al.265
Production and reductive amination of biobased HMF
25
OH
CH2OHHOH2C
HO
OHO
OH2
CH2OHHOH2C
HO
OHOH+ CH2OH
HOH2C
HO
OHO
CH2OH
HOH2C
HO
OHO
CHOH
HOH2C
HO
OHO
CHO
HOH2C
HO
OHO
-H+
-H2OCHO
HOH2C
HO
O-H2OOHOH2C CHO
CH2OH
O
HHO
OHH
OHH
CH2OH
3 Scheme 2: Mechanism of fructose dehydration to HMF265
Adjustment of solvents and reaction conditions is essential to fine-tune the
HMF production without degradation.
Separation from the reacting environment and final purification of HMF
remains an issue. HMF is not easy to extract since the distribution coefficient
between the organic and the aqueous phase is not very favourable. High
vacuum distillation is another option, but this technique is rather energy
demanding. The above mentioned degradation processes occur relatively fast
during purification, resulting in yield losses. Partially related to this problem,
the yield of HMF in most of the published research work is reported in
solution, as analysed by HPLC – without the physical isolation of the product.
Conversion of hexoses to HMF depends on a combination of factors: the
nature and the concentration of substrate, type and quantity of catalyst,
reaction medium and reaction temperature are the most important.
Preferred substrates for HMF production are ketohexoses, particularly
fructose (see Scheme 2), due to its high availability and low price. As a rule,
aldoses give lower yields of HMF. Alkaline medium is namely required for the
formation of the enol which can be further converted to HMF; in the acid
environment, required for dehydration reaction, aldoses form a stable
pyranose ring and the enolisation rate is low (Scheme 3).251
Chapter 2
26
CHO
OHH
HHO
OHH
OHH
CH2OH
CHOH
OH
HHO
OHH
OHH
CH2OH
CH2OH
O
HHO
OHH
OHH
CH2OH
OH-
H2O
OH
HOH2C
HO
OHO H+ O
HO OOH
O
H
HO
H
HO
H
HOHH
OH
OHH+
-3 H2O
H
Scheme 3: Glucose tautomerisation in acid and in alkaline solution
As a rule, oligo- and polysaccharides give slightly smaller conversions to
HMF. This depends on the quantity of the ketoses in the carbohydrate and the
rate of starting material hydrolysis to monosaccharide.
2.1.1.1. Catalytic systems for HMF production
The traditionally applied homogeneous catalysts are inorganic acids:
hydrochloric (HCl), sulphuric (H2SO4), or phosphoric (H3PO4) acid.
Alternatively, organic acids catalyse the reactions: citric or oxalic acid, for
example. In all of these processes, the catalyst nature and quantity has
influence on the turnover rate and the side products formation – for example,
HCl increases the levulinic acid formation (product of HMF rehydration),
whereas the use of H2SO4 and H3PO4 results in lower yields of undesired
products. Also, lower pH values result in an increased conversion, but also in
an increased side products formation.266,267
As solid heterogeneous catalysts for hexose degradation, the most often
applied ones include ion exchange resins268–271 and zeolites.272–276 Their
efficiency is related to their acidity, and also to their three-dimensional
structure. The structure of the catalyst is also important when using
mesoporous silica carriers for various catalyst combinations .277–280 Other solid
catalysts include Lewis acids: metal chlorides,281–286 especially chromium
salts,284,287–295 boron trifluoride,296 as well as rare earth metal triflates,297
tungsten salts, 298 niobic acid,299,300 metal oxides,301,302 ammonium halides,303
and heteropolyacids. 276,304,305
Production and reductive amination of biobased HMF
27
2.1.1.2. Solvent systems for the HMF production
Water is traditionally in which the reactions take place, being abundantly
available, cheap and efficient for fructose dissolution. However, high
conversions in water are accompanied by high amounts of side products –
most notably, the rehydration products of HMF, levulinic and formic acid, as
well as the humins (vide supra). In order to suppress these undesired reactions,
various alternative solvents have been explored. Dimethyl sulfoxide (DMSO)
is a popular medium for HMF production, as it improves the conversions and
suppresses the side-products’ formation; this is probably related to the fact
that the β-furanoid form of fructose is predominant in this solvent.306
HO
OH
OH
OH OH
O
O
O
OH
OH
OHHO
OH
OH
OH
HO
OH
OH
OH
OHO
OH
OH
OHO
HO
OH
OH
OH
-pyranose
-furanose
-pyranose-furanose
keto
Scheme 4: Furanose and pyranose tautomers of D-fructose in solution
Even reactions in pure DMSO, without the addition of a catalyst were
reported. This is attributed to the effects of partial DMSO decomposition
which might decrease the pH in the mixture.296 Some other favourable solvents
include acetone155,270 or DMF.272 One of the often applied PI (process
intensification) strategies in HMF production is the use of biphasic solvent
systems, containing an aqueous and an organic phase. Fructose is dissolved in
the aqueous phase, and during the reaction, the produced HMF is
immediately transferred to the organic phase. The product separation is thus
enhanced, and the side-product formation reduced. Commonly used organic
solvents for biphasic processes or extractions are methyl isobutyl ketone
(MIBK), 2-butanol, ethanol, diethyl ether, ethyl acetate or tetrahydrofuran
(THF).268,270,273,286,307–312 Other improvements might include the use of
dichloromethane (DCM),313 polyethylene glycol (PEG),257,314 liquid CO2 in
Chapter 2
28
supercritical systems 315 or saturation of the aqueous phase with an inorganic
salt.316
Alternatively, HMF was produced by hydroxymethylation of furfural by
formaldehide. The addition of a formyl group to position 5 is difficult due to
the electron-withdrawing character of the aldehyde group in position 2. This
effect can be partially suppressed by blocking the aldehyde with thioacetal
function (Scheme 5); the yields of HMF, however, remain rather low. 317,318
OS
HCHO
H+
S
HO
S
S
H
OH
Scheme 5: Hydroxymethylation of furfural 1,3-dithiolane as a route to HMF318
Some of the other PI strategies include the application of supercritical
conditions,155,315,319–323 microwave heating,269,270,288,302,324,325 ultrasonic energy326,327
or continuous processes.265,273,309–311
2.1.1.3. Ionic liquids as media and catalysts
Ionic liquids (ILs) have received a lot of attention in the recent years as
potentially green reaction media.295 The action of ionic liquids as both reaction
media and catalysts for the production of HMF is extensively explored. Some
early work on the production of HMF by the action of ionic media includes a
solid-phase dehydration of fructose and its precursors, by pyridine chloride
and pyridinium perbromate.328 The most common and often applied ILs have
alkylimidazolium-containing cations. Some of the most common anions of
these media are chloride,270,271,280–282,288,291,293,294,298,329–334 but also
fluoroborate/fluorophosphates,271,335 trifluoromethanesulfonate336 or N-
methylmorpholinium methylsulphate.333
Several mechanisms have been proposed for the action of ILs in the HMF
formation. One suggested mechanism includes the action of the chloride anion
to the dehydration (Scheme 6); another mechanism, including the action of
imidazolium cation, has been proposed by Ryu et al.337 (Scheme 7).
Production and reductive amination of biobased HMF
29
H+
-HCl
-H2O -H2O OHOH2C CHO
Cl
O
OHHO
HOH2CCH2OH
OH
O
OHHO
HOH2CCH2OH
OH2
O
OHHO
HOH2C CH2OH
O
OHHO
HOH2C CH2OHO
OHHO
HOH2C CH
OH
HCl
O
OHHO
HOH2CCHOH
O
HO
HOH2CCHO
-H2O
O
HO
HOH2CCH
OH
O
Scheme 6: A suggested mechanism for the formation of HMF in imidazolium
chloride ionic liquids in the presence of acid330
N
NH
H
R
Cl
O
OHHO
HOH2CCH2OH
OH
N
NH
R
Cl
O
OHHO
HOH2C CH2OH
H
N
NH
R
HOO
OHHO
HOH2C CH2OH
O
OHHO
HOH2C CH2OH
Cl
O
OHHO
HOH2CC
HOH
H
Cl
Cl
O
OHHO
HOH2C OHOHOH2C CHO
O
OHHO
HOH2CCH2OH
OH
H
A
B
Scheme 7: A suggested mechanism of catalytic action of imidazolium ionic liquids,
with Cl- performing as a “base” (route A) or as a nucleophile (route B), whereas the
imidazolium cation has Brönsted acidity337
Ionic liquids are generally applied together with homogeneous,338,339 or, more
often, heterogeneous catalysts.270,271,280–282,288,294,298,329–331 PI is often achieved by
application of biphasic systems and continuous extraction of HMF from the
reaction medium, similarly to the processes described above.334,338,340 In a large
number of reported procedures, the conversions are reported as quantified by
HPLC in solution – without the actual purification of the product.
In order to increase the sustainability of the process, the use of bio-based ionic
liquids has been suggested. These are, for example, choline chloride341–343 or
betaine hydrochloride.344 Systems mimicking the properties of ionic liquids
Chapter 2
30
(for example, chloride salts in N,N-dimethylacetamide, DMA) have also been
applied.329,345–348 The hypothesis is that the high concentration of Cl - ions would
allow a similar ionic pairing as in IL containing a Cl - ion loosely bound to the
cation (Figure 6).
N
O
Li
ClN
N
Cl
Figure 6: DMA + LiCl system, mimicking the structure of ionic liquid
Fructose is the most common starting material for the HMF production in the
ILs. Production processes of HMF are furthermore often reported starting
from glucose,285,286,288,291,301,313,329,330,347 or hexoses precursors, such as
inulin313,315,328,342 saccharose,272,275,328,342 cellulose,270,276,304,305 cellobiose or
starch.287,332 Some of the less common reported starting materials included
glucosamine349 or chitosan,350 and also raw plant material after minimal
pretreatment: raw chicory root,338 rice straw,351 or raw grape berry.352
2.1.2. HMF derivatives
The critical step in the HMF production from renewable resources is the
separation and purification of the final product. Extraction usually demands
large solvent volumes, and furthermore, HMF degrades rather quickly during
the usually applied purification procedures, such as extraction or distillation
(vide supra). Due to this, alternatives have been proposed: the “technologically
friendlier” derivatives of HMF (i.e. molecules obtained in simple processes,
most preferably in one-pot processes from carbohydrate feedstocks, more
chemically stable than HMF and easier to purify) readily find their use in
large-scale applications, such as the production of valuable polyamides,
polyesters and macrocycles, but also as fuel or fuel additives (Figure 7). These
derivatives are molecules obtained by oxidation (2,5-diformylfuran, DFF, 4,
and 2,5-furandicarboxylic acid, FDCA, 5) or by reduction of HMF (2,5-
Production and reductive amination of biobased HMF
31
bis(hydroxymethyl)furan, BHF, 6, and 2,5-dimethylfuran, 2,5-DMF, 7iv).52,353
DFF is a starting material for the production of BHF and of the Schiff bases
used in further conversions.345,354–356 FDCA can be successfully used as a
substitute for petrochemically produced terephtalic and isophtalic acid in the
production of polymers;40,357–360 BHF is already used in the production of
polyurethane foams.52,361–364 2,5-Dimethylfuran, a potential fuel additive with
high energy content, has recently received much attention.37,52,345,354,355,365 It can
be obtained from hexoses and their sources in a one-pot, two-step system.
Levulinic acid (8), a product of HMF hydrolysis, is an interesting building
block for fuel additives, and for the production of polymer and resin
precursors.40,350,366–372 5-Halogenomethyl derivates, 5-(chloromethyl)furfural
(CMF, 9) and 5-(bromomethyl)furfural are also obtained directly from the
carbohydrate sources and can be used for the further conversions.328,373–376
Other industrially useful HMF derivatives obtained directly from biomass
include HMF ethers and esters, which can also be used in the production of
polymers and fuel additives.319,369,377–379 A “dimer” of HMF, 5,5’-
oxydimethylene-bis-(2-furfural) (OMBF) was reported by Gaset et al.380 and
can open a route to polymers. Precursors to liquid alkanes or oxygenated fuel
derivatives can be obtained from HMF.381,382 Furthermore, interesting
derivatives of HMF include δ-aminolevulinic acid, a herbicide,383 caprolactam,
the feedstock for Nylon 6,384 halides,385,386 and 6-aromatic rings – benzenetriol
or 3-pyridinol.387–391
A large number of pharmaceuticals have a HMF-related structure.392 (5-
Alkylaminomethyl-2-hydroxymethyl)furan containing structures are found in
a large number of pharmaceutical preparations (vide infra).
iv The usually accepted abbreviation for dimethylfuran is DMF; in this text, we used a slightly
different abbreviation, in order to avoid confusion with dimethylformamide, a widely used
organic solvent.
Chapter 2
32
O
OHO
O
OO
O
OO
HO OH
O
NH2H2N
O
OHHO
OH
O
O
N
OH
OH
OH
OHO
ORO
O
OOR
O
O
O
NHHN
O
OCl
O
OO
OH
O
NRHO
HO
O
OHHO
O
4
5
6
7
8
9
H H
H
H
H
H
2
Figure 7: Some of the most interesting HMF derivatives
2.1.2.1. Reductive amination of HMF
Reductive amination of the carbonyl group results in (5-alkylaminomethyl-2-
hydroxymethyl)furan structures. These molecules can be efficiently converted
into 6-substituted 3-pyridinols388,389,393 – Maillard products, useful in sensory
research,391,393 or starting materials for further conversions, into various
pharmaceuticals394–398 or agrochemicals.399–401 Chemical transformations in
which the furan ring stays intact can also lead to several interesting classes of
drugs. 2-Alkylaminomethylfurans are known for their wide range of
pharmacological activity. These structures show activities of
antihistaminics,402–411 glutamate modulators,412 glycine transport antagonists,413
muscarinic agonists,414 renin inhibitors,415 glucan synthase inhibitors,416 kinase
inhibitors,417,418 etc. In most cases, these structures are not produced from
HMF, but from 2-furfural or other feedstocks; the production procedures
usually include long reaction times and rather drastic temperature/pressure
conditions. The reason for this is the deactivating effect of the C2 carbaldehyde
group, which makes the addition to the C5 position of the furan ring fairly
difficult (vide supra).
Production and reductive amination of biobased HMF
33
Several production processes of similar compounds were also reported
starting from HMF as feedstock. Using a template directed approach, Gupta et
al. synthesized a library of similar heterocyclic compounds starting from resin-
immobilized HMF, using a solid catalyst.392 In an automated synthesizer, more
than fifty compounds were produced with good purities, but in rather modest
yields. The process involved prolonged heating in several organic solvents,
several equivalents of resin and/or extensive purification by preparative
HPLC. Similarly, Sun et al.419 used solid support and complex solvent mixtures
for the reductive amination of HMF. Taveras produced the positive
modulators of the mGlu2 (metabotropic glutamate) receptor412 and the
chemokine receptor ligands with overnight reflux temperatures.420 In several
other reports, 3-cyanoquinoline inhibitors of Tpl-2 (tumour progression locus)
kinase,418 DNA methyltransferase inhibitors421 and indolopyrrolocarbazole
derivatives with antitumor activity422 were all synthesized with prolonged
heating in anhydrous solvents. (5-(2-Propynyl)aminomethyl-2-
hydroxymethyl)furan,423 and (5-aminomethyl-2-hydroxymethyl)furan,388,389
used for further conversions, were also produced under prolonged heating, in
anhydrous solvents, optionally with high H2 pressure conditions, and with
complicated purification steps. In a recently published paper, Mascal and
Dutta presented a procedure for producing ranitidine, a “classic”
antihistaminic preparation, from 5-(chloromethyl)furfural (CMF) obtained
from cellulose.376
2.2. Results and discussion
2.2.1. HMF production from inulin
Following some recently reported work on fructose production in ionic
liquids, the production of HMF starting from fructose precursor inulin
(Scheme 8), without the addition of any other catalyst, was tested. Two novel
zeolite catalysts were tested as well for the conversion of inulin and fructose to
HMF.
Chapter 2
34
O
HO OO OH
HO
HO OH
OH
O OH
HO
HO OH
O
O OH
HO
HO
O
O OH
HOO OH
O
HOOH
OH
OH
n
H+ H+
- 3H2O
+ (n+2)H2O
H
Scheme 8: Conversion of inulin to fructose and HMF
Inulin is a form of plant energy storage alternative to starch. Inulin is a
polysaccharid from the class of fructans; it is thus formed prevalently from
fructose, with one glucose unit optionally found at the end of the chain. Inulin -
rich materials are usually roots and rhizomes of plants, most notably
Jerusalem artichoke and chicory. Inulin is mainly used in the food industry;424
some medically interesting applications have been reported as well.425 Its
chemically interesting transformations include the modification of hydroxyl
groups in the inulin chain, resulting in surface active characteristics of the
product.59,426
2.2.1.1. Production of HMF from inulin using ionic liquids as reaction
media and catalysts
Our experiments were performed in three commercially available, water
miscible ionic liquids: 1-methylimidazolium chloride ([HMIM]Cl) (a), 1-bytyl-
3-methylimidazolium chloride ([BMIM]Cl) (b), and 1,2,4-trimethylpyrazolium
methylsulphate ([TMP]MS) (c) (Figure 8). The experiments were carried out in
a relatively high concentration of substrate, of 10-30 mass%. One series of
experiments was done in the presence of aluminium(III) chloride (AlCl3) as a
catalyst, for a comparison with the reactions in pure ILs.
Production and reductive amination of biobased HMF
35
NN
S
O
O
OONH
N
ClN
N
C4H9
Cl
a b c
Figure 8: Ionic liquids used in the production of HMF: 1-methylimidazolium
chloride [HMIM]Cl (a), 1-bytyl-3-methylimidazolium chloride [BMIM]Cl (b), and
1,2,4-trimethylpyrazolium methylsulphate [TMP]MS (b)
Conventional heating was applied (oil baths). HMF was removed by
extraction from the reaction mixture. Extraction was performed using three
different approaches: batch, continuous via a continuous extraction apparatus,
and continuous via simple stirring with solvent in a flask (method used by
Sanborn et al. for HMF recovery.308,427) Solvents used for the HMF extraction
were diethyl ether, as usually reported solvent for HMF production processes ,
as well as 2-methyltetrahydrofuran (2-MeTHF) and cyclopentyl methyl ether
(CPME). The latter two have recently been labelled “green” considering their
renewable nature and chemical stability.137,138,428 2-Butanol was also tested as a
solvent, being previously reported as a useful organic phase modifier to
extract HMF.307
Alternatively, HMF was purified from the reaction mixture by distillation
under reduced pressure (boiling point of HMF is 123 °C at 2 mmHg). This
technique has led to fast polymerisation of the HMF material in the receiver
and was consequently abandoned.
Prior to the HMF production in the IL medium, the recovery of the HMF
from these reaction media was tested. It is namely known that the distribution
ratio of HMF over an organic and an aqueous phase is rather low.
Accordingly, the extraction procedures are inevitably extensive and can often
result in the use of rather large solvent volumes. In order to determine the
correct recovery of the HMF product from the ionic liquid reaction medium,
pure commercially available HMF was extracted from a mixture with ionic
liquids. Following a continuously performed extraction with diethyl ether
during 24 h, only 75 % of the initial quantity of HMF was recovered.
Chapter 2
36
Prolonging the extraction time to 48 h resulted in a full HMF recovery. Batch
extraction with rational solvent volumes (4-6 six portions of solvent, up to 60
ml in total for 3 g of IL and 1 g of HMF substrate) resulted in an HMF recovery
of no more than 65 %. 2-MeTHF proved to be partially miscible with the ionic
liquid, and an extraction was thus not possible. A similar problem of mixing
with the IL was encountered when using 2 -butanol. CPME extracted
exclusively HMF and did not mix with the IL, but unfortunately did not prove
as a suitable solvent for HMF either – only about 20 % was recovered after 24 h
stirring at room temperature, and only 23 % after a “classical” continuous
extraction with this solvent. Recovery values for HMF extraction from ionic
liquids reaction media, using various solvents and methods, are shown in
Table 1.
Table 1: Recovery of pure HMF from the ionic liquids using different solvents and
extraction methods
Exp IL Solvent Type extract.
V
solvent
(ml)
m
IL (g)
m
HMF (g)
T
(h) HMF recovery (%)
1 [BMIM]Cl 2-Butanol Batch 100 3.0 1.0 / / (a)
2 [HMIM]Cl Et2O Cont. 60 3.0 1.0 24 75
3 [HMIM]Cl Et2O Cont. 100 3.5 1.0 48 100
4 [HMIM]Cl 2-MeTHF Cont. 100 2.6 0.5 22 / (a)
5 [HMIM]Cl Et2O Cont. 135 2.1 0.9 24 76 6 [TMP]MS Et2O Batch 60 3.0 1.0 / 65
7 [TMP]MS CPME Stirring 15 2.2 1.0 24 20
8 [TMP]MS CPME Cont. 160 2.4 1.0 120 23
9 [TMP]MS 2-Butanol Cont. 150 2.0 1.0 48 / (a)
(a) Solvent was miscible with the IL
The initial set of reactions of HMF production from inulin was performed in
[BMIM]Cl (pH 7.9 at 100 g/l). The reactions were followed by batch extraction
with diethyl ether, which resulted in a fast polymerisation of the extracted
material; as a consequence, the product yields were difficult to determine.
Addition of AlCl3 as catalyst to the [BMIM]Cl/inulin mixture resulted in fast
conversions. These were, however, accompanied by high polymerisation of
the material in the reaction vessel, resulting in insoluble and partially soluble
polymers.
Production and reductive amination of biobased HMF
37
[HMIM]Cl was the next IL of choice. In comparison to [BMIM]Cl, this is a
more acidic ionic liquid (pH 4.3 at 100g/l). An operating range for temperature
and time was defined (Table 2). Conversions were clearly temperature
dependant (see experiments 3 and 4), as seen on the NMR. Reaction at 90 °C,
followed by batch extraction with diethyl ether, resulted in a 7.6 % HMF yield.
Having in mind the established recovery value for batch extraction from IL
medium (65 %) this yield was recalculated to 11.7 %, which corresponded to
the yield observed on the NMR. A reaction temperature of 100 °C resulted in a
fast polymerisation of the reaction mixture (conditions of concentration and
time repeated from experiment 4, not shown in the table).
[TMP]MS was used as a third IL of choice, under analogous reaction
conditions to the previous ones. This IL has a slightly higher acidity (pH 2.8 at
100g/l), and a lower melting point than the two previously applied ILs (mp 33
°C vs. 70 and 75 °C for [HMIM]Cl and [BMIM]Cl, respectively). It was thought
that the lower viscosity of this IL would contribute to a better mixing during
the process. In one of the experiments, after a reaction time of 2 h at 90 °C,
extraction by simple stirring with CPME at room temperature resulted in 3.7 %
yield. Considering the recovery value from this solvent (20 %), this yield was
recalculated to 18.6 % (experiment 6). If the continuous extraction with Et2O
during 24 h was applied, after the reaction under the same conditions (2h at 90
°C), this resulted in 12.6 % yield of HMF. Having in mind the recovery value
of HMF from the reaction medium using continuous extraction of 75 %, the
yield was recalculated to 16.8 % (experiment 7). Prolongation of the reaction
time to 4 h resulted in a lower yield of HMF (experiment 8).
All experiments were performed in highly concentrated inulin solutions: the
molar ratio of feedstock (inulin) to the reaction medium (ionic liquid) was
between 0.15 and 0.4.
To compare the activity of the ionic liquid to the monosaccharides,
experiments were performed in [TMP]MS with glucose and fructose. The
glucose reaction did not show any HMF formation (followed using TLC and
NMR). Reaction with fructose resulted in a 7.3 % yield of HMF, after a 2 h
reaction time at 80 °C, and after extraction performed by simple stirring with
Chapter 2
38
CMPE. Recalculated to 20 % recovery from the reaction mixture, the yield of
HMF starting from fructose was 36.5 %, in pure ionic liquid [TMP]MS.
From the series of performed experiments, it was clear that conversion of
inulin to HMF in IL depends on several factors, the acidity of the IL and the
reaction temperature being the most important. Separation of the product
HMF from the reaction medium remained the critical point in this process.
Larger solvent volumes and prolonged extractions were obviously needed for
the purification of the product; this would significantly increase the process
energy demands.
Table 2: Examples of reactions producing HMF in ionic liquids
Exp Medium/
catalyst Feed
t
(°C)
RT
(h)
m
substr.
(g)
m
IL
(g)
Mol
ratio
feed/
IL
Extr.
solvent
Extr.
method
Yield
after
extr.
(%)
Recalc.
yield
(%)
1 [BMIM]Cl Inulin 100 1 0.5 2.5 0.20 Et2O Batch / (b) /
2 [BMIM]Cl(a) Inulin 90 0.5 0.5 2.5 0.20 Et2O Batch / (c) /
3 [HMIM]Cl Inulin 80 3 2.0 5.0 0.30 / / / Traces(d)
4 [HMIM]Cl Inulin 90 2.5 1.0 3.0 0.24 / / / 11(d)
5 [HMIM]Cl Inulin 90 2 1.0 3.4 0.20 Et2O Batch 7.6 11.7
6 [TMP]MS Inulin 90 2 0.7 2.8 0.35 CPME Stirring 3.7 18.5
7 [TMP]MS Inulin 90 2 1.0 3.5 0.40 Et2O Contin. 12.6 16.8
8 [TMP]MS Inulin 90 4 1.1 3.6 0.40 Et2O Batch 9.2 14.2
9 [TMP]MS Inulin 60 14 0.5 5.1 0.15 / / / Traces(d)
10 [TMP]MS Fructose 80 2 1.0 3.6 0.35 CPME Stirring 7.4(b) /
11 [TMP]MS Glucose 90 7 1.0 3.6 0.35 Et2O Stirring / (e) /
(a) 20 mass% AlCl3 added as catalyst
(b) Fast polymerisation of the extracted material
(c) Fast polymerisation of the reaction mixture
(d) 1H NMR yield
(e) No HMF observed on the TLC or 1H NMR
2.2.1.2. Production of HMF from inulin using zeolite catalysts
In the second part of this work, the novel zeolite catalysts, produced at the
Faculty of Sciences, Ghent University (Prof. P. Van Der Voort) were tested.
These are catalysts of the USY and ZSM-5 type, with catalytic activities of 1.5
and 0.54 mol H+/kg, respectively. Reactions were performed in DMSO, in 2 h
Production and reductive amination of biobased HMF
39
reaction time at 100 °C. Typically, reactions were performed in concentrations
of ~6 mass%, on a scale of 1.2 mmol of substrate. At a catalyst loading of 30
mass%, a complete conversions to HMF could not be achieved. In comparison,
the same conditions of catalyst loading of acidic commercially available
cation-exchange resins (Amberlite IR-120 and Dowex 50Wx8) resulted in much
higher conversions under the same operating conditions. This could be related
to the physical properties of the catalysts (pore size and geometry) and to the
difference in acidity (Amberlite and Dowex resins have a capacity of 1.8 and
1.7 mol H+/kg, respectively).
Table 3: Examples of HMF production using several heterogeneous and
homogeneous catalysts
Exp. Substrate Catalyst Solvent t
(°C)
RT
(h)
Yield
(%)
Corrected
yield (%)
1 Inulin USY-type DMSO 150 2.5 / (a) /
2 Inulin ZSM-5 type DMSO 150 2.5 / (a) /
3 Inulin Dowex DMF 153 1.5 >95(b)
4 Inulin Dowex DMSO 150 1.5 >95(b)
5 Inulin Amberlite DMSO 150 2.5 >95(b)
6 Inulin Levulinic
acid H2O 95 4 / Traces(b)
7 Inulin Levulinic
acid
H2O/DMSO
3/1 95 2.5 12.9(c) 19.8
8 Inulin Citric acid H2O 90 5.5 /(d) / 9 Fructose Citric acid H2O 100 2 /(d) /
10 Inulin HCl H2O 90 2 16.9(c) 26
11 Inulin HCl H2O/DMSO
3/1 95 2 26(c) 40
(a) Incomplete conversions detected on the 13C NMR, not quantified
(b) NMR conversion
(c) Batch-wise extraction with diethyl ether
(d) TLC and visual detection (yellow colour typical for HMF solutions)
2.2.1.3. Production of HMF from inulin using homogeneous catalysis
Several experiments were performed with organic and inorganic acids as
catalysts. Reactions were typically performed on a 1.9 mmol scale, in
concentrations of ~ 3 mass%. Reactions in a 0.1 N levulinic acid resulted in
trace conversions to HMF (noticed on the 1H NMR), if the reaction was
performed in aqueous medium. Upon addition of DMSO to the reaction
mixture, the conversion was improved; after the extraction and evaporation,
Chapter 2
40
the final HMF yield was 12.9 %. Similar conditions with the use of citric acid
(0.1 N) as catalyst did not result in any conversions. Reaction in 0.1 N HCl
resulted in good conversions of inulin to HMF; after a batch extraction with
diethyl ether, 26 % HMF was isolated after a reaction time of 2 hours at 95 °C.
All extractions in this part of the work were performed batch-wise with
diethyl ether.
2.2.2. Production of HMF derivatives by reductive amination
In second part of this work, a simple procedure for the
conversion of HMF to (5-alkylaminomethyl-2-
hydroxymethyl)furan structures has been developed,
based on reductive amination of HMF. Since the yields
of HMF produced from inulin were rather low and the
purification was rather tedious, the reductive amination reactions were
performed on the commercially available substrate, as this provided more
flexibility in the further work.
Reductive amination is a widely used tool in organic synthesis and is mostly
performed in two steps: (1) production of aldimines, followed by (2) in situ
reduction with sodium borohydride.429 Schiff bases of aromatic aldehydes are
easily obtained by condensation with amines. The chemistry of this process
involves the elimination of water from an intermediately formed amino
alcohol (vide infra, Scheme 9). Water elimination is usually facilitated by
various means. Typical examples are the use of magnesium or calcium
sulphate,430 molecular sieves431 or azeotropic distillation with a suitable
organic solvent.432 On the contrary, Simion et al.433 reported a simple procedure
for the reaction between various aldehydes and amines to form a range of
imines in an aqueous medium. Reactions were conducted in the absence of a
catalyst, during short reaction times and at room temperature, and gave
generally good yield of imines with high purity.
In this work, a one-pot, two-step reductive amination, without purification of
the intermediate imine
O
HOHN
R
klm
Production and reductive amination of biobased HMF
41
Scheme 9) was applied for the production of aminomethylfuran structures ,
with a potential use as pharmaceuticals (vide supra, § 2.1.2.1.).
OHO
O
RNH2
OHO N
OHO NHR
NaBH4
O
H
H OHO N
OH
H
OHO NR
OHO N
R
H
OH
R
R
3 Scheme 9: The mechanism of production of the HMF based amines
By the choice of the reaction media, we have attempted to increase the
greenness of this process. Ionic liquids, water and simple alcohols (ethanol and
methanol), were chosen as reaction solvents. Water is the most abundant, the
cheapest and environmentally most benign solvent that can be found (vide
supra).126 Of course, a negative aspect of using water as the reaction medium is
the difficulty and the cost of its purification, which may add cost to the entire
process. Ethanol and methanol can be obtained in a sustainable way by
biomass fermentation. Industrially mature processes for their production are
available.434,435
2.2.2.1. One-pot approach for the production of (5-alkylaminomethyl-2-
hydroxymethyl)furan structures from HMF precursors
In an initially performed set of experiments, a one-pot reaction was
performed for the production of these structures directly from inulin or
fructose (Scheme 10).
O
HO OO OH
HO
HO OH
OH
O OH
HO
HO OH
O
O OH
HO
HO
O
O OH
HOO OH
O
HOOH
OH
OH
n
H+ H+
O
HO NR
NH2R
NaBH4
O
HOHN
R
10 11
H
Scheme 10: Production of (5-alkylaminomethyl-2-hydroxymethyl)furan
structures 11 from HMF precursors
Chapter 2
42
The reductive amination was performed following the reaction procedures
for the production of HMF in the presence of ionic liquids, solid
(heterogeneous) catalysts and homogenous catalysis, as previously described
in § 2.2.1. Without the separation of the intermediate, an amine was added in
the second step (in our representative case, benzylamine) to form the
corresponding aldimine (10). By the addition of sodium borohydride, this
imine was subsequently reduced to the final amine product (11).
In the ionic liquid [TMP]MS, experiments were performed on inulin and
fructose. After the first step (HMF production), the second step was performed
by adding benzylamine directly in the reaction mixture. Imine (4) was
detected by NMR after a 2 h reaction time at 40 °C. Unfortunately, the third
step, the imine reduction to the amine by addition of sodium borohydride,
resulted in a high number of side products, and, consequently, very low yields
– also difficult to quantify on the NMR. A test experiment, however,
performed on pure commercial HMF in the same IL, resulted in a successful
reductive amination and isolated 92 % of the final amine product. This has led
to the conclusion that the side-products in HMF production process are
interfering with the reductive amination.
A similar result was noticed when the process was performed using two
other types of tested reactions for the HMF production: a homogenously and
heterogeneously catalysed reaction, by levulinic and hydrochloric acid, or by a
solid resin catalyst Amberlite IR-120. The HMF production step was followed
by the formation of the imine, which was identified by NMR. Reduction of this
imine, however, has again led to a great number of unwanted side products
and to low final yields.
2.2.2.2. Production of (5-alkylaminomethyl-2-hydroxymethyl) furan
structures starting from HMF
The reductive amination in situ, starting from HMF precursors, proved to
give rather low yields, probably due to the interactions with the side -products
during HMF formation. However, as reductive amination on pure commercial
HMF as substrate was successfully performed in a non-dried IL [TMP]MS (vide
supra), we focused on this reaction.
Production and reductive amination of biobased HMF
43
Following the approach of Simion et al.,433 who performed the reductive
amination in water as reaction medium, a number of reactions were
performed using aqueous solutions of HMF. Reactions were conducted
without the use of a catalyst and under very mild conditions. By using this
facile and straightforward method, a small library of compounds containing a
hydroxymethyl and an aminomethyl moiety on the furan ring was produced,
in high yields and requiring only minimal purification. Surprisingly and to the
best of our knowledge, most of these simple structures were never described
before.
Initial reactions were performed at room temperature. Addition of pure
aliphatic amines to the aqueous solution of HMF resulted in relatively fast
complete conversions to imines (2, Scheme 9). Complete conversions of HMF
were obtained within hours. In a one-pot approach, the imines were then
reduced to the corresponding amines (3) with sodium borohydride (NaBH4);
reduction was generally performed during one hour at room temperature.
This simple procedure typically gave very good results in reactions with
aliphatic amines (Table 4). However, when repeating the experiments under
the same operating conditions, the results for reactions of HMF with aromatic
amines gave significantly different results: conversions to the imines of up to
50 % were observed after several days of stirring at room temperature. It was
therefore decided to test other reaction media, methanol and ethanol.
Methanol is a good solvent for starting materials and reagents, and a preferred
solvent for reduction reactions with borohydride. Unfortunately, reactions in
dry methanol with aromatic amines gave poor results, similarly to the results
when water was used as reaction medium. On the other hand, if methanol was
used for the reactions with the aliphatic amines, the required reaction times
were drastically improved: e.g. imine formation from allylamine and HMF (a
complete conversion) took 45 minutes in methanol whereas reaction in water
needed 4 hours for completion (entries 2 and 2’, Table 4).
Dry ethanol was the next solvent of choice. Ethanol is, similarly to methanol,
a good solvent for the starting materials and reagents (sodium borohydride
has a limited solubility of 4g/100ml at 20 °C, which was, however, enough for
the reactions to take place). Acting as water scavenger, ethanol is also assumed
Chapter 2
44
to increase the rate of imine formation. The reactions with aliphatic amines
were repeated with ethanol as reaction medium, which again resulted in a
decrease of the required reaction time as compared to water: a couple of hours
were sufficient for the formation of the imines (entries 4’ and 5’, Table 4).
Aromatic amines, however, were only formed after a longer reaction time (up
to 50 hours, entries 9-12, Table 4).
Addition of molecular sieves was tested to improve the efficiency of the
reaction, i.e. to shorten the reaction time: sieves 4Å in entries 4’ and 8, and 3Å
in entry 10’, Table 4). This approach was moderately successful (as it was
estimated that the reaction time was enhanced already by the solvent change).
The addition of the sieves did not have a significant influence on the reaction
with an aliphatic amine (entry 4’ compared to entry 5’, and entry 8 compared
to entry 9). On the other hand, for reactions demanding longer reaction times,
the addition of the sieves had a larger influence. Comparing entries 10 and 10’,
it can be seen that the addition of the sieves substantially reduced the reaction
time, from 50 to 30 hours.
Using the described procedure, a small library of derivatives was produced,
presented in Table 4. Reactions were followed by TLC and 1H-NMR, and the
structures of the end products were confirmed by LC-MS, 1H- and 13C-NMR,
IR spectroscopy and elemental analysis. In the first step of the reaction (the
imine formation), a significant difference in the reactivity of amines was
noticed. A decreasing reactivity order can be determined: aliphatic amines >
aromatic amines with electron donating groups > aromatic amines > aromatic
amines with electron withdrawing groups (the experiments with aromatic
amines containing NO2 and Cl substituents did not yield more than 30 %
conversion of HFM into the corresponding imines in 24h time; the further
procedure was therefore abandoned).
Production and reductive amination of biobased HMF
45
Table 4: Overview of the reductive aminations performed at room temperature
Entry R Solvent Reaction time
step 1
Reaction time
step 2
Yield
(%)
Chromatographic
purification
1
H2O 5h 1h 92 MeOH/CH2Cl2 10/90 Rf=0.42
2 H2O 4h 1h 80 MeOH/CH2Cl2
10/90 Rf=0.12
3
H2O 4h 1h 97 MeOH/CH2Cl2
10/90 Rf=0.55
4
H2O 4h 1h 77 EtOAc/PE 5/95 Rf= 0.45
5 H2O 6h 1h 82 MeOH/CH2Cl2
10/90 Rf=0.24
6
H2O 6h 1h 88 MeOH/CH2Cl2
10/90 Rf=0.26
6’
MeOH 2h 30’ 94 Same as 6
7 MeOH 1h 1h 99 MeOH/CH2Cl2
10/90 Rf=0.30
2’ MeOH 45’ 30’ 93 Same as 2
8
EtOH 30h 1h 96 MeOH/CH2Cl2 2/98 Rf=0.36
9
EtOH 30h 1h 86 MeOH/CH2Cl2 2/98 Rf=0.22
4’
EtOH 2h 1h 96 Same as 4
5’ EtOH 1.5h 1h 92 Same as 5
10
EtOH 50h 1h 83 MeOH/CH2Cl2
2/98 Rf=0.18
11
EtOH 50h 1h 91 MeOH/CH2Cl2
2/98 Rf= 0.30
10’
EtOH 30h 1h 83 MeOH/CH2Cl2
2/98 Rf=0.18
12
EtOH 50h 1h 97 MeOH/CH2Cl2
10/90 Rf=0.61
In an additional attempt to reduce the reaction times for imine formation,
reactions were conducted under conventional and microwave heating. In this
part of work, the conversions to the imines, as critical steps for the whole
process, were followed by HPLC. The experimental results are presented in
Table 5.
H3C
5
O
OOH3C
5
N
NO
Chapter 2
46
Table 5: Reactions conducted under conventional and microwave heating
Entry R Solvent Time t (°C) Heat source Convers.(%)
5a H2O 5’ 50 Microwave 100
5b H2O 15’ 50 Conventional 100
6a
H2O 15’ 50 Conventional 100
11a
EtOH 1.5h 40 Microwave 50
11b
EtOH 6h 100 Microwave 65
11b
EtOH +24h 100 -> -20 Microwave 85
11c
H2O 2h 100 -> 200 Microwave 70
12a
EtOH 20’ 40 Microwave 65
12a
EtOH 1h 40 -> 100 Microwave 70
12b
EtOH 72h -20 None 80
It was noticed that both conventional and microwave heating indeed resulted
in a drastic improvement of the iminations with aliphatic amines – at 50 °C,
reaction time was reduced to 15 minutes for the conventional (entries 5b and
6a), and to 5 minutes (entry 5a), for the microwave heating.
In the reactions with aromatic amines, mild microwave heating did not
produce such dramatic results (entry 11a). Some improvements were noticed
on the conduction of reactions above boiling points of the solvents, which was
possible in the pressurised vessel in the microwave synthesizer (entries 11b
and 11c).
Due to the high energy absorbing nature of ethanol, it was noticed that the
energy required to reach this temperature (100 °C) was only 1-2 W during the
course of the reaction. For reactions in water, temperatures of 100 °C were
achieved and retained by the use of 10-20 W of power. The maximal energy
feeding potential of the reaction setup (200 W) was only needed during
heating of reactions in water to 200 °C. No experiments with methanol were
performed in pressurized vessels.
O
O
O
Production and reductive amination of biobased HMF
47
As a conclusion, both heating methods (conventional and microwave)
improved the reaction rates of the imines formation. Application of microwave
heating allowed for the reaction temperatures above the boiling points of
solvents. However, in the times mentioned in Table 5, no complete conversion
of HMF could be observed. Additionally, under the prolonged heating, the
degradation products of HMF were formed; these were humic substances,
noticed as black, partially soluble, accumulations in the reaction mixture, also
detected by the HPLC. Under these conditions, a part of the substrate thus
remains unavailable for further reaction, lowering the final yields.
Interestingly, the formation of imines was noticed on simple standing at -20
°C in the freezer for prolonged time periods. In entry 11b, 6 hours microwave
irradiated reaction is followed by 24 hours stay in the freezer; this resulted in
additional conversion to imine, up to 85 %. Similarly, in entry 12b, a significant
conversion (80 %) was measured without any prior heating, simply by keeping
the reaction mixture at -20 °C for 72 hours. Obviously, apart from the reaction
temperature, the reaction time was a very important factor for the HMF
conversions.
2.3. Experimental part
The reaction materials, including organic solvents for the reactions or for the
work-up were purchased from Sigma-Aldrich and Acros Organics and used as
such, except otherwise mentioned. Methanol was dried over molecular sieves
(4Å) and fractionally distilled. Ethanol was dried over CaO, refluxed and
fractionally distilled.
Microwave-assisted reactions were performed on a CEM BenchMate
synthesizer equipped with the IR temperature sensor. High-resolution 1H-
NMR (300 MHz) and 13C-NMR (75 MHz) spectra were recorded on a Jeol
JNM-EX 300 NMR spectrometer. HPLC analysis of reaction mixtures and final
products was performed on an Agilent 1200 series HPLC, equipped with a
UV/Vis DAD detector at 254 and 280 nm, coupled with an Agilent LC/MSD VL
with ES API, on a Zorbax Eclipse XBD-C18 4.6×150×5µm RP column. Low-
resolution mass spectra were recorded with an Agilent 1100 Series VS (ES =
Chapter 2
48
4000 V) mass spectrometer. IR spectra were recorded on a Perkin–Elmer
Spectrum BX FT-IR spectrometer. All compounds were analysed in neat form
with an ATR accessory. Melting points of the solid products were measured
with a Büchi 540 apparatus and have not been corrected. Elemental analysis
was performed on a Perkin-Elmer 2400 Elemental Analyzer. Additional
purification of the reaction mixtures was performed by column
chromatography in a glass column on silica gel (Acros, particle size 0.035–
0.070 mm, pore diameter ca. 6 nm). TLC chromatography in experiments with
HMF production was performed on glass-backed silica plates (Merck Kieselgel
60 F254 precoated 0.20 mm).
2.3.1. Production of HMF
2.3.1.1. Determination of the recovery of HMF from an ionic liquid
In a typical recovery determination procedure, 0.5 g of HMF was mixed
with 3 g of ionic liquid with a short heating in a 20 ml round bottom reaction
flask, until a homogenous mixture was obtained.
1) In a batch-wise performed extraction, 10 ml of brine was added to this
mixture and the complete mixture was transferred to a separating funnel.
Extraction was performed with 4-6 portions of solvent, up to volumes between
60 and 100 ml.
2) In a continuously performed extraction, this mixture was transferred to
a continuous extraction apparatus, and was connected to a flask containing the
solvent, which was then set to reflux.
3) In a continuously performed extraction with mixing, solvent was added
to the mixture of IL and HMF and stirred for a specified period of time. After
this, the mixture was diluted with brine, transferred to a separating funnel and
separated.
In all three manners of extraction, the organic phases were combined,
washed with 20 ml of water, dried over MgSO4 and concentrated under
vacuum. The HMF purity was confirmed using NMR.
Production and reductive amination of biobased HMF
49
2.3.1.2. Production of HMF in IL media
In an example procedure, 3 g of ionic liquid was weighed in a 50 ml round-
bottom reaction flask, melted and heated to the desired temperature in an oil
bath. 1 g of inulin was added to the ionic liquid. The reaction mixture was
stirred while heating for a specified period of time. During the reaction,
samples were withdrawn and submitted to a 1H NMR analysis. After a
specified reaction time, the IL medium was diluted with brine and the
extraction was performed, as described in the previous section. The solvent
was evaporated and the sample was analysed by 1H and 13C NMR.
2.3.1.3. Production of HMF with homogenous and heterogeneous catalyst
For the heterogeneously catalyzed reactions, in an example procedure, 200
mg inulin (1.23 mmol) and 60 mg solid catalyst were weighed in a 20 ml
round-bottom flask and 3 ml solvent was added. The reaction mixture was
stirred under heating for a specified reaction time. Reactions were followed by
1H NMR.
For a homogeneously catalysed reaction, in a typical procedure 300 mg
inulin (1.9 mmol) was weighed in a 50 ml round-bottom reaction flask. 10 ml
of an acid solution (0.1 N) in water was added. Alternatively, 7.5 ml acid
solution 0.1 N and 2.5 ml DMSO were added (see Table 3). The reaction
mixture was stirred while heating for a specified period of time. Reactions
were followed by 1H NMR. If the product was extracted, the reaction flask was
cooled under running water, reaction mixture neutralized with 0.1 N NaOH
and then batch-wise extracted with diethyl ether (6x15 ml). Combined solvent
portions were washed with water, brine and dried over MgSO4. The solvent
was evaporated and the product purity confirmed by NMR.
2.3.2. Reductive amination of HMF
2.3.2.1. Production of amines from HMF precursors
After the reaction procedure described in § 2.3.1.2 and 2.3.1.2, to the
reaction mixture 1.1 equivalents (calculated on 100 % yield of HMF) of
benzylamine was added to the reaction mixture. The reaction was further
Chapter 2
50
stirred at 40 °C for 4 h. Samples were taken and the reaction followed by 1H
NMR. After the conversion of HMF to imine was confirmed, 1.5 equiv. NaBH4
was added to the reaction mixture and the reaction was continued for 1 h.
After this, extraction with diethyl ether was performed and the product purity
tested on 1H NMR. Low yields and a high number of side-products were
characteristic for this reaction. Further purification was not performed.
2.3.2.2. Reductive amination of pure HMF
2.3.2.2.1. Procedure in water
In a 50 ml round-bottom reaction flask, 300 mg of HMF (2.3 mmol) and 1.1
equiv. of primary amine were stirred in 10 ml of deionised water at room
temperature. After the imine formation, 1.5 equiv.. of sodium borohydride
were added and the reaction mixture was stirred for an hour. The resulting
amine was extracted with 3x15 ml of diethyl ether. The combined organic
phase was washed with brine, dried over MgSO4 and evaporated under
reduced pressure. This procedure results in crude end products with a purity
of 95 % (determined by 1H-NMR). Additional purification was performed by
column chromatography, resulting in high yields of isolated material in all
cases.
2.3.2.2.2. Procedures in methanol and ethanol
In a 50 ml round-bottom flask, 1.1 equiv. of primary amine was added to
~300 mg of HMF (2.3 mmol) in 10 ml of alcohol, and the reaction mixture was
stirred under a nitrogen flow at room temperature. In entries 4’ and 8, ~1 g of
dry molecular sieves 4Å was added to the reaction mixture. In entry 10’, ~1 g
of dry molecular sieves 3Å was added to the reaction mixture. After the
reaction was completed, the resulting imine was reduced by addition of 1.5
equiv. of sodium borohydride for generally one hour. Alcohol was then
evaporated, and 1 ml of water was added to the resulting dry mixture. The
final product was extracted with 2x15 ml of dichloromethane. The organic
phase was washed with water and brine, dried over MgSO4 and evaporated
under reduced pressure. This procedure gave purities over 95 % of the
resulting amines (determined by 1H-NMR). The products were additionally
purified by column chromatography and characterised.
Production and reductive amination of biobased HMF
51
2.3.2.2.3. Reactions performed under microwave heating
In a 10 ml sealed vessel, 1.1 equiv. of primary amine was added to ~150 mg
of HMF (~1.16 mmol) in 5 ml of solvent (water or ethanol). Reactions were
followed using HPLC and 1H-NMR.
2.3.2.2.4. Reactions performed under conventional heating
In a 25 ml round-bottom flask, 1.1 equiv. of primary amine was added to
~150 mg of HMF (1.16 mmol) in 5 ml of solvent (water or ethanol). Reaction
mixtures were heated in an oil bath and followed by HPLC and 1H-NMR.
2.3.2.2.5. Product characterization
(5-Benzylaminomethyl-2-hydroxymethyl)furan (1): 1H-NMR (ppm, CDCl3, Si(CH3)4) δ: 2.12 (2H, br s, OH,
NH); 3.75 (2H, s, furylCH2NH); 3.78 (2H, s, NHCH2phenyl); 4.54 (2H, s, CH2OH); 6.12
(1H, d, J=2.8, Hfuryl4); 6.19 (1H, d, J=3.0, Hfuryl3); 7.20-7.43 (5H, m, phenyl); 13C-
NMR (ppm, CDCl3, Si(CH3)4) δ: 45.48 (furylCH2NH); 52.90 (NHCH2phenyl); 57.45
(CH2OH); 108.05 (Cfuryl4); 108.34 (Cfuryl3); 127.19 (Cphenyl4); 128.38 (Cphenyl2,
Cphenyl6); 128.56 (Cphenyl3, Cphenyl5); 139.73 (CH2phenyl); 153.71 (Cfuryl5,
Cfuryl2); IR (cm-1) νmax: 697; 737; 792; 920; 1012; 1073; 1182; 1359; 1453; 1495; 1560;
1603; 2849; 2920; 3028; 3061; 3301; MS (ES+) m/z: 218.2 (M+H+); yellow viscous liquid.
(5-Allylaminomethyl-2-hydroxymethyl)furan (2): 1H-
NMR (ppm, CDCl3, Si(CH3)4) δ: 3.27 (2H, dt, J=6.1, J=1.3,
NHCH2CH); 3.77 (2H, s, CH2NH); 4.57 (2H, s, CH2OH); 5.09
(1H, d, J=10.5, CHHcisCHCH2); 5.13 (1H, d, J=17.6, CHHtransCHCH2); 5.82 (1H, ddt,
Jcis=17.1, Jtrans=10.5, JCH2=6.1, NHCH2CHCH=); 6.13 (1H, d, J=3.3, Hfuryl4); 6.21
(1H, d, J=3.3, Hfuryl3); 13C-NMR (ppm, CDCl3, Si(CH3)4) δ: 45.17 (NHCH2CH); 51.22
(CH2NH); 57.02 (CH2OH); 108.06 (Cfuryl4); 108.14 (Cfuryl3); 116.93 (CH2CH); 135.94
(CH2CH); 153.00(Cfuryl5); 154.17 (Cfuryl2); IR (cm-1) νmax: 790; 921; 1012; 1075; 1143;
1186; 1355; 1447; 1560; 1643; 2919; 2840; 3078; 3286; MS (ES+) m/z: 168.2 (M+H+);
yellow viscous liquid.
(5-(2-Phenylethyl)-aminomethyl-2-
hydroxymethyl)furan (3) (CAS 66356-43-2): Elemental
analysis data are reported elsewhere.432 Additional characterisation is given. 1H-NMR
(ppm, CDCl3, Si(CH3)4) δ: 2.77-2.95 (4H, m, CH2CH2NH); 3.77 (2H, s, furylCH2NH);
HO
O
HN
HO
O
HN
HO
ONH
Chapter 2
52
4.56 (2H, s, CH2OH); 6.09 (1H, d, J=2.8, Hfuryl4); 6.19 (1H, d, J=2.8, Hfuryl3); 7.34-7.18
(5H, m, phenyl); 13C-NMR (ppm, CDCl3, Si(CH3)4) δ: 36.22 (NHCH2CH2); 46.27
(NHCH2CH2); 50.39 (furylCH2NH); 57.62 (CH2OH); 107.92 (Cfuryl4); 108.46 (Cfuryl3);
126.32 (Cphenyl4); 128.60 (Cphenyl2, Cphenyl6); 128.80 (Cphenyl3, Cphenyl5); 139.91
(Cphenyl1); 153.48 (Cfuryl5); 153.80 (Cfuryl2); IR (cm-1) νmax: 698; 747; 791; 921; 1012;
1086; 1188; 1358; 1453; 1495; 1560; 1603; 2849; 2922; 3026; 3293; MS (ES+) m/z: 232.3
(M+H+); yellow viscous liquid.
(5-Dodecylaminomethyl-2-hydroxymethyl)furan (4): 1H-NMR (ppm, CDCl3, Si(CH3)4) δ: 0.88 (3H, t, J=6.6 CH3);
1.25 (18H, s, CH2); 1.48 (2H, t, J=6.3, NHCH2CH2); 2.58 (2H,
t, J=7.4, NHCH2CH2); 3.74 (2H, s, CH2NH); 4.51 (2H, s, CH2OH); 6.11 (1H, d, J=2.8,
Hfuryl4); 6.17 (1H, d, J=3.3, Hfuryl3); 13C-NMR (ppm, CDCl3, Si(CH3)4) δ: 14.22
(C12); 22.78 (C11); 27.41 (C3); 29.45 (C4, C9); 29.70 (C5-C8); 30.03 (C2); 32.01 (C10);
46.44 (C1); 49.39 (furylCH2NH); 57.59 (CH2OH); 107.71 (Cfuryl4); 108.43 (Cfuryl3);
153.45 (Cfuryl5); 154.17 C (Cfuryl2); IR (cm-1) νmax: 718; 791; 883; 897; 938; 1008; 1016;
1115; 1198; 1351; 1470; 1572; 1604; 2788; 2849; 2915; 2954; 1744; 3156; 3263; MS (ES +)
m/z: 296.3 (M+H+); mp=35 °C; white fatty solid.
(5-Propylaminomethyl-2-hydroxymethyl)furan (5): 1H-
NMR (ppm, CDCl3, Si(CH3)4) δ: 0.92 (3H, t, J=7.4, CH3); 1.52
(2H, sext, J=7.4, CH2CH3); 2.59 (2H, t, J=7.2, NHCH2CH2); 3.77
(2H, s, furylCH2NH); 4.58 (2H, s, CH2OH); 6.13 (1H, d, J=3.3, Hfuryl4); 6.21 (1H, d,
J=3.3, Hfuryl3); 13C-NMR (ppm, CDCl3, Si(CH3)4) δ: 11.82 (CH3); 23.03 (CH2CH3); 46.29
(NHCH2CH2); 51.11 (furylNHCH2); 57.70 (CH2OH); 107.81 (Cfuryl4); 108.50 (Cfuryl3);
153.51 (Cfuryl5); 153.94 (Cfuryl2); IR (cm-1) νmax: 791; 1013; 1072; 1096; 1189; 1358;
1458; 1560; 1637; 2873; 2931; 2958; 3279; MS (ES+) m/z: 170.2 (M+H+); yellow viscous
liquid.
(5-Isopropylaminomethyl-2-hydroxymethyl)furan (6)
(CAS 66356-44-3): Elemental analysis is reported
elsewhere.402,409 Additional characterisation is given. 1H-NMR
(ppm, CDCl3, Si(CH3)4) δ: 1.09 (6H, d, J=6.1, CH(CH3)2); 1.97
(2H, br s, NH, OH); 2.84 (1H, sept, J=6.2 CH(CH3)2); 3.77 (2H, s, CH2NH); 4.57 (2H, s,
CH2OH); 6.12 (1H, d, J=3.3, Hfuryl4); 6.20 (1H, d, J=3.3, Hfuryl3); 13C-NMR (ppm,
CDCl3, Si(CH3)4) δ: 22.74 (CH3); 44.01 (NHCH); 47.91 (CH2NH); 57.59 (CH2OH);
107.63 (Cfuryl4); 108.50 (Cfuryl3); 153.50 (Cfuryl5); 154.14 (Cfuryl2); IR (cm-1) νmax:
788; 1013; 1064; 1129; 1173; 1339; 1383; 1443; 1467; 1560; 1654; 2864; 2922; 2965; 3270;
MS (ES+) m/z: 170.5 (M+H+); yellow viscous liquid.
HO
O
HN
5
HO
O
HN
HO
O
HN
Production and reductive amination of biobased HMF
53
(5-(2-Methoxyphenylamino)methyl-2-
hydroxymethyl)furan (7); 1H-NMR (ppm, CDCl3, Si(CH3)4)
δ: 3.84 (3H, s, OCH3); 4.32 (2H, s, CH2NH); 4.58 (2H, s,
CH2OH); 6.19 (1H, d, J=3.3, Hfuryl4); 6.22 (1H, d, J=3.3,
Hfuryl3); 6.65-6.90 (4H, m, phenyl); 13C-NMR (ppm, CDCl3, Si(CH3)4) δ: 41.39
(CH2NH); 55.54 (OCH3); 57.48 (CH2OH); 107.83 (Cfuryl4); 108.60 (Cphenyl6); 109.76
(Cfuryl3); 110.57 (Cphenyl3); 117.42 (Cphenyl4); 121.33 (Cphenyl5); 137.67
(Cphenyl1); 147.21 (Cphenyl2); 153.04 (Cfuryl5); 153.65 (Cfuryl2); IR (cm -1) νmax: 735;
791; 1012; 1178; 1221; 1246; 1339; 1456; 1508; 1601; 2836; 2867; 3066; 3400; MS (ES +)
m/z: 234.3 (M+H+); yellow viscous liquid.
(5-Butylaminomethyl-2-hydroxymethyl)furan (8); 1H-
NMR (ppm, CDCl3, Si(CH3)4) δ: 0.91 (3H, t, J=7.2 CH3); 1.34
(2H, sext, J=7.3, CH2CH3); 1.49 (2H, sext, J=7.4, CH2CH2CH3); 2.63 (2H, t, J=7.2,
NHCH2CH2); 3.78 (2H, s, furylCH2NH); 4.58 (2H, s, CH2OH); 6.14 (1H, d, J=2.8,
Hfuryl4); 6.21 (1H, d, J=2.8, Hfuryl3); 13C-NMR (ppm, CDCl3, Si(CH3)4) δ: 13.98 (CH3);
20.42 (CH2CH2CH3); 31.55 (CH2CH2CH3); 45.87 (NHCH2CH2); 48.55 (furylNHCH2);
56.89 (CH2OH); 107.94 (Cfuryl4); 108.20 (Cfuryl3); 152.63(Cfuryl5); 154.37 (Cfuryl2);
IR (cm -1) νmax: 789; 1012; 1071; 1097; 1188; 1258; 1357; 1458; 1560; 1662; 2860; 2928;
2928; 2956; 3280; MS (ES+) m/z: 184.5 (M+H+); dark yellow viscous liquid.
(5-(2,4-Dimethoxyphenylaminomethyl)-2-
hydroxymethyl)furan (9); 1H-NMR (ppm, CDCl3,
Si(CH3)4) δ: 3.75 (3H, s, OCH3(p)); 3.82 (3H, s, OCH3(o));
4.28 (2H, s, CH2NH); 4.58 (2H, s, CH2OH); 6.17 (1H, d,
J=2.8, Hfuryl4); 6.22 (1H, d, J=3.3, Hfuryl3); 6.39 (1H, dd, J=2.8, J=2.8, Hphenyl3); 6.46
(1H, d, J=2.8, Hphenyl5); 6.59 (1H, d, J=8.8, Hphenyl6); 13C-NMR (ppm; CDCl3,
Si(CH3)4) δ: 42.16 (CH2NH); 55.57 (OCH3(o)); 55.83 (OCH3(p)); 57.65 (CH2OH); 99.27
(Cphenyl3); 103.76 (Cphenyl5); 107.73 (Cfuryl4); 108.69 (Cfuryl3); 110.99 (Cphenyl6);
131.90 (Cphenyl1); 148.34 (Cphenyl2); 152.51 (Cphenyl4); 153.39 (Cfuryl5); 153.42
(Cfuryl2); IR (cm-1) νmax: 790; 1012; 1030; 1136; 1154; 1204; 1287; 1359; 1455; 1513; 2834;
2936; 3396; MS (ES+) m/z: 264.2 (M+H+); dark yellow viscous liquid.
(5-Quinolin-6-yl-aminomethyl-2-
hydroxymethyl)furan (10); 1H-NMR (ppm,
(CD3)2CO, Si(CH3)4) δ: 4.42 (2H, s, CH2NH); 4.70
(2H,s, CH2OH); 6.19 (1H, d, J=3.3, Hfuryl4); 6.28 (1H,
d, J=3.3, Hfuryl3); 7.22-7.31 (2H, m, Hquin5, Hquin7); 7.33 (1H, d, J=2.7, Hquin3); 7.77
HO
O
HN
O
HO
O
HN
HO O
HN O
O
HO
O
HN
N
Chapter 2
54
(1H, d, Hquin4); 7.97 (1H, d, J=8.3, Hquin8); 8.53 (1H, dd, J=6.2, J=6.2, Hquin2); 13C-
NMR (ppm, (CD3)2CO, Si(CH3)4) δ: 40.68 (CH2NH); 56.50 (CH2OH); 102.75 (Cquin5);
107.60 (Cfuryl4); 107.76 (Cfuryl3); 121.28 C (Cquin3); 121.50 (Cquin7); 130.08
(Cquin4a); 130.26 (Cquin8); 133.33 CH (Cquin4); 143.45 (Cquin8a); 145.74 (Cquin6);
146.51 (Cquin2); 152.27 (Cfuryl5); 155.07 (Cfuryl2); IR (cm-1) νmax: 796; 832; 942; 1011;
1031; 1124; 1186; 1252; 1318; 1378; 1546; 1624; 2734; 2826; 2895; 3073; 3310; MS (ES +)
m/z: 255.2 (M+H+); El.anal. (%) Calc. for C15H14N2O2: C 70.85; H 5.55; N 11.02; O 12.58;
found: C 69.75; H 5.44; N 10.60; mp=148 °C; dark orange powder.
(5-(2,6-Dimethylphenylamino)methyl-2-
hydroxymethyl)furan (11) (CAS 241128-35-8); 1H- and 13C-
NMR data and elemental analysis are reported elsewhere.436
Additional characterisation is given. 1H-NMR (ppm, CDCl3,
Si(CH3)4) δ: 2.26 (6H, s, (CH3)2); 3.40 (1H, br s, NH); 4.11 (2H, s, CH2NH); 4.57 (2H, d,
J=5.8, CH2OH); 6.05 (1H, d, J=3.6, Hfuryl4); 6.19 (1H, d, J=3.6, Hfuryl3); 6.84 (1H, t,
J=7.4, Hphenyl4); 6.99 (2H, d, J=7.7, Hphenyl3, Hphenyl5); 13C-NMR (ppm, CDCl3,
Si(CH3)4) δ: 18.36 (CH3)2; 45.24 (CH2NH); 57.68 (CH2OH); 107.70 (Cfuryl4); 108.76
(Cfuryl3); 122.55 (Cphenyl4); 128.83 (Cphenyl2, Cphenyl6); 130.14 (Cphenyl3,
Cphenyl5); 145.15 (Cphenyl1); 153.39 (Cfuryl5); 154.11 (Cfuryl2); IR (cm -1) νmax: 777;
798; 849; 1014; 1028; 1172; 1357; 1448; 1471; 1557; 1592; 2849; 2894; 2930; 2955; 3224;
3352; MS (ES+) m/z: 232.2 (M+H+); mp=96 °C; light yellow crystals.
(5-(3-Methoxyphenyl)aminomethyl-2-
hydroxymethyl)furan (12): 1H-NMR (ppm, CDCl3,
Si(CH3)4) δ: 3.65 (3H, s, OCH3); 4.16 (2H, s,
CH2NH); 4.42 (2H, s, CH2OH); 6.8 (2H, dd, J=3.3,
J=3.3, Hfuryl3, Hfuryl4); 6.13 (1H, t, J=2.2, Hphenyl3); 6.20 (2H, td, Jt=8.5, Jd=2.0,
Hphenyl3, Hphenyl5); 6.98 (1H, t, J=8.0, Hphenyl5); 13C-NMR (ppm, CDCl3, Si(CH3)4)
δ: 41.56 (OCH3); 55.19 (CH2NH); 57.42 (CH2OH); 99.47 (Cphenyl2); 103.30 (Cphenyl4);
106.44 (Cphenyl6); 107.79 (Cfuryl4); 108.66 (Cfuryl3); 130.08 (Cphenyl5); 149.12 C
(Cphenyl1); 152.77 (Cfuryl5); 153.62 (Cfuryl2); 160.84 C (Cphenyl3); IR (cm -1) νmax:
687; 727; 908; 1010; 1161; 1209; 1341; 1496; 1509; 1600; 1613; 2836; 2933; 3387; MS (ES+)
m/z: 234.2 (M+H+); yellow viscous liquid.
HO O
HN
HO
O
HN O
Production and reductive amination of biobased HMF
55
2.4. Conclusions
In the first part of this work, it was shown that ionic liquids are suitable
media for HMF production from a fructose precursor, inulin. ILs are praised
as designer solvents with interesting physical and chemical characteristics and
diverse applications. Acidic ionic liquids, 1-methylimidazolium chloride,
[HMIM]Cl, and 1,2,4-trimethylpyrazolium methylsulphate [TMP]MS proved
to be able to catalyse the conversion to HMF. Reactions were performed
without catalyst, in rather concentrated solutions (10 – 30 mass %). Removal
and purification of HMF remained a problematic issue for this process. This is
due to the sensitivity of HMF to rehydration during purification, and its
tendency to polymerise to soluble and insoluble humic substances. If these
issues are correctly addressed (with optimised solvent combinations, increased
solvent volumes) purification may be optimised. Optimisation of ionic liquids
properties could possibly result in increased conversions and yields.
In the second part of this work, a simple and convenient procedure was
developed for the production of novel and known alkylaminomethylfuran
structures in high yields starting from HMF. This procedure can be used for
synthesizing these structures, useful in pharmaceutical and chemical industry.
In contrast to the currently employed processes for obtaining these structures,
the presented method (a) was performed in sustainable and readily available
reaction media – water and short chain alcohols, (b) does not necessarily
involve extreme conditions of pressure or temperature, (c) does not involve
catalysts, and (d) demands a minimal work-up. Mild conditions of room
temperature and atmospheric pressure were applied for the aliphatic amine
reactants. Alternatively, conventional and microwave heating was applied to
reduce the reaction time. Only a minimal purification of the product was
necessary.
Chapter 2
56
Kiliani reaction under microreactor conditions
57
3. The application of microreaction technology on the
Kiliani reaction on ketoses
3.1. Introduction
Due to their structure (one or more chiral centres in the molecule),
carbohydrates can be valuable starting materials for the production of
optically active patterns. This can be performed by carrying out
transformations limited to a chiral core while retaining the generic
carbohydrate structure, or by total transformations into compounds that are
structurally no longer related to carbohydrates. Ketoses constitute an
important share of monohydrates available from nature, especially D -fructose
and L-sorbose, hexoses obtained in bulk quantities.364,437 The chemical potential
of ketoses, however, still seems unexploited – branched sugar chirons are
seldom available and functionalized on commercial scale.364 The main reasons
behind this are related to some practical limitations typical for carbohydrates
as chemical feedstocks, such as their solubility, limited to polar solvents, and
high density of functional groups, which can lead to unexpected and
unwanted side reactions, including isomerisations (such as tautomerisation of
fructose in solution, see Scheme 4), rearrangements and unwanted
derivatisations. This has lead to a rather limited number of industrially
interesting chemical reactions on carbohydrate feedstocks.437–444
One of the classical reactions in carbohydrate chemistry is the Kiliani
cyanohydrin synthesis (Scheme 11). The condensation of cyanide with an
aldose in an aqueous solution to produce 2-epimeric aldononitriles
(cyanohydrins) was first reported in 1885.445,446
Chapter 3
58
R
O
NC
H
R
O
C
H
N
OHOH
H+
R
O
C
H
N
OH
H
H2O R
O
C
H
N
OH
HO
HH
R
O
C
H
O
OH
HO
OH-
R
O
C
H
NH
OH
HO
R
O
C
H
NH2
OH
O
R
O
C
H
N
OH
HOH
H
Scheme 11: Mechanism of cyanohydrin formation and hydrolysis, under acidic or
basic conditions
Cyanohydrins were hydrolyzed in situ to 2-epimeric salts of aldonic acid.
Kiliani also demonstrated that aldonic acids could lose water to form
aldonolactones. The utility of the Kiliani reaction was extended when
Fischer447 reduced the aldonolactones with sodium amalgam to aldoses,
providing a convenient route for the preparation of aldoses with one more C
atom in the chain. The Kiliani-Fischer reaction has ever since been used to
prepare a wide variety of aldoses.448
The α-hydroxycarboxylic acids, obtained by the hydrolysis of
cyanohydrins (Scheme 11) are interesting and important carbohydrate
derivatives. They are used in cosmetology,449–453 but are also important
building blocks for the synthesis of depsides and depsipeptides,454 compounds
that exhibits significant biological activity,455 and used as chiral ligands455–458 or
emulgators.459,460
The applicability of flow chemistry for the Kiliani reaction, using lower
ketoses as substrates, various cyanide sources and short chain organic acids
(acetic or formic) has been explored. The main advantages of microreaction
technology, such as the control of the local stoichiometry, the high mixing and
heat exchange efficiency, as well as the sealed micrometric reaction channels,
result in a significant improvement in reaction flexibility, efficiency and
applicability (vide infra, § 1.2.4.). The danger of released HCN has been
avoided by the use of the closed system. The obtained conversions were
clearly better in flow than in batch (compared with literature data and o wn
experiments).
Kiliani reaction under microreactor conditions
59
The research presented in this and the following chapter is part of a
program dedicated to determine the applicability of microreactor technology
for organic synthetic transformations.197,461–473
3.1.1. Kiliani reaction
Cyanohydrin formation is a very important reaction in organic chemistry,
leading to derivatives with a wide potential for further transformations.474
Formation of cyanohydrins from carbohydrates (i.e. the Kiliani reaction) is
especially important as the starting materials are available in nature and
possess diverse functionalities. Over the years, various operating conditions
for the Kiliani reaction, with a wide range of conversions and yields, were
described. Reactions are, however, mostly reported using aldoses as starting
materials, resulting in linearly elongated chains. Blazer and Whaley, for
example,475 reported a 7 h reaction time for the formation of glucono- and
manononitrile from D-arabinose. Arena476 obtained conversions of arabinose in
shorter reaction time (one hour under cooling conditions) and explored the
effect of chelating agents on the reaction stereoselectivity. Uguen et al.477
reported the improved Kiliani-Fischer synthesis by using a Hünig base (i.e.
DIPEA) to enhance the cyanide addition to the aldehyde produced in situ
from an alcohol, under Swern conditions (i.e. with addition of oxalyl chloride
and DMSO), and subsequently reduced the nitrile to the aldehyde, prolonging
the carbohydrate chain. The cyanide addition reaction, however, took hours
and high equivalents of cyanide were used.477 Addition of cyanides to
protected aldoses needed hours, and their hydrolysis days for completion, as
described in the work published by Fleet et al.478 Final products of this process,
the acetonides, are useful chirons.
Alternative procedures for the production of cyanohydrins from carbonyls
have been reported, such as the reaction with hydroxylamine hydrochloride.479
Cyanation of benzaldehyde with TMSCN or acetyl cyanide was performed on
a flow microreactor using solid Lewis acid-Lewis base catalyst.480 Solid
catalysts have been used for the asymmetric addition of cyanide to the
carbonyl group.481 Reactions of nitrile formation482,483 and hydrolysis to amides
and acids484–487 are often biochemically catalysed.
Chapter 3
60
Serianni et al.448,488,489 pointed out to the importance of the pH for the
conversion and, as a rule, obtained faster conversions to cyanides and to acids
at higher pH values. In some cases, however, 3 to 12 hours were needed for
the hydrolysis of aldononitriles.448 Hydrolysis of β-nitriles to amides were
even reported to take days.490
α-Hydroxycarboxylic acids can also be produced from carbohydrates by
the direct oxidation of the carboxylic group. Kiliani prepared sugar-based
acids by oxidation with nitric acid.491 Acid lactones were reported to be
obtained by the oxidation of aldoses, functionalised at position 4, with
hydrogen peroxide in basic media.492,493
Very little work is reported on the use of unprotected ketoses as feed.
Reactions invariably include very long reaction times (several days) for the
conversions to nitriles and drastic conditions (usually prolonged reflux) for the
hydrolysis of nitrile.445,494–497 In a series of articles, Fleet et al.498–502 reported on
the conversion of various ketoses to a mixture of epimeric lactones, using
inorganic cyanides in water and hydrolyses catalysed by an acidic ion
exchange resin. However, the required reaction times were high (24 h at room
temperature + 12 h reflux). The nitriles were not isolated from the reaction
mixture but could further react to give acetonides. Reactions mostly include
water as reaction medium; however, in another approach, cyanohydrin was
obtained from D-fructose under anhydrous conditions in DMF with 2.3 equiv.
liquid HCN in 5h at -6 °C.503 D-fructopyranosyl and L-sorbopyranosyl cyanides
have been prepared via reaction of the respective 2-O-acetyl-1,3,4,5-tetra-O-
benzoyl derivatives with BF3-trimethylsilyl cyanide in nitromethane, by
Lichtenthaler et al.,504 repeating an earlier reported procedure by De las
Heras.505 Coleman et al.506 converted DHA to nitrile and directly hydrolysed it
to the hydroxyacid; the first step of the procedure involved several hours at
0°C and the second step, hydrolysis, required days. Snyder and Serianni507
used 5 equiv. KCN to obtain complete conversion of dihydroxyacetone to the
corresponding nitrile.
Various cyanide sources are regularly used in practice. Liquid HCN is
nowadays generally avoided, due to its high toxicity; TMSCN is a very
Kiliani reaction under microreactor conditions
61
efficient agent but its high price limits its applicability. Viable alternatives
include alkaline cyanides, acetone cyanohydrin and cyanoformates.508
3.2. Results and discussion
The experiments were performed on three keto-substrates: a C3 ketose,
dihydroxyacetone (DHA), a C4 ketose L-erythrulose, and a C6 ketose D-
fructose. These substrates are easily available from chemical suppliers and
relatively inexpensive.
DHA is typically derived from plant sources, such as beets or sugarcane.509
In the biosynthetic route, DHA is a precursor of hexoses.510 Industrially, it is
largely obtained by fermentation509,511 DHA is normally present as a dimer; in
solution, this dimer converts to the monomer. DHA is widely used in cosmetic
industry, as a constituent of self-tanning products and other topical
preparations.512–514 By simple reactions, it can easily be transformed to other
carbohydrates and carbohydrate-like molecules,265,515–517 used for production of
drugs518 and other transformations.510 There are scarce reports on the
cyanohydrin formation from DHA.506,507
L-Erythrulose is produced by bacterial fermentations.519–524 Similarly to
DHA, it is used in cosmetics.525,526 Some recent research shows its anticancer
properties.527 It can be used as starting materials for the production of chiral
synthons;528–536 for example, 2-aminoalditols, which can be used as starting
materials for various natural products.537
3.2.1. Reaction setup
Potassium (KCN) and sodium cyanide (NaCN) in combination with a
small carboxylic acid, and, alternatively, acetone cyanohydrin in alkaline
medium, were used as cyanide sources. Carboxylic acids used in the
experiments were acetic (in all but one experiment) and formic acid (in one
experiment); the choice of the acid was dictated by the reactor material
corrosion resistance. Acetic acid can also be produced by fermentations, and
this possibility would increase the sustainability of the process.
Chapter 3
62
Additional attention is dedicated to avoid the dangers of cyanides.v The
closed system greatly enhances the process safety, as HCN was created in situ
and retained and neutralised in the system.
Our experiments were initially performed in methanol. Methanol was the
solvent of choice due to the compatibility with the reactants, reagents and
reactor system, and the ease of manipulation and of the removal from the
reaction mixture (by evaporation). This was possible for the reactions with
DHA and erythrulose; however, for the reactions with fructose as reactant,
water was necessary for the complete dissolution of the starting material.
Water was used in combination with methanol in ratios from 1/1 to 5/1 v/v
methanol/water. For some representative experiments, acetonitrile was added
as a co-solvent to the solvent mixture of water and methanol (1/1/3,
respectively). Ethyl acetate was tested in the same mixture with methanol and
water, in the same ratio as acetonitrile.
The experiments were performed using two commercial continuous flow
reactor setups: the CPC CYTOS® College system538 (47 ml total volume, fully
integrated with a heat exchanger; in further text, referred to as CPC) and the
X-CubeTM from ThalesNano539 (6 ml total volume, partially integrated with a
heat exchanger). The CPC reactor was operated at various temperatures and at
atmospheric pressure. Experiments requiring higher pressures were carried
out using the X-Cube.
v Cyanide exerts very high acute toxicity, and, as a consequence, the data on the toxicity can
somewhat differ according to different sources. Estimated values for the LC50 of gaseous hydrogen
cyanide are 100-300 ppm, the LD50 for ingestion is 50-200 milligrams, or 1-3 milligrams per kilogram
of body weight, calculated as HCN, and for contact with intact skin, the LD50 is 100 milligrams (as
HCN) per kilogram of body weight.634 The main mechanism of cyanide poisoning includes the
binding of the cyanide to the cytochrome C oxidase, the terminal oxidase of the mitochondrial
respiratory chain, competitively inhibiting the protein from functioning rendering it unavailable for
the oxygen transport. This leads to a cytotoxic hypoxia.635 The antidotes include the methaemoglobin
generators (methaemoglobin binds with the cyanide and enhances t he removal from the circulation),
such as amyl- or sodium nitrite, sulphur donors, such as sodium thiosulphate (enhance the
detoxification route to thiocyanate), and the binding agents, such as dicobalt edetate and vitamin B12
or hydroxocobalamine.635,636
Kiliani reaction under microreactor conditions
63
The CPC reactor has been extensively described in our publications.461–
465,467,469,472 The microreactor consists of stacked stainless steel plates forming
channels of 100 to 500 µm width, depending on the position in the reactor. The
fluid path consists of three parts: the entrance zone, the mixing zone and the
reaction zone. The mixing in the reactor is based on an interdigital principle.
After the mixer, the fluid paths join in a stacked laminar flow. The volume of
the reactor after the mixer is 1.2 ml, and the total volume of the reactor is 2 ml.
Thermoregulation of the system is provided by an external device, able to
regulate the temperature between -40 and +200 °C. The design of the reactor
allows the flow of the thermoregulating fluid through the reactor, providing
efficient temperature control. Two inlets of the reactor are operated by two
piston pumps, in our setup able to operate between flows 0.2 and 9 ml/min.
The system is limited to temperatures slightly below the boiling points of
solvents used in reactions. The microreactor is followed by an optional outlet
and an additional residence time unit (RTU), aiming to prolong the retention
time thus increasing the reaction efficiency. The RTU is a stainless steel coil of
1 mm diameter and 45 ml volume, surrounded by a thermoregulating coil
(Figure 9).
Figure 9: CPC College System, Cytos (DE), now YMC (JP)
The series of experiments under increased pressure were performed on the
commercially available X-CubeTM system. This system is also made of stainless
steel. The system has two inlets, operated by HPLC pumps, and a possible
third inlet equipped with a loop injector. The flows from the two inlets are
mixed by a microspray technique. The channel diameter is 1 mm and the total
volume of the system is 6 ml (a possible RTU loop gives an additional volume
Chapter 3
64
of 1.2 ml). The system can be operated under pressure of up to 150 bar. Two
CatCart® cartridges can be filled with heterogeneous catalysts or reactants; for
our application, the cartridges were filled with inert material (quartz).
Cartridges are equipped with an internal heater, capable of heating the system
up to 200 °C (Figure 10).
Figure 10: X-Cube system from Thales Nano (HU)539
In the usual setup (Figure 11), a mixed solution of the ketose substrate and
the carboxylic acid was pumped via inlet 1, and the cyanide salt via inlet 2. In an
alternative experimental procedure, acetone cyanohydrin was used as cyanide
source (inlet 2), in combination with an organic base (inlet 1 , together with the
substrate). Both inlets were operated at equal flow (ranging from 0.4 to 3.2
ml/min for the CPC and 0.1 to 1 ml/min for the X-Cube setup), and the ratio of
reagents was adjusted in the feeds. This is done to avoid the problem of
insufficient mixing of the feeds at low flow rates due to a difference in pressures.
R
OOH
1a, R= CH2OH1b, R= (S)-CH(OH)-CH2OH1c, R= (S)-CH(OH)-(R)-CH(OH)-(R)-CH(OH)-CH2OH
CN- source
acid/base
R
OHOH
R
OHOH
N NH2O
R
OHOH
OHO
2 3 4
1
Figure 11: General setup for the flow production and hydrolysis of carbohydrate-
based nitriles
Kiliani reaction under microreactor conditions
65
Fresh cyanide solutions were prepared for each experiment, using
sonication during 10-15 minutes. This procedure enhanced the dissolution of
the starting materials and provides the degassing of the feeding solutions, thus
avoiding cavitations in the flow systems.
The systems were stabilized until steady state is reached (as a rule of
thumb, a minimum stabilisation time equal to 1.6x internal volume). Once the
system was stabilised, the samples were collected at the outlet. Alternatively, a
column filled with ion exchanger resin was connected to the outlet of the
system for the online filtration of the collected sample. In order to capture and
neutralize the excess of gaseous and highly toxic HCN, the system outlet was
connected to two consecutive vessels containing 1M Na2S2O3 and 1M KOH,
respectively. As an additional safety measure, nitrogen was bubbled through
the final solution during the sample collection and also 30 minutes after the
sampling stop, to enhance the removal of the remaining HCN. During the
system equilibration and wash, the system remained closed. The separation of
the flows was achieved by the use of the glass separator (usually used for
fractional distillation) with three outlets leading to three separate recipients,
for the prewash, the collection and the system cleaning.
The conversion of the substrate was determined by 13C NMR of the crude
reaction mixtures, with enhanced relaxation time on comparison of the ratio of
the C-1 signal in DHA and the C-2 signals in respective products, and the C-3
signals in erythrulose and derivatives (marked with *, see Scheme 12).
O
OH
1a
HO
O
OHHO
1b
OH
OH
2a, 3a, 4a
HO
OHR= CN, CONH2, COOH
R
2b, 3b, 4b
HOOH
HO
OH
R
Scheme 12: Structures of the starting materials and the products
Table 6: Selected examples for the observed conversion of DHA with alkaline salts as cyanide sources
Exp. CN-
source
Eq.
CN-
Ratio
H+/CN-
M
(mol/l)
Scale
(mmol)
Flow*
(ml/min)
RT outlet
1 (min)
RT
(min) t (°C) Solvent
Conv. to 2 at
outlet 1
(%)
Conversion
outlet 2 (%)
2 3 4
1 KCN 1.1 1.1 0.3 3 Batch / 120 0->25 MeOH / 50 / /
2 NaCN 1.5 0.7 0.3 2 Batch / 180 60->25 MeOH/H2O 3:1 / 60 / 40
3 KCN 1.1 1.1 0.3 21 0.4 5 117.5 25 MeOH 50 >98 / /
4 KCN 1.1 1.1 0.3 30 0.4 5 117.5 25 MeOH 70 >98 / /
5 KCN 1.1 1.1 0.3 30 0.4 5 117.5 45 MeOH 90 >98 / /
6 KCN 1.1 1.8 0.3 30 0.4 5 117.5 25 MeOH 85 >98 / /
7 KCN 1.1 1.8 0.3 30 2.0 1 23.5 50 MeOH 88 >99 / /
8 NaCN 1.9 0.05 0.2 20 1.0 / 47.0 60 MeOH/H2O 3:1 / / / >99
*Total flow.
All experiments performed on the CPC reactor, under atmospheric pressure.
Table 7: Selected examples for the observed conversion of L-erythrulose with alkaline salts as cyanide sources
Exp. CN-source
Eq. CN-
Ratio H+/CN-
M (mol/l)
Scale (mmol)
Flow* (ml/min)
RT (min)
t (°C) Solvent Conversion (%) 2 3 4
9 KCN 1.4 1.0 0.21 3.5 batch 60 60 MeOH/H2O 1:1 / / 65
10 KCN 1.2 0.2 0.12 3.5 batch 120 60 MeOH/H2O 3:1 / 50 50 11 NaCN 1.1 1.0 0.08 15.3 2.0 23.5 40 MeOH 50
12 NaCN 1.1 1.0 0.08 15.3 2.0 23.5 50 MeOH 90 / /
13 NaCN 1.4 1.2 0.10 5.8 1.0 47 80 H2O / / >99
14 NaCN 1.7 1.0 0.09 5.1 3.2 14.5 55 MeOH/H2O 1:1 50 / / 15 NaCN 1.8 0.9 0.04 2.6 1.5 31.3 50 MeOH/H2O 1:1 70 / /
16 NaCN 1.6 0.9 0.15 30.1 2.5 18.8 55 MeOH/H2O 3:1 60 / /
17 KCN 1.9 0.9 0.15 15.1 1.0 47.0 55 MeOH/H2O 3:1 50 / 10
18 KCN 1.9 0.8 0.15 15.1 0.5 94.0 55 MeOH/H2O 3:1 / / 75
19 KCN 3.0 1.0 0.15 15.1 0.5 94.0 55 MeOH/H2O 3:1 70 / <5 20 KCN 1.6 1.1 0.15 14.2 0.4 117.5 55 MeOH/H2O 3:1 / / 45
21 KCN 2.4 2.1 0.15 15.1 0.4 117.5 55 MeOH/H2O 3:1 40 / 20
22 KCN 1.1 1.0 0.50 50 1.5 31.1 55 MeOH/MeCN/H2O/ 3:1:1 / 40 45
23 NaCN 2.7 0.7 0.08 8.4 1.0 47.0 60 MeOH/MeCN/H2O/ 3:1:1 / / >99
24 KCN 2.4 0.2 0.15 15.1 1.0 47.0 55 MeOH/MeCN/H2O/ 3:1:1 / 23 77 25 KCN 1.2 0.1 0.15 15.1 1.0 47.0 55 MeOH/MeCN/H2O/ 3:1:1 / 10 90
26 NaCN 1.6 0.6 0.50 50 1.0 47.0 60 MeOH/EtOAc/H2O/ 3:1:1 / / >99
*Total flow All experiments performed on the CPC reactor, under atmospheric pressure.
Chapter 3
68
3.2.2. Experiments on dihydroxyacetone using alkaline cyanides as CN-
source
In the experiments with DHA (Table 6), the collection was performed at both
outlets 1 and 2 (Figure 11). In these experiments, the use of methanol as solvent
allowed complete a conversion to the nitrile within a short reaction time.
A preliminary reaction performed in a batch reactor on DHA (1a) in
methanol resulted in a 50 % conversion to cyanohydrin (2a), after a residence
time (RT) of 120 min at 25 °C on a 3 mmol scale (determined by the ratio of the
tertiary C-3 carbon signals, Table 6, entry 1). In contrast to this, under continuous
flow conditions, a conversion of 98 % was obtained after a RT of 117.5 min at 25
°C on a 30 mmol scale (Table 6, entry 6). Increasing the temperature to 50 °C
resulted in a complete conversion in 23.5 min retention time (Table 6, entry 7).
Introduction of water as a co-solvent invoked partial or complete in situ
hydrolysis of the nitrile, to the -hydroxyamide, or -carboxylic derivative,
respectively (compounds 3a and 4a in Figure 11). A clear difference was seen
between the batch and the microreactor performed experiments. In a batch
reaction, in 3 hours of reaction time (1 h at 60 °C, then 2 h at room temperature)
the conversion of the starting material was complete, but only about 40 % of the
produced nitrile was hydrolysed (entry 2). On the other hand, under flow
conditions, a complete hydrolysis to the hydroxycarboxylic acid was achieved
within 47 minutes retention time (entry 8). These experimental data were clearly
superior to the previously reported long reaction times needed for the hydrolysis
of short chain carbohydrate nitriles.448,506
3.2.3. Experiments on erythrulose using alkaline cyanides as CN - source
Using erythrulose as a substrate resulted in a 90 % conversion to the
corresponding cyanohydrin (2b), using the optimized conditions for DHA (Table
7, entry 12). If only water was used as reaction solvent, a complete conversion
and hydrolysis to the -hydroxycarboxylic acid (4b) was obtained in water at 80
°C after 47 min residence time (entry 13). In batch, on the contrary, after 60 min
reaction time at 50 °C, only a partial hydrolysis of the nitrile was noticed (entry
9). A complete hydrolysis of the nitrile, however to a mixture of the
Kiliani reaction under microreactor conditions
69
corresponding amide and acid (2b and 3b, in 1:1 ratio; see Table 7, entry 10) was
only achieved after a reaction time of 120 min at 60 °C. This was a remarkable
result as, according to previous reports, nitrile hydrolysis normally demands
considerably more severe operating conditions (longer reaction times, higher
temperatures and extreme pH values).
In accordance with the literature,540 the addition of acetonitrile in the solvent
mixture proved to be beneficial for the formation of cyanohydrins and assured
complete conversions. The same effect, interestingly, was noticed with the use of
ethyl acetate instead of acetonitrile, in the same ratio with methanol and water
(experiments 22-25, Table 7).
The conversion and the hydrolysis were observed to change when varying
the solvent mixture composition, the flow rate and the temperature. Apart from
the solvent choice, the occurrence and the extent of hydrolysis also depend on
the retention time and the temperature in the reactor. The intermediate amide
(compound 3 in Figure 11) could be identified using NMR for some experiments.
Residence time was especially important for the hydrolysis: as a rule, flows of
0.5 ml/min (i.e. RT of 47 minutes on the CPC reactor) were needed for the
hydrolysis.
A temperature of minimum 50 °C seemed critical for the conversions. The
choice of the cation (K+ or Na+) did not seem to have an effect on the conversion
and product yields. The use of sodium cyanide was, however, recommended in
view of the compatibility with the reactor material.541 Formic acid was used in
one run and gave the same results as acetic acid (same conditions as in
experiment 22, Table 7).
The acid quantity was related to the nitrile hydrolysis: less equivalents of
acid, in combination with long retention times, invariably resulted in a more
complete hydrolysis (e.g. experiments 8, 23 and 24, Table 7). Higher equivalents
of cyanide salt did not seem to have an influence on the reaction. This is
important as, in published procedures, the CN- equivalents used for the reaction
tend to be higher than 2.
Chapter 3
70
A simple online purification of the obtained product was considered.
Continuous removal of the alkaline acetate side product was initially performed
by pumping the effluent through a column loaded with Amberlite IR-120. This
procedure was efficient for the removal of the cation; however it has also led to
the formation of side products, repetitively noticed by NMR analysis of the
effluent. This was probably due to the strongly acidic nature of the resin – the
sulphonic acid functionality – which catalyses the partial decomposition of the
product. Weakening the acidic strength of the resin in the column efficiently
solved this problem: filtration over Amberlite IRC-86 (with a carboxylic
functionality) successfully removed the cation without the formation of side
products.
A parallel approach was applied for the removal of the acetate anion from
the side product – the filtration over an anionic resin. However, upon filtration
over the anionic exchanger Amberlite IRA-67, adsorption of the acetate was
hindered by competitive absorbance of the carbohydrate substrate, resulting in
significant losses of the product. This effect was already described.542
A combined approach was tested for the simultaneous removal of the
anion and cation, by a mixed bed exchanger Amberlite MB-150, a mixture of
the IRA-400 (OH-) and IR-120 (H+) resins. This led to the combined negative
effect of both resins: the alkaline cation was successfully absorbed, as well as
the acetate anion, but some side products were formed and the substrate was
competitively absorbed together with the anion.
3.2.4. Reactions under increased pressure
To evaluate the influence of an increased pressure on the conversion, several
experiments were performed on the X-Cube (Table 8). The experiment setup was
analogous to the experiments on the CPC (Figure 11). CatCart cartridges were
filled with inert material (quartz). Special attention was paid to the isolation of
the reaction flow of the system, as normally only the cartridge blocks are
thermoregulated.
Kiliani reaction under microreactor conditions
71
The increase in pressure did not seem to affect the conversion; dependence
of conversion and hydrolysis on the temperature and time was, however,
confirmed.
Table 8: Reactions with erythrulose as substrate under increased pressure on the
X-Cube system
Exp. Scale (mmol) Eq.
CN-
Ratio
H+/CN- t (°C)
p
(bar)
Flow*
(ml/min)
RT
(min)
Conversion (%)
2 3 4
27 30.1 1.6 0.9 60 50 1.0 6.0 25 / /
28 30.1 1.6 0.9 60 50 0.4 15.0 35 / / 29 30.1 1.6 0.9 100 50 0.2 30.0 60 / /
30 30.1 1.6 0.9 150 75 0.2 30.0 40 10 10
31 30.1 1.6 0.9 100 100 0.1 60.0 70 / /
32 7.4 1.6 1.0 100 100 0.2 30.0 45 / 20
*Total flow rate.
Concentration for all experiments was 0.15 mol/l. Experiments performed with NaCN as
the CN- source. Solvent mixture was MeOH/H2O 3/1.
3.2.5. Acetone cyanohydrin as cyanide source
Alternatively, acetone cyanohydrin was used as a cyanide source, in the
presence of an organic base in catalytic amounts (Table 9).
Table 9: Selected examples on erythrulose with acetone cyanohydrin as CN- source
Exp. M
(mol/l)
Scale
(mmol)
Eq.
CN- Base
Ratio
base/CN- Solvent t (°C)
Flow*
(ml/min) RT (min)
Conversion (%)
2 3 4
33 0.07 3.3 1.2 TEA 1.0 MeOH 45 2.0 23.5 55 / /
34 0.08 3.8 1.5 TEA 0.1 MeOH 50 1.5 31.3 80 / / 35 0.08 4.0 1.1 DBU 0.2 H2O 50 1.0 47.0 / 20 80
36 0.08 4.8 1.3 DIPEA 0.04 H2O 60 2.0 23.5 / / 60
37 0.08 4.7 1.3 DIPEA 0.1 H2O 80 1.0 47.0 / 20 75
38 0.07 4.2 1.3 DIPEA 0.1 H2O 80 0.8 58.8 10 15 75
*Total flow rate.
All experiments performed on the CPC, under atmospheric pressure
Table 10: Selected examples for the observed conversion of fructose under acidic conditions
Exp. M
(mol/l)
Scale
(mmol)
Eq.
CN-
Ratio
H+/CN-
Flow*
(ml/min)
RT
(min)
t
(°C) Solvent
Conversion (%)
2 3 4
39 0.10 6.0 1.5 1.0 2.0 23.5 60 MeOH/H2O 1/1 / / / 40 0.50 30.0 1.5 0.5 2.0 23.5 60 MeOH/H2O 1/1 / / /
41 0.15 15.0 2.4 2.2 0.4 117.5 55 MeOH/H2O 3/1 / / <5
*Total flow rate.
All experiments performed on the CPC, under atmospheric pressure. KCN used as CN- source in all experiments.
Kiliani reaction under microreactor conditions
73
The reaction setup was analogous to the previous experiments. The cyanide
source was introduced via inlet 1 (Figure 11), and the solution of the substrate and
the base was introduced via inlet 2. Sample collection and the system setup were
identical (closed system, with the air outlet connected to the two alkaline solutions
in order to capture traces of HCN and the nitrogen purge). All experiments were
performed on the CPC system.
Filtration over Amberlite IRA-86 resin was in these experiments a successful
way of removing the base catalyst. The base was removed by adsorption on the
resin.
Conversions obtained in these experiments, both to the cyanohydrin and the
products of its hydrolysis, are comparable to the conversions obtained in the first
approach (alkaline salts as CN- source). Reactions performed in methanol have
exclusively led to conversions to the nitrile (2b), while water as solvent invoked
the hydrolysis to the α-hydroxyamide (3b) and -acid (4b). Triethylamine (TEA),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and N,N-diisopropylethylamine
(DIPEA) were used as bases. The choice of the base did not seem to make any
difference. Low equivalents of the base were sufficient for the reactions.
The experiments with acetone cyanohydrin as a CN- source in alkaline
conditions led to a difference in the stereoselectivity as compared to the first set
of experiments (with alkali salts as CN- sources): a different ratio of the produced
C-2 epimers was noticed. On the experiments with acetic acid as the H+ source,
this ratio was close to 1:1; in the strongly alkaline environment, this ratio was
about 1:2. Similar ratios have previously been observed and described in
literature, using other substrates. This is attributed to the influence of the
operating pH, but a clear explanation was not offered.475
3.2.6. Experiments on D-fructose
In case of D-fructose (1c) as substrate under analogous conditions of
temperature, retention time and solvent composition as compared to the first
Chapter 3
74
series of experiments with DHA and L-erythrulose, hardly any reaction was
observed; only a trace of lactone was noticed after a residence time of 117.5 min
(with a minimal flow rate of 0.2 ml/min) at 55 °C, in a methanol/water 3/1 solvent
mixture, using 2.4 equiv. KCN and 5.2 equiv. acetic acid (experiments 39-41,
Table 10). Possibly, longer reaction times would invoke a conversion of the
fructose feed; however, this could not be tested due to the limited residence time
in commercial reactors used.
3.3. Experimental part
3.3.1. General
All substrates, reactants, solvents and resins were purchased from Sigma-
Aldrich Belgium and used without further purification. Fresh cyanide solutions
were prepared before each run with the corresponding solvent, binary or tertiary
solvent mixture, by the aid of sonication during 15 minutes. Water (<0.4Ω) was
deionized by a Werner Aquadem® column ion exchanger. Amberlite IR-120 (H+
form), Amberlite IRC-86 (H+ form) and Amberlite MB-150 (H+/OH- form) resins
were washed with deionised water prior to use. Reactions were followed and
products identified and quantified by 13C NMR on a Jeol Eclipse FT 300 NMR
spectrometer. Spectra were taken in water.
3.3.2. Flow reactors
The CYTOS College System reactor was manufactured by CPC—Cellular
Process Chemistry Systems GmbH. Temperature is controlled by an external heat
exchanging circuit via a circulation thermostat (Peter Huber Kältemaschinenbau
GmbH, Huber Unistat Tango). Flow is pressure-driven via two rotary piston
dispensing pumps (Ismatec®, REGLO-CPF Digital, pump head: Fluid Metering
Inc., FMI 005, ceramic piston, 5-50μL/stroke). The X-CubeTM system is produced
by ThalesNano, Hungary and was used without modifications.
Kiliani reaction under microreactor conditions
75
3.3.3. Example run with DHA (with an alkaline cyanide salt and acetic acid)
The general setup used for this experiment is depicted in Figure 11. Prior to the
experiment, when using CPC, the pump flow was controlled, and the pumps
readjusted if necessary. In case of experiments on the X-Cube, the pumps were
primed before use. The system was flushed with several volumes of solvent or
solvent mixture.
An example run procedure for the continuous synthesis of 2,3-dihydroxy-2-
(hydroxymethyl)propanenitrile 2a typically consists of charging the feed at one inlet
with DHA and acetic acid, and with sodium cyanide at the other inlet. The
following setup of the system (optimized conditions) has been used (Figure 11):
flow 1 (DHA and acetic acid, 0.3 M and 0.6 M, respectively, in methanol; Feed 1): 1
ml/min, flow 2 (sodium cyanide 0.36 M in methanol; Feed 2): 1 ml/min. The reactor
was stabilized at 50 °C over a period of 37.6 min. 2,3-Dihydroxy-2-
(hydroxymethyl)propanenitrile (2a) was obtained in >99 % yield at a 4.2 g/h scale.
(2a): 119.70 (C1), 72.94 (C2), 62.78 (C3, CH2OH).
3.3.4. Example run with L-erythrulose (with dihydroxyacetone and the
addition of base)
The general setup used for this experiment is depicted in Figure 11.. Prior to the
start of the reaction, the same procedure was applied for the pump adjustments and
the system prewash, as described above. The outlet of the reactor is connected to a
column filled with Amberlite IRC-86. An example run procedure for (3S)-2,3,4-
trihydroxy-2-(hydroxymethyl)butanoic acid 4b (as a 1:2 mixture of 2S,3S and 2R,3S
diastereomers) continuous synthesis typically consists of the inlet feeds charged
with L-erythrulose, acetone cyanohydrin and DIPEA. The following setup of the
system (optimized conditions) has been used ( Figure 11): flow 1 (L-erythrulose and
DIPEA, 0.08 M and 8mM, respectively in water; Feed 1): 0.5 ml/min, flow 2 (acetone
cyanohydrin 1.05 M in water; Feed 2): 0.5 ml/min. The reactor was stabilized at 80
°C over a period of 75.2 min. (3S)-2,3,4-Trihydroxy-2-(hydroxymethyl)butanoic acid
(4b) was obtained witha yield above 90 % at a 0.8 g/h scale. (4b): 176.90, 176.74 (C1),
79.52, 79.40 (C2), 72.21, 72.00 (C3), 69.08, 64.04 (CH2OH), 61.11, 60.99 (C4).
Chapter 3
76
3.4. Conclusions
The Kiliani reaction, resulting in an extension of the carbohydrate chain by
the formal addition of HCN to a carbonyl group, is a well -known reaction and a
convenient synthetic tool to open the route towards the production of α-
hydroxycarboxylic acids, important building blocks in organic chemistry. Due to
the unfavourable equilibrium conditions, it is difficult to obtain high conversions
in a reasonable reaction time in a batch reactor. If a microreactor with continuous
flow is used, it is possible to obtain a significant increase in reaction efficiency
and proceed towards a complete conversion into nitriles and/or the
corresponding acids, i.e. the products of an in situ nitrile hydrolysis. The
introduction and the choice of an alkaline cyanide salt do not seem to have an
impact on the conversions. Sodium cyanide is preferred in view of material
compatibilities. In situ hydrolysis of the produced nitriles is achieved in a
relatively short reaction time, contrary to the results previously reported for
batch operations. Addition of acetonitrile to the solvent mixture is beneficial for
the feed conversion. Acetone cyanohydrin is equally successful as an alternative
source of cyanide. The hydrolysis of the nitriles depends on the amount of
available catalyst: strongly alkaline conditions are beneficial for the hydrolysis .
Beside the solvent mixture and the catalyst, reaction time and temperature are
certainly the most important factors influencing the obtained conversions.
Purification of the products is performed in a continuous manner, by filtration of
the effluent over an ion exchanger. Microreactor technology has clearly proven to
be beneficial for the production of useful building blocks starting from natural
materials. The handling of large amounts of hydrogen cyanide is made user- and
environmental-friendly by the introduction of a continuous flow microreactor.
77
4. Application of microreactor technology for amino acid
coupling via α-aminoacylbenzotriazoles
4.1. Introduction
The use of microwaves in chemical synthesis, due to its rapidity and
efficiency, was proven to be largely superior to conventional heating, in lab-scale
chemical synthesis.543 In this type of process, heating of the reaction mixtures is
achieved by direct coupling of the microwave energy with the molecules in the
reaction mixture (microwave dielectric heating). Using sealed vessels, microwave
heated reaction mixtures can reach temperatures above the boiling points applied
of solvent, which can result in a considerable decrease of a required reaction time
as compared to classically heated reactions, performed at reflux temperatures.
Furthermore, microwave enhanced processes often showed to be superior to
classical process conditions regarding side-product formation and product
purity. On the other hand, this technology suffers from several drawbacks that
seriously hamper the scale-up process. For instance, the heating efficiency rapidly
drops with the increase of the reaction scales above gram quantities, and the
scale-up becomes virtually impossible on certain conditions of volume,
temperature and solvent. A recent trend to circumvent these hurdles utilizes the
translation of microwave to microreactor technology (“microwave -to-flow”
paradigm).207 Considering the features that these two technologies have in
common – easy automation and exquisite control of reaction parameters, efficient
heating and the possibility of performing the reactions under supercritical
conditions – it is possible to perform this translation and open a route for the
scale-up of the chemical processes.544
Peptidomimetics and peptide conjugates are of considerable interest in the
design and the optimization of new leads in the pharmaceutical and
agrochemical industries.545–547 In particular, oligopeptidoylamino-substituted
heterocycles have served as leads for the development of a wide variety of
Chapter 4
78
biologically active molecules (Figure 12), including efflux pump inhibitors,548
peptide deformylase inhibitors,549 cytotoxic compounds,550 inhibitors of apoptosis
proteins,551,552 inhibitors of tumor necrosis factor-α converting enzymes,553,554 anti-
inflammatory555 and antisickling556 compounds, pesticides557 and for the design of
biosensors.558 Beyond the pharma- and agrochemical applications, these scaffolds
were also utilized in the development of new organocatalysts for a variety of
useful synthetic transformations (Figure 12).559–563
H2NNH
OHN
ON
NH2
MC-02,595
N
O
NHO
OH
ONH
N
O
F
LBM415
N NHHN
O
NH2
O
NHBoc
Figure 12: Oligopeptidoylamino-substituted heterocycles
The synthesis of these compounds usually required an acylation step using a
variety of coupling reagents (such as 1-hydroxy-benzotriazole (HOBt)/1-ethyl-3-
(3-dimethylaminopropyl) carbodiimide (EDCI)549 or N,N'-
dicyclohexylcarbodiimide, DCC554) under prolonged and often drastic operating
conditions, even though recent examples using a Ugi four component reaction
were presented.548
Another coupling strategy involves the use of 1H-Benzotriazole (BtH). BtH
has a range of benefits, having rather low toxicity, being easy to handle, soluble
in organic solvents and efficiently coupled with carboxylic substrates (Scheme
13).564 Bt-activated derivatives are prepared directly from substrates in high
yields, they are solid crystalline substances, stable, non-hygroscopic, compatible
with a wide range of functionalities in the substrates and well suited for various
syntheses.
Amino acid coupling via -aminoacylbenzotriazoles
79
ClS
Cl
O NH
N
N
N N
N
NN
NS
O
N N
N ClS
O
or
R OH
O
R
O
N
N NTHF or CH2Cl2
THF or CH2Cl2
Scheme 13: Production of Bt-activated amino acid derivatives
Benzotriazole (Bt) is an excellent leaving group: it is readily replaced by N-, S-
, O-, and C- nucleophiles. Therefore is BtH very useful in amino acid chemistry as
it serves as an efficient coupling agent for the production of di-, tri- etc. peptides,
as well as other types of molecules (e.g. peptides and peptide conjugates,
dipeptide alcohols, glycoamino acids and glycopeptides).565–567 Amongst many
other applications, the Bt unit has proven useful in the synthesis of various
classes of organic heterocycles.568–570 Katritzky et al. recently reported the
convenient synthesis of a library of (N-protected--aminoacyl)amino heterocycles
by coupling (N-protected--aminoacyl)benzotriazoles to a variety of heterocyclic
amines under microwave irradiation.571 The desired compounds were isolated
after short reaction times (30 min) with modest to good yields at mmol scale.
H2N-Het
Cbz
HN
R
Bt
O
Cbz
HN
R
NH
O
Het
µwave heating,70°C, 30min, DMF
40-98%
Scheme 14: Preparation of (α-aminoacyl)amino-substituted heterocycles in batch571
Being interested in the agrochemical properties of such compounds, we have
assessed flow chemistry in order to improve the yields of these reactions, and to
evaluate the possibility of scaling up. With several modifications, the process was
optimized and a small library of heterocyclic amides was produced, with
conversions equal or higher compared to the reported.
Chapter 4
80
4.2. Results and discussion
4.2.1. Production of starting materials, N-protected α-
aminoacylbenzotriazoles
Starting materials were prepared from the commercially available amino
acids in a two-step procedure. In a first step, a carboxybenzyl (Cbz) N-protection
of the amino acids was performed, with slight modifications, according to the
classic method of Carter et al.572 This procedure gave yields of about 90 %. The
second step, Bt activation, was performed following the procedures published by
Katritzky et al.564
H2N
R
OH
ONaOH 2N, pH 8-10
Cbz-Cl, 0°C->rt, 3h
HN
R
OH
O
Cbz
BtH SOCl2 S
O
BtBt
2BtH HCl
SO2 BtH
+4 eq 1 eq
+
+ +
1 eq
THF rt
THF, 0°C HN
R
Bt
O
Cbz
30min
180min
Scheme 15: Two-step synthesis of N-protected α-aminoacylbenzotriazoles
Alternatively, commercially available Cbz-N-protected -amino acids were
converted into their benzotriazole derivatives. Several successful attempts led us
to slight modifications to the original procedure which claimed the use of 4
equivalents of 1H-benzotriazole (BtH) for this procedure, to the use of 3
equivalents.
The produced derivatives and yields are shown in the Table 11.
NH
R
O
O
N
O
NN
R = HCH3
S
NHHN
1 2/5 3 48/96
Amino acid coupling via -aminoacylbenzotriazoles
81
Figure 13: N-protected α-aminoacylbenzotriazoles amino acids
Table 11: Cbz-N-protected α-amino acids production in batch
Exp. R Amino acid Scale (mol) Equiv. BtH Yield (%)
1a H Gly 5 4 85
1b H Gly 10 3 98
1c H Gly 100 3 60
2a Bn L-Phe 10 3 82
2b Bn L-Phe 10 4 80 3 CH3 L-Ala 10 4 67
4 (CH2)2SCH3 L-Met 10 4 66
5 Bn D,L-Phe 100 4 64
6 (CH2)3CH L-Pro 10 4 66
7 CH3 D,L-Ala 50 4 61
8 CH2-Indol-3-yl L-Trp 10 4 58
9 CH2-Indol-3-yl D,L-Trp 50 3 66
Experiments 1a, 1b, 2a and 7 and were conducted on Cbz-protected amino acids as starting
materials.
Alternatively, we attempted to produce the benzotriazole-activated Cbz-N-
protected α-amino acids under flow conditions (vide infra for description of the
apparatus). However, the clogging of the system made it virtually impossible to
perform the reactions. The clogging is a consequence of the formation of a solid
side-product in this reaction, the HCl salt of Bt, which is insoluble in reaction
solvent (tetrahydrofuran) and inevitably caused the clogging of the fluid paths.
Various strategies have been employed in efforts to circumvent this problem –
higher dilution and the change of solvent – however, the clogging was impossible
to avoid. This strategy to produce N-protected α-aminoacylbenzotriazoles was
eventually abandoned.
4.2.2. Production of α-aminoacylamino substituted heterocycles
Having produced a series of N-protected α-aminoacylbenzotriazoles in batch
(vide supra), we focused on the coupling of these materials with azaheterocycles in
flow reactions in the Chemtrix573 glass reactors. Process windows and parameters
were determined on the small scale microreactor (with a 10 µl volume, Labtrix®
Start system574). Upon optimization on micro scale, scale-up was performed using
Chapter 4
82
the commercially available meso flow-reactor Kiloflow® 575 (with a 13.8 ml
internal volume).
Figure 14: Labtrix and Kiloflow reactor573
CbzHN
R1
Bt
O
Het-NH2
CbzHN
R1
O
HN
Het
Scheme 16: Production of (α-aminoacyl)amino-substituted heterocycles in flow
The Labtrix system operates with borosilicate glass chip reactors, in the µl
range volumes (1-10 µl). A standard T-mixer 10 µl reactor chip was used in the
presented work (Figure 15). It has channels of 300 µm width and 60 µm depth.
The minimal operating flow is 0.1 µl/min, which gives a maximal retention time
of 50 minutes. However, at such low flow insufficient mixing was sometimes
observed; therefore, the recommended lowest flow is 0.2 µl/min. The pressure in
the system is optionally controlled to 10 bar by a back pressure regulator (BPR)
connected to the outlet of the reactor.
Amino acid coupling via -aminoacylbenzotriazoles
83
Inlet 1 Inlet 2Quench inlet
(not used) Outlet
10 µl volume
Figure 15: Scheme of the reactor used in the reactions, type 3203, Labtrix® Start
system
The reactor output is collected in an LC vial and directly injected in the LC-
MS apparatus to check the conversion.
Reactions are firstly performed using dimethylformamide (DMF) as solvent,
as in the original procedure.571 Because of the toxicity issues related to DMF
(suspected carcinogen and teratogen), dimethyl sulfoxide (DMSO) was
introduced as an alternative solvent.576,577 Suitability of DMSO as replacement for
DMF was evaluated by conducting reaction 1 (Table 12) n a batch microwave
heated reaction, as described by Katritzky et al.,571 and in a continuous process in
both DMF and DMSO, and comparing the results. Microwave heated reaction 1
performed in DMSO gave a lower conversion as compared to the reported results
(~50 % conversion, i.e. 20 % instead of 40 %). The reason for this can lie in the
different absorbing capacity of the two solvents . Prolonged reaction time did not
have a beneficiary effect on the conversion. However, under microreactor
conditions, DMSO proved to be when equally suitable as DMF: performing
reaction 1 in DMF and in DMSO under the same conditions in the Labtrix reactor,
a similar conversion was measured on the LC; no influence of the solvent was
noticed. It was thus decided to replace DMF by DMSO in all consecutive
experiments.
The conversion of the reactions was followed using LC-MS. By injection of the
external standards containing equimolar solutions of N-protected -
aminoacylbenzotriazole starting materials and 1H-benzotriazole (free in solution
Chapter 4
84
after the amide bond formation reaction), it was noticed that the benzotriazole
moiety exhibits the same absorption of the aminoacyl Bt derivative at 254 nm. In
this way, it was possible to quantify the conversions in a straightforward manner.
It was noticed that the reaction temperature is extremely important for the
conversions: for experiment 1 (Table 12) at 70 °C (as mentioned in the original
procedure), relatively low conversions were observed (less than 5 %). With the
increase of temperature to 100 °C and 130 °C, increased conversions were
obtained. At 150 °C, conversions were similar to the reactions at 130 °C; however
a number of side products were observed on the LC-MS spectrum. Therefore, the
optimal temperature for the reactions was set to 130 °C.
The conversions showed a clear dependence on the retention time (RT) as
well; an increased RT resulted in higher conversions.
Several reactions were performed on a scaled-up, Kiloflow® reactor system.
This flexible system is built from three borosilicate glass mesoreactors, one of 0.8
and two of 6.5 ml, thus 13.8 ml in total. The reactors are equipped with an
advanced mixing system (integrated static mixers). Two inlets are operated by
two piston pumps with a minimal flow of 0.1 ml/min; however, the
recommended minimal flow for optimal mixing in the system is 0.2 ml/min, and
thus gives a maximal reaction time of 32.5 minutes.
Amino acid coupling via -aminoacylbenzotriazoles
85
NN
Ph
H2N NH2N
N
SH2N
ONH2N
N
SH2N
EA B C D
Table 12: Cbz-N-(aminoacyl)amino heterocycles produced on a 10 µl scale (Labtrix®)
Exp. Amine Scale
(mmol)
M
(mol/l) Solvent
Flow
(µl
/min)
RT
(min)
T
°C
Convers.
(%)
Reported
yield571
1a A 5 1.25 DMF/
acetone 1 10.0 70 <1 40
1b A 0.5 0.05 DMF 0.1 100 70 10 40
1c A 0.5 0.5 DMF 0.1 100 130 40 40 1d A 1 0.25 DMSO 0.1 100 130 40 40
2a B 0.5 0.25 DMF 0.66 15.2 130 99 55
2b B 0.5 0.25 DMF 0.8 12.5 130 95 55
2c B 0.5 0.25 DMSO 0.66 15.2 130 99 55
3a D 0.07 0.07 DMSO 1.0 10 100 77 98 3b D 0.07 0.07 DMSO 0.5 20 100 88 98
3c D 0.07 0.07 DMSO 1.0 10 130 94 98
3d D 0.07 0.07 DMSO 0.5 20 130 99 98
4a B 0.5 0.25 DMSO 0.4 25 130 99 68
4b B 0.5 0.25 DMSO 0.4 25 100 93 68 4c B 0.5 0.25 DMSO 0.66 15.2 130 99 68
5a B 0.25 0.125 DMSO 1.0 10 130 95 70
5b B 0.25 0.125 DMSO 0.66 15.2 130 95 70
5c B 0.25 0.125 DMSO 0.5 20 130 98 70 5d B 0.25 0.125 DMSO 2.0 5 130 82 70
6 C 0.5 0.260 DMSO 0.2 50 100 99 98
7a D 1.0 0.5 DMSO 0.5 20 130 99 78
7b D 1.0 0.5 DMSO 1.0 10 130 99 78
8a E 0.25 0.25 DMSO 0.66 15.2 130 99 81 8b E 0.25 0.25 DMSO 1.0 10 130 99 81
9a E 0.25 0.125 DMSO 0.4 25 130 94 66
9b E 0.25 0.125 DMSO 0.3 33 130 96 66
On the scale-up from µl to ml quantities, a given correction of retention time
was necessary: it was noticed that reactions required more time for completion
when transferred from the Labtrix to the Kiloflow system. This was expected, as
the mixing is less efficient due to the increase of the reactor scale.205 On the other
Chapter 4
86
hand, high throughput was achieved on the Kiloflow system: up to 1.5 kg/h for
reaction 9, for example (Table 15).
Table 13: Cbz-N-(aminoacyl)amino heterocycles produced on a 13.8 ml scale
(Kiloflow®)
Exp. Amine Scale
(mmol)
M
(mmol/l)
Flow
(ml/min)
RT
(min)
Conv.
(%)
Through-
put (g/h)
Final
isolated
yield (%)
3e D 0.05 0.5 0.6 23 99 7.1 52
5e B 0.80 8 0.6 23 99 108 68
8c E 0.5 5 0.4 34.5 99 50.5 / 9c E 5.05 50.5 0.6 23 99 1529 /
Two reactions performed on the Kiloflow® (3e and 5e) were eventually
submitted to an offline purification – that is, a quench with water and an
extraction with ethyl acetate, followed by purification by the column
chromatography.
4.3. Experimental part
All reagents and solvents were purchased from Sigma -Aldrich Belgium and
used as such, unless specified otherwise. THF was dried over sodium and
distilled.
LC-MS was performed on an Agilent 1200 with DAD detector, coupled with
an Agilent LC/MSD VL with ES API, on Eclipse Plus C18 4.6*50mm*1.8µm
column. The gradient solvent protocol was as follows: 30 % acetone in water, up
to 100 % in 5 min, run time 8 min, flow 1ml/min. The column temperature was 40
°C. 1H (300MHz) and 13C-NMR (75 MHz) spectra were recorded on a Jeol JNM-
EX 300 NMR spectrometer. Additional purification of the reaction mixtures was
performed by column chromatography in a glass column on silica gel (Acros,
particle size 0.035–0.070 mm, pore diameter ca. 6 nm).
Amino acid coupling via -aminoacylbenzotriazoles
87
The Labtrix® Start system is equipped with two syringe Chemyx pumps,
holding 1 ml SGE gas tight syringe each. The syringes are connected via PEEK
tubing to the two inlets of the reactor chip. The third, quench inlet, was not used
in our set-up (see Figure 15). Two check valves between the pumps and the chip
ensure the flow direction. The reactor is mounted on a holder and placed on a
thermoregulating block, which enables the control of the reaction temperatures
between -15 and +195 °C. The outlet of the reactor is connected via PEEK tubing
to the back pressure regulator (BPR), set to 10 bar.
The Kiloflow® is a flexible system and can be constructed by combining
several modules, resulting in various system volumes and reaction patterns. In
the presented case, the system is constructed from three separate reactors with
total volume of 13.8 ml. The system is driven by dual piston LC Flom pumps. The
pumps are connected via Teflon tubing to the preheating modules of the reactor,
followed by the reactor self. The flow is controlled with check valves between the
pumps and the reactor. The system is equipped with an external
thermoregulating unit Lauda Integral XT 150, capable of setting the temperature
between -40 and +195 °C. The back pressure is set to 7 bar.
4.3.1. Production of starting materials, N-protected α-
aminoacylbenzotriazoles
To a solution of 10 mmol amino acid in 10 ml 2N NaOH at 0 °C, 1.05
equivalents of benzyl chloroformate and 5 ml 2N NaOH were added dropwise to
the vigorously stirred solution. The reaction temperature was kept at 0 °C for 4 h.
The reaction mixture was washed once with diethyl ether; the aqueous layer was
subsequently poured into 6N HCl, with an instant solid formation. Filtration and
drying of this precipitate gave the pure desired Cbz-N-protected amino acid.
Alternatively, the acidified layer was extracted with dichloromethane (DCM) or
ethyl acetate, washed with acid, brine and water, dried and evaporated.
Optionally, this material was recrystallised from chloroform.
Chapter 4
88
In the second step, 4 equivalents of BtH was dissolved in dry THF at 0 °C and
1.05 equiv. of SOCl2 were added.vi The mixture was stirred for 1 hour. The
reaction temperature was then allowed to rise to room temperature and 1 equiv.
of N-protected amino acid in THF was added. The reaction mixture was stirred
for 3 h. THF was evaporated under reduced pressure and DCM was added to
redissolve the dry residue. The organic layer was washed three times with 4N
HCl to remove the unreacted BtH, and subsequently with brine and water. After
drying and evaporation of the solvent, the remaining yellow oil gave >95 % pure
product of N-protected aminoacylbenzotriazole (LC purity), which could easily
be recrystallized from DCM/hexanes 1:1.
4.3.1.1. Production of N-protected α-aminoacylbenzotriazoles in flow
0.21 g Cbz-N-glycine (1 mmol) was dissolved in 50 ml dry tetrahydrofuran
(THF) and used as solution 1. In a 100 ml round-bottom flask 3 equiv. BtH (0.357
g, 3 mmol) and 1.05 equiv. SOCl2 (0.08 ml, 1.05 mmol) were weighed, dissolved in
50 ml dry THF and premixed during 1 h at 0 °C. This mixture was filtered and
used as solution 2. The Labtrix® system was prewashed with dry THF for 10
system volumes, and then the solutions 1 and 2 were injected in the inlets 1 and 2
respectively. Clogging of the system followed very quickly. Alternative
approaches, of injecting Cbz-N-protected amino acid together with SOCl2 in inlet
1 and BtH in inlet 2, using different solvents (DCM, DMF, acetonitrile), and
higher dilutions always resulted in system clogging. This approach was therefore
abandoned.
vi 4 equiv. of BtH were used in the original procedure. In our experience, 3 equiv. of BtH were sufficient
for this reaction (see Table 11).
Amino acid coupling via -aminoacylbenzotriazoles
89
4.3.2. Production of N-protected--aminoacylamino heterocycles
4.3.2.1. Example of a reaction performed in the Labtrix® system
The system was prewashed with reaction solvent for at least 10 reactor
volumes. 1 mmol -aminoacylbenzotriazole (solution 1) and 1.05 mmol
heterocyclic amine (solution 2) were dissolved in 2 ml DMSO each, in 10 ml
round-bottom flasks, using ultrasonic energy if necessary. Two syringes were
prewashed with 0.5 ml solutions each, filled with solutions and connected to the
inlets 1 and 2. System was prewashed with at least 5 system volumes at higher
flow (10 µl/min). The flow is then set to the desired value and system equilibrated
at the determined flow and temperature conditions . After at least 3 system
volumes, collection of the sample was performed in an LC 1.5 ml vial, the sample
diluted with acetonitrile until 1 ml volume and analyzed on the LC-MS. The
conversion was estimated by comparing the absorbance of free BtH and -
aminoacylbenzotriazole at 254 nm.
4.3.2.2. Example of a reaction performed on the Kiloflow® system
The system was preheated to the reaction temperature and prewashed with
reaction solvent for at least three reactor volumes. The flow was controlled by
measuring the output of the reactor after a determined time. Then, 25 mmol -
aminoacylbenzotriazole (solution 1) and 1.05 equiv. of heterocyclic amine
(solution 2) were dissolved in 50 ml of DMSO each, in 50 ml measuring cylinders
equipped with stoppers with ground glass joints, in an ultrasonic bath during 30
minutes. The inlets 1 and 2 were then immersed in the cylinders containing
solution 1 and 2, respectively, and the system was equilibrated for 2 system
volumes at the desired flow. After this, the collection of the material is
performed. A sample of the collected material is submitted to the LC-MS
analysis.
The work up of the reaction was performed as previously reported:571 1.5
volumes of water were added to the collected reaction output, and the product
was extracted in a separating funnel, in three times with ethyl acetate. The
Chapter 4
90
combined ethyl acetate extract was washed twice with 4N HCl and with water.
The solvent was evaporated and the product purified by column
chromatography with hexane/ethyl acetate 1/1 to obtain the pure (-
aminoacyl)amino-substituted heterocycles. Conversions and throughputs are
presented in Table 13. The complete characterisation of all compounds has
already been published.571
4.4. Conclusions
Microreactor technology was successfully applied to improve the existing
microwave heated benzotriazole-mediated coupling of amino acids. A small
library of (-aminoacyl)amino-substituted heterocycles was produced. A
microwave procedure was efficiently translated to a flow process, opening the
possibility of an efficient scale-up. Flow chemistry allowed the use of a less toxic
solvent and resulted in improved conversions as compared to the microwave
heated process.
91
5. Optimization and scale-up of biodiesel production from
crude palm oil and effective use in developing countries
5.1. Introduction
The concept of using vegetable oils as fuels is as old as the diesel engine itself.
The first compression-ignition engines actually did run on vegetable oil as well;
on the World Fair in Paris 1900, a car fuelled by peanut oil was presented by
Rudolf Diesel, by the request of the French government; the idea behind this
presentation was to make the engines run on the easily available renewable fuel
that would make then-colonies to be independent on the resources from the
mother countries. Also, as Diesel himself correctly stipulated, this principle
would allow to have engines that would not depend on the limited quantities of
fossil based fuels: “The fact that fat oils from vegetable sources can be used may
seem insignificant to-day, but such oils may perhaps become in course of time of
the same importance as some natural mineral oils and the tar products are
now.[...] In any case, they make it certain that motor-power can still be produced
from the heat of the sun, which is always available for agricultural purposes,
even when all our natural stores of solid and liquid fuels are exhausted.” The
idea of using vegetable oils as fuel lingered in the literature in the period between
the two world wars and the 1950s.578 Palm oil was especially interesting as it was
a readily available feedstock in those countries.579–581 However, the availability,
low prices and the governmental support of the use of fossil-based fuels made the
energy users almost solely dependent on this source of energy throughout the
larger part of the 20th century (see Figure 16), and this resulted in a substantially
decreased interest in transforming natural resources into energy sources.
Chapter 5
92
Figure 16: Crude oil prices through the 19th and 20th century, and oil price levels in
the second half of the 20th century, related to political events582
However, after a relatively long period of low oil prices, the 1970s witnessed
their sharp increase; after this period it became evident to what extent the oil
prices are crucial for the world economy; this fact sparked a more intensive
search for alternative energy sources.
Figure 17: World primary energy production in 2009236
The volatile market prices of the oil are also unmistakeably related with the
exhaust of the Earth fossil resources. Even though different sources give different
estimations of the actual volumes of the remaining reserves and the timing of the
oil peak, it is clear that the fossil resources are going to be exhausted in a
relatively near future.
oil
coal
natural gas
nuclear
hydro
other
Biodiesel production from crude palm oil
93
Figure 18: One of the outlooks of the world oil supply234
Another strong drive for the redefinition of the energy sources is the threat of
the global warming. Factors contributing to the global climate change are clearly
defined since the 1980s – most important being the increase of the greenhouse
gases (GHG) in the atmosphere. Carbon dioxide (CO2) emissions from the burned
fossil fuels make a serious portion of these gasses. In other words, fossil fuels are
strongly carbon positive, as carbon is simply added to the atmosphere. When
fuels are made from renewable sources, the same amount of CO2 captured by
plants by photosynthesis during their growth is released to the atmosphere,
which makes the balance of captured and released carbon equal (or almost equal)
to zero and these fuels carbon neutral (more precisely, close to neutralvii).235
vii This reasoning does not, however, take into account the energy used in the production of the biofuels,
which also contributes to the carbon footprint of the fuel in whole (see the Introduction); this is the reason
that we can define biofuels close to neutral, but not strictly neutral fuels.
Chapter 5
94
Table 14: Average biodiesel emissions (in %) compared to diesel583
Emissions B100 B20*
Carbon monoxide -48 -12
Total unburned hydrocarbons -67 -20
Particulate matter -47 -12
Nitrogen oxides +10 +2
Sulphates -100 -20
* B100 – 100% pure biodiesel, B20 – 20% biodiesel in mixture with petroleum diesel
Biofuels use is now made obligatory in various countries; in the USA, for
example, the Biomass Research and Development Technical Advisory Committee
recommended that 4 % of transportation fuel demand is covered by biofuels by
2010, 10 % by 2020, and 20 % by 2030;17 EPA is adjusting the requested volumes
of biofuels production on a yearly basis by its Regulation of Fuels and Fuel
Additives.584 The European Council accepted an action plan aiming at increasing
the share of biofuels to 10 % of the European transport petrol and diesel
consumption by 2020.239 This target was, however, recently reformulated to only
5 % in a recent proposal; this is a lower value than the 5.75 % target for year 2010,
set in 2003.240
5.1.1. Biodiesel as a transport fuel
Vegetable oils are rich energy sources: the cetane number (describing the
ignition quality of the fuel) of most of the vegetable oils are close to or exceed the
American Society for Testing Materials (ASTM) minimum of 40 for No. 2 diesel
fuel.585 On the other hand, the use of the unprocessed vegetable oils often leads to
various operational and durability problems: poor cold engine start -up (the cloud
points and pour points, flow characteristics of a fuel in cold weather, of the
vegetable oils are higher than those of diesel fuel), misfire and ignition delay (due
to the high molecular weights leading to low volatility and high flash points),
incomplete combustion due to the high viscosity, deposit formation due to the
polymerisation reactions, carbonization of injector tips, etc.586 Additionally, due
to their chemical composition (oxygen content and unsaturated bonds), vegetable
oils have significantly lower storage stability compared to the diesel fuel. To
circumvent these problems, several approaches are used to transform the
Biodiesel production from crude palm oil
95
vegetable oils into more suitable fuels: pyrolysis,587,588 blending,589,590 additives,591
microemulsification,592 or transesterification.585,592–594
Transesterification is the most widely accepted manner of vegetable oil
modification into a motor fuel; biodiesel is made of a mixture of fatty acid alkyl
esters. These are short chain esters, basically limited to methyl or ethyl esters.
Transesterification of the vegetable oils in order to produce fuel of vegetable
origin was reported rather early – in 1937, a Belgian patent was granted to G.
Chayennne, describing ethanolysis of palm oil to produce fuel;579 this was the
first known patent on the production of fuel by transesterification. The fuel was
used for a successful commercial bus ride between Brussels and Leuven in
1938.581 Transesterification of the vegetable oils was reported sporadically in the
1950s, and then again in the 1970s (correlating to the global oil crisis); in 1977,
Brazilian E. Parente (nowadays known as the “father of biodiesel”) was granted a
patent for the transesterification of the vegetable (cottonseed) oil.578 Research
boomed in the area in the 1990s. Literature on the topic is abundant – in the last
20 years, several thousands of patents, scientific articles and books about
biodiesel are granted and published.
Biodiesel fuel has a range of positive features: a high cetane number (giving it
higher combustion potential), a higher flash point (making it a lesser fire hazard)
and good lubricating properties (beneficial for the engines). On the other hand,
the negative sides of biodiesel are generally a higher viscosity, cloud point and
pour point (inherent from the oil characteristics), and these can limit the use of
the biofuel in colder climates. The comparison of some quality parameters of the
standards for diesel and biodiesel fuel is presented in Table 15. Only methyl
esters are covered by the EU standards. The national versions of the EU
standards can be different due to cold weather related demands.
Chapter 5
96
Table 15: Comparison of some of the EU and US standards parameters for diesel and
biodiesel fuel (cloud point and pour point are not defined by EU standards)
Property Diesel Biodiesel
Standard EN 590 EN 14214
Viscosity at 40 °C (mm2/s) 2.0 – 4.5 3.5 – 5.0
Density at 15 °C (kg/m3) 820 – 845 860 – 900 Flash point (°C) >55 >101
Water (mg/kg) <200 <500
Carbon residue on 10 % distillation residue (%m/m) <0.30 <0.30
Ash content/Sulphated ash content (%m/m) 0.01 0.02
Cetane number >51 >51 Copper strip corrosion (3 hours at 50 °C) Class 1 Class 1
Total contamination (mg/kg) 24 24
Standard ASTM D975 ASTM D6751
Cloud point (°C) -15 to 5 -3 to 12
Pour point (°C) -35 to -15 -15 to 16
Generally, fatty acid esters are obtained in a transesterification reaction from a
triglyceride (TG) source and an alkyl alcohol (Scheme 17).
OH
OH
OH
3 ROH
R1
O
O
R2
O
O
R3
O
O
R
R
R
R1
O
O
O
O
R2
O
O
R3
Scheme 17: General summary of biodiesel production reaction
Transesterification is an equilibrium reaction; in order to move the
equilibrium to the desired ester products, catalysts are used. As a rule, these are
heterogeneous strong alkaline catalysts. Reaction can be catalysed by acids as
well; however, in this case, the reaction times are long – as the reaction is 4000
times slower583 – and the reaction demands higher temperatures and higher
alcohol quantities.595 On the other side, the acid catalysts are rather robust as they
are not very sensitive to the presence of water or free fatty acids : acids catalyse
the esterification as well as the transesterification reaction. The acid catalysed
Biodiesel production from crude palm oil
97
esterification therefore remains “reserved” for the high free fatty acids containing
feedstocks – for example, waste oils.596,597 Sulphuric acid is the typically accepted
acidic catalyst, but other acids have been used as well: hydrochloric, phosphoric
or sulphonic acids. These are easily available and relatively cheap catalysts.
Sodium and potassium hydroxide, carbonate or methoxide are used as the
alkaline homogenous catalysts for biodiesel production from palm oil. The
methoxides show the highest catalytic activity;595 this higher reactivity is in a way
a certain disadvantage of these catalysts as they are explosive in the presence of
moisture. Strong safety measures therefore need to be applied when handling
these reagents. Another downside of the methoxides is their higher price in
comparison to hydroxides – roughly about twice.598 However, due to their higher
reactivity, methoxides are stronger catalysts for biodiesel production and less
catalyst is needed for this purpose – the price difference thus becomes less
important.595
Alkaline catalysts are sensitive to water and free fatty acids in the reaction
mixture, and their use is linked to large waste streams.
OR
O
OR
OHH
OR
OHR'OH
OR
OH
OH
R'
H2O
OR
OH
OR'
OH2
H
O
OH
OR'
H R
OH
OR'
OH
OR'
-HO
OR'
-ROH
R'OH
OHR'O
O
ROO
R'OR'O O
OR
RO- H2O
1)
2)
Scheme 18: Mechanism of the 1) acid-catalysed and 2) alkaline-catalysed
transesterification
Other factors that influence the performance of the transesterification reaction
are the quantity of alcohol (6:1 molar ratio is the usually applied alcohol
Chapter 5
98
quantity), temperatures (higher temperatures give faster conversions), and
mixing power (as triglycerides are not well soluble in alcohol).595,599,600
Chemically catalysed processes have certain drawbacks: they are energy
intensive, high amounts of waste are produced during the purification, the
recovery of side-product glycerol is difficult, and reaction is hampered by the free
fatty acids and water. In attempt to circumvent these problems, alternative
procedures have been developed. These include heterogeneous (resins or metal
oxides)158,161,162,601–603 or enzymatic catalysis,604,605 or the use of the ionic liquids,606,607
as well as non-catalytic approaches, such as the use of supercritical solvents,158,162–
165,608,609 ultrasonic mixing606,610,611 or microreactor technology.612 These processes
are, however, less commercially interesting as the investment costs of these
technologies are much higher.613
Vegetable oils used for biodiesel production are characteristic for the regions:
the main biodiesel feedstock in the USA is soybean oil, rapeseed in Europe, and
palm oil in the tropical regions. These biofuels are a success, as the production
processes are industrially accepted and the yields of good quality fuels are
reliable. Nevertheless, they belong to the so-called first generation biofuels: fuel
made from the crops which are traditionally used in human nutrition. The
production of fuel from these feedstocks has in some cases lead to an increase in
food prices, especially in the poorer regions which correctly saw profit
opportunities; this sparked some heated debates – the “food vs. fuel” dilemma
(vide supra, Introduction chapter). Not only socio-economic, but also
environmental concerns are linked to this issue, as in some regions the vast land
areas are being transformed into revenue-bringing biodiesel commodities 242,614
This has led to further research into finding alternative feedstocks for biofuel
production – or the fuels of the second, third and fourth generation. Some of the
alternative feedstocks are parts of the plants not used for food, non -food crops,
waste oils, animal fats and algae. 130,159,243,244,597,615 Genetic modification is also used
to improve the yields of the feedstock materials.616
Biodiesel production from crude palm oil
99
EU biodiesel production contributes to about 65 % of the total world
production.617 Largest EU producers are Germany and France.
Figure 19: Production of biodiesel in the EU618
5.1.2. Palm oil as biodiesel feedstock
Palm oil possesses a range of positive features. The African oil palm (Elaeis
guineensis) gives yields of several tons/ha/yr, which is substantially higher than
other biodiesel crops. Palm oil constitutes the third largest volume vegetable oil
used for food purposes in the world.619 The oil palm is a permanent crop that can
be grown on poor soils. It can be harvested throughout the year, and harvesting
and processing inputs are low.620 All this makes it a very efficient crop. The oil
palm is found mainly around the equator, as it grows best in the wet tropics. It
originates in west Africa and has since mid 19 th century spread onto tropical
South East Asian countries – generally Malaysia and Indonesia. These are
nowadays the largest world producers, delivering more than 80 % of the total
world production of palm oil.620
Chapter 5
100
Table 16: Typical fatty acid composition of palm oil
Fatty acid Chain length Mean Range
Lauric 12:0 0.23 0.1–1.0
Myristic 14:0 1.09 0.9–1.5
Palmitic 16:0 44.02 41.8–46.8
Palmitoleic 16:1 0.12 0.1–0.3
Stearic 18:0 4.54 4.2–5.1
Oleic 18:1 39.15 37.3–40.8
Linoleic 18:2 10.12 9.1–11.0
α-linolenic acid 18:3 0.37 0–0.6
Arachidic acid 20:0 0.38 0.2–0.7
Crude palm oil (CPO) is obtained from palm fruit mesocarp by cooking,
pressing and clarification. Due to the high content of saturated fatty acids
(approx. the half of the total fatty acids content (Table 16), palm oil is semisolid at
room temperature; due to this consistence, palm oil and its derivatives are widely
used as a cheap butter replacement in food products, as a healthier alternative to
hydrogenated fats. CPO contains about 1 % of various minor components,621
including tocopherols, carotenoids, sterols, terpenes, and other. It is especially
rich in tocotrienols and tocopherols (vitamin E); this is the probable reason for
rather high oxidative stability of palm oil during thermal food processing.622
Carotenes (in particular β-carotene, pro-vitamin A) give the characteristic orange-
red colour to palm oil and, together with the tocopherols, contribute to the
stability and nutritional value of the oil. Most of the carotenoids in palm oil are
destroyed during the refining process; they can be extracted and recovered from
the crude oil prior to processing.594 Other minor components in CPO include
sterols (mostly β-sitosterol), phosphatides and glycolipids.
In over-ripe fruits or during harvesting, free fatty acids (FFA) and partial
acylglycerols are found. A lipase from the surface of the fruit, which stays active
in the oil and hydrolyses the triglycerides, is responsible for this . Crude oil from
fresh ripe fruit can contain only 0.02 % FFA, while the acidity of commercial
crude palm oil is on average about 3.5 %.622
To be suitable for human consumption, crude oil is refined. By the manner
the FFA are removed, the refining can be physical or chemical; in the former, FFA
Biodiesel production from crude palm oil
101
are removed from the previously bleached and degummed oil in the deodorizer,
in the latter, the FFA are removed as soaps. Physical refining is a “cleaner”, more
sustainable process, largely used nowadays, giving as the final product refined,
bleached and deodorized (RBD) palm oil.622 Fractionation, interesterification and
hydrogenation are processes which are used to further modify the oil to make it
suitable for the desired purposes.623
Our project was performed in cooperation with an industrial partner, a palm
oil producer with production sites in equatorial Africa. The project goal was to
develop a straightforward method to produce biodiesel from crude palm oil. The
process was to be finally used on a one ton scale. Fuel produced in this manner
was not intended for commercial purposes, but to be used on the spot for the ride
of own vehicle fleet of the company, in a B20 mixture (20 % biodiesel with 80 %
fossil diesel fuel). This implied the production of a relatively small capacity and
no change in the usual palm oil production was planned. The use of biodiesel
instead of fossil diesel was in complete accordance with the company’s
sustainable image and policy. The financial aspect was also very important as
well – the feedstock for the fuel production being very cheap, produced by own
resources on the spot and was not meant to be refined. The process had to be
optimised, to use a minimal amount of chemicals, and to be carried out in the
most straightforward possible manner.
Palm oil can be a rather difficult feedstock for biodiesel production because of
the high content of saturated and monounsaturated fatty acids, which results in a
high melting point of the oil (33-39 °C) and its corresponding methyl esters: it
was shown already in 1942 that precipitation of the esters occurs at a temperature
of 8 °C.581 Additionally, refined palm oil and its fractions usually contain about 2
% of 1,2-diglycerides and about 4 % of 1,3-diglycerides with trace amounts of
monoglyceride. These “partial” glycerides are problematic as they affect the
crystallization behaviour of the oil.620 This problem can be avoided by either
adding fuel additives that will prevent the precipitation, or by using the palm
based biodiesel in mixtures with fossil fuel (common mixtures contain 2, 5 and 20
% biodiesel, respectively B2, B5 and B20). Furthermore, some minor compounds
Chapter 5
102
contained in the CPO, which are normally removed during the refining process,
are undesired in biodiesel production:624,625 especially sterols and phosphatides.
The former tend to form solid particles in the end product on standing, alone or
in the combination with mono- and diglycerides, and the latter form gums with
alkaline catalysts.622,626,627 Additionally, the free fatty acids present in the CPO619,622
form soaps with part of the catalyst, decreasing the amount of active catalyst
available for the process.
On the other hand, the natural antioxidants present in CPO can contribute to
the increased oxidative stability of biodiesel.628 Additionally, relatively high cloud
and pour points are not essential for our project, as the biodiesel needs to be used
on the spot, and due to the tropical temperatures this does not pose problems.
The low price of the unprocessed product is a strong positive feature.
For our project, the more sophisticated technologies, such as the use of solid
catalysts, biotechnology, supercritical solvent, ultrasonic or microwave energy, or
flow technology were not considered, as the process needed to be performed in a
technologically straightforward and highly economical manner.
In the biodiesel industry, acid catalysed esterification is usually applied for
feedstocks with a high content of free fatty acids (> 6 %). The drawbacks of this
method are usually the long reaction times (up to 50 hours are reported)600 and
high amounts of required catalyst.583,595,597,599 Base catalysed transesterification of
glycerides to fatty esters is a much faster process and requires lower reaction
temperatures. In order to make the process more efficient, the two approaches are
combined and various two-step procedures have been published in which an
acid catalysed esterification of FFA is followed by a base catalysed
transesterification of the TG.597,602,629–633 However, these procedures often involve a
separation step after the esterification of the FFA – otherwise excessive alkaline
catalyst is used in the second step, as the catalyst from the first step needs to be
neutralised. This leads to a more complicated procedure and to increased waste
streams. On top of this, during the washing step, some of the esters can be
Biodiesel production from crude palm oil
103
hydrolysed back to the free fatty acids, which hinder the second, alkaline
catalysed step.
In this work, we have therefore evaluated an opposite approach: firstly, a
base catalysed step, followed by an acid catalysed esterification; in this way, a
part of the acid in the second step neutralizes the alkaline catalyst from the first
step, i.e. the catalyst removal is improved. Additionally, in the first step the FFA
are partially converted to alkaline soaps that (as emulgators) enhance the mixing
of methanol and CPO (triglycerides are little soluble in methanol). Potassium
hydroxide (KOH) and potassium methoxide (MeOK) were evaluated as alkaline,
and sulphuric acid (H2SO4) as the acidic catalyst. This combination of the
catalysts gives potassium sulphate (K2SO4) as a side product of the reaction.
K2SO4 is a useful fertilizer, providing potassium and sulphur to the crops;
therefore it was interesting to purify this salt from the reaction waste steam.
In order to optimize the process with regards to the amount of used materials
and to the yields and quality of the biodiesel, several other approaches were
evaluated as well: 1) the “classical” approach of acid catalyzed esterification of
FFA followed by the base catalysed transesterification, however without the
purification after the first step, 2) purification of biodiesel by distillation, and 3)
removal of the FFA before or after the transesterification step, in two different
manners – soap formation and removal before the reaction, or washing out the
FFA together with the waste streams.
5.2. Results and discussion
Our experiments were performed on crude palm oil from two origins with a
clearly different profile (feedstocks 1 and 2). General characteristics of the
feedstocks are presented in Table 17.
Chapter 5
104
Table 17: Some quality parameters of crude palm oil feedstocks 1 and 2
Parameters CPO 1 CPO 2
Free fatty acids (% palmitic acid) 5.5 3.7
Water content (ppm) 400 1145
P content (ppm) 12.23 9.9
5.2.1. Use of potassium hydroxide as basic catalyst
Our first choice of a basic catalyst was potassium hydroxide (KOH). In the
first series of experiments, oil was first submitted to transesterification with KOH
dissolved in methanol, and then to esterification by the addition of pure H2SO4,
or H2SO4 dissolved in methanol. A strongly exothermic reaction was observed on
the addition of pure acid, accompanied by the change of the colour of the reaction
mixture. This is due to the formation of side products – oxidation products of
unsaturated fatty acids. After the reaction, FAME were separated from glycerol
and other side products and washed with water.
We evaluated quantities of KOH between 1.4 and 3.2 mass% of oil (or 1.2 – 2.7
mass%, recalculated on the KOH commercial quantity of 85 %), quantities of
H2SO4 between 49 and 174 mass% of FFA, and molar ratios of MeOH/oil between
4.9 and 12.3. Reaction times for step 1 were between 0.5 and 5 hours, and for the
second step between 1.5 and 4 hours. In a series of experiments (Table 18) it was
clear that the lower quantities of KOH resulted in lower conversion of
triglycerides and the appearance of mono-, di- and triglycerides, respectively
(MG, DG and TG) in the final sample, seen on the NMR and confirmed by GC. At
the same time, these compounds acted as emulsifiers and made the washing step
difficult, leading to lower yields and to biodiesel of lower quality. Lower
quantities of added sulphuric acid resulted in the appearance of free fatty acids,
with similar consequences to the washing process and the final result.
Additionally, glycerides in the final products were linked to the appearance of
solid particles after relatively short storage time at temperatures slightly lower
than room temperature – between 15 and 20 °C.
Biodiesel production from crude palm oil
105
A lower molar ratio of methanol to oil (below 7:1, e.g. experiment 10 from
Table 18, other examples not shown in the table) resulted in incomplete
conversions; the massive quantities of partial glycerides made the washing step
very difficult (bad separation of water and FAME phase), which resulted in lower
yields of biodiesel of poor quality (relatively high content of glycerides and FFA
clearly observed on the NMR). Molar ratios between 7:1 and 8:1 methanol to oil
resulted in better conversions and easier separation of the layers during the
washing step; however, on the NMR the traces of glycerides and FFA were
noticed (experiments 8 and 10). Above 8:1 ratio, the methanol quantity did not
have an influence on the conversions.
A similar effect was perceived after the use of lower quantities of acid catalyst
(below 70 mass% of the FFA content, see e.g. experiment 10). The incomplete
conversions of the free fatty acids have led to difficulties in the separation step
and the rejection of the experiments. Using between 70 and 100 mass% of H2SO4
on the FFA content, the conversion was dependant on the methanol content and
the reaction time (with a lower catalyst content, more methanol was needed as
well as a longer reaction time; see e.g. experiment 7).
A reaction time shorter than 1.5 h for the first step and 2 h for the second was
not satisfying in view of the conversions (see for example experiments 3 and 10).
Temperatures below reflux temperature of methanol had a strong negative
influence on the conversion in the second step (experiments not shown). For the
first step, no influence of the temperature was noticed in the range of 50 °C –
reflux temperature (65 °C). Temperatures lower than 50 °C were not tested, as the
mixing became insufficient due to the high viscosity of the mixture related to the
high melting point of the oil.
It was noticed that the use of warm water was beneficial for the washing of
the product in the final stage; cold tap water, on the contrary, led to increased
emulsion formation, difficult separation and loss of the product.
Chapter 5
106
The reactions were followed using NMR. If FFA and TG were observed on
the NMR spectra, the titration for the FFA content was in most cases not
performed.
Biodiesel from an experiment satisfactory according to our analysis (16, Table
18), was sent for analysis to an external institution.
The optimal reaction time for the first step was 1.5 h and the optimal quantity
of the basic catalyst was 2 mass% (commercial purity of 85 % KOH). The second
step was catalyzed by H2SO4 between 100 and 150 mass% related to the FFA
content. This high amount of catalyst was needed since part of the acid is
neutralized by the basic catalyst from the first step. The optimal reaction time for
the second step was 3 h.
Table 18: Transesterification catalysed by KOH, followed by acid catalysed esterification
Exp. Feed
CPO
mass
(g)
KOH
(g)
KOH/ oil
(mass%)
Time
step 1
(h)
Total
H2SO4
/FFA
(mass %)
Total
MeOH/
oil
(mol)
Total
MeOH/o
il
(mass%)
Time
step 2
(h)
Yield
(%) NMR
FFA
(%)
(as
C16:0)
Acid
nr
(as
C16:0)
FG
(%)
MG
(%)
DG
(%)
TG
(%)
1 1 48.6 0.8 1.6 3 103.3 7.2 27.6 3 88.1 OK 0.9 1.9 / / / /
2 2 52.1 1.1 2.1 1.5 143 7.9 30.3 2 93.3 OK 0.7 1.4 / / / /
3 1 50.4 1.6 3.2 1.5 106.2 8.1 31.3 1.5 73.1 FFA / / 4* 1 50.5 1.0 2.0 3.5 86.1 8.1 31.3 4 87.2 OK 1.2 2.3 <0.01 / / 0.15
5 1 50.0 1.0 2.0 2 87 8.2 31.6 3 69.4 TG / / / / / /
6 1 50.0 0.8 1.6 5 80.3 8.2 31.6 4 81.7 OK / / / / / /
7 1 50.1 1.0 2.0 4 86.8 8.2 31.5 3 79.5 OK 1.5 3.0 / / / /
8 1 109.6 2.1 1.9 1.5 76.3 7.5 28.8 3 79.3 TG 0.8 1.6 / / / / 9 1 101.0 2.1 2.1 5 82.8 8.1 31.3 4 92.6 OK / / / / / /
10 1 529.8 8.4 1.6 1 63.1 7 26.8 2 / TG,FFA / / / / / /
11 2 506.2 10 2.0 1.5 147 8.1 31.0 3 96 / 0.8 1.6 <0.01 1.39 0.23 0.03
12 1 501.1 10 2.0 2 100.1 8.2 31.5 2 90.1 OK / / / / / / 13 2 502.5 9.5 1.9 1.3 148 8.2 31.4 2 86.7 TG 0.9 1.8 / / / /
14 1 471.1 10 2.1 1.5 106.5 8.7 33.5 3 / OK 0.5 1.0 <0.01 2.52 0.57 0.17
15 2 502.2 12 2.4 1.5 168 9.4 36.2 3 90 OK 0.5 1.0 / / / /
16 2 1000.0 21.2 2.2 1.5 157 8.3 32.0 3 95 / / / <0.01 0.52 0.15 <0.01
*The water content was determined for experiment 4, and was 504.5 ppm
Chapter 5
108
Table 19: Quality of the biodiesel and of the waste water from experiment 16
Parameter Result Method EU standard EN 14214 EN limit method
Ester content 96.8 EN 14103 Min 96.5 % (m/m) pr EN 14103
Carbon residue <0.001 % ISO 6615 Max 0.3 % (m/m) EN ISO 10370 Sulfateed ash content <0.01 % ASTM D 874 Max 0.02 % (m/m) ISO 3987
Total contamination 44 mg/kg ISO 12662 at 80 °C Max 24 mg/kg EN 12662
Acid value 1.7 mg/kg AOCS ca 5a-60 Max 0.5 mg KOH/g EN 14104
Methanol content 0.02 % EN 14110 Max 0.2 % (m/m) EN 14110 Monoglyceride
content 0.52 % EN 14105 Max 0.8 % (m/m) EN 14105
Diglyceride content 0.15 % EN 14105 Max 0.2 % (m/m) EN 14105
Triglyceride content <0.01 % EN 14105 Max 0.2 % (m/m) EN 14105
Free glycerol <0.01 % EN 14105 Max 0.02 % (m/m) EN 14105 Total glycerol content 0.15 % EN 14105 Max 0.25 % (m/m) EN 14105
Biodiesel quality, determined at BfB Oil Research, Gembloux, Belgium.
BOD waste water 5000 mg O2/l Oxitop method
COD waste water 133155 mg O2/l
pH waste water 2.92
Waste water quality, determined at the Laboratory of Microbial Ecology and Technology, Faculty
of Bioscience Engineering, Ghent.
As seen in Table 19, the biodiesel quality was in agreement to almost all of the
parameters. An exception, as anticipated, was the total contamination; this is due
to the fact that crude palm oil was used as the feedstock. The acid value was also
higher. As biodiesel was initially not going to be used in pure form, but in a B20
mixture (20 % mixture with petroleum diesel), according to the industrial partner,
this was not expected to be a problem.
Waste water analysis has also been performed for experiment 10. The wash
water mainly contains residual methanol, glycerol, salt (K2SO4) and free fatty
acids. The water is used to remove the sulphuric acid and the hydrophilic
contaminants from the biodiesel (pH = 2.92), therefore neutralization with lime is
advised before the disposal. This results in high values of COD (chemical oxygen
Biodiesel production from crude palm oil
109
demand, 133 g O2/l) and BOD (biochemical oxygen demand, 5 g O2/l).viii Clearly,
waste water properties and handling needed to be further evaluated.
5.2.2. Use of potassium methoxide as basic catalyst
In the second series of experiments, potassium hydroxide was replaced by
potassium methoxide (KOMe). Reactions were performed on feedstock 2, in an
analogous manner as the experiments with KOH. Some representative
experiments are presented in Table 3. In accordance with the literature,595 the
methylate proved to be a good catalyst leading to faster conversions under the
same conditions, additionally providing biodiesel of a better quality. Due to the
faster and more complete conversion, the layer separation during the washing
step is much faster, and this greatly facilitates the purification; the total yield of
the biodiesel was similar to the experiments with KOH.
With potassium methylate, 4 mass% of a 32 % solution in methanol, calculated
on the oil content (recalculated 1.3 mass% pure MeOK) was sufficient to perform
the transesterification in 1.5 hours. This was followed by the addition of 100
mass% of sulphuric acid (calculated on the FFA content) to neutralise the alkaline
catalyst and to complete esterification; the second step was done in 3 additional
hours (as seen from Table 20). Because of the better conversions with MeOK, it
was possible to optimise the methanol quantity. The molar ratio of total methanol
to oil was 7:1 to 7.1:1 (this includes the methanol content from the MeOK solution
and the added methanol in both steps; the quantity of the added methanol was
about 19 mass%). A lower catalyst content or methanol content led to difficult
viii Chemical and biochemical oxygen demand (COD and BOD) are wastewater quality parameters.
COD is related to the chemical oxidation of the organic compounds in the water and is indicating the
mass of oxygen per liter of solution consumed for the oxidation. BOD is defined as the amount of
oxygen needed by aerobic biological organisms to break down the organic pollutants in water. Both
parameters are further defined by time, as the complete breakdowns are too time consuming to
perform in the lab.
Chapter 5
110
separations, biodiesel of poorer quality and/or lower yields (e.g. experiment 8,
Table 20).
In these experiments, special attention was paid to the waste water treatment
and the recuperation of the chemicals from the waste stream. Methanol was
successfully recuperated from the reaction mixtures by distillation, in yields of
74–86 %. This methanol was, after drying with CaO or molecular sieves,
successfully reused in the biodiesel production. In case methanol was not dried
before use, the biodiesel was produced in slightly lower yields and quality. This
is due to the water residue in the redistilled methanol (noticed by a boiling point
change to 67 °C instead of 64.7 °C).
Potassium sulphate was almost quantitatively recuperated from the reaction
mixture (about 2 mass% salt on the mass of the oil). This was possible since K2SO4
is not soluble in methanol. Keeping the wash water on the lab bench, the crystals
were formed overnight. The salt is then easily filtrated from the solutions.
Attention needs to be paid to the order of the recuperation of methanol and the
salt. As the salt is soluble in water, it needs to be separated before the methanol
distillation.
Table 20: Transesterification catalyzed by MeOK, followed by acid catalysed esterification
Exp.
CPO
mass
(g)
MeOK
32 % sol
(g)
MeOK
sol
mass%
H2SO4/
FFA
(mass%)
Total
MeOH/oil
(mol)
Added
MeOH
mass%
Yield
(%)
FFA
(%)
(as
C16:0)
Acid nr
(as
C16:0)
FG
(%)
MG
(%)
DG
(%)
TG
(%)
1 499.9 20 4.0 99 8.1 28.4 94.6 0.41 0.8 <0.01 1.07 0.19 0.03
2 499.0 20 4.0 130 8.1 28.5 95.2 0.43 0.9 <0.01 0.89 0.14 0.36
3 500.9 23.7 4.7 40 8.2 28.5 99.3 3.8 7.6 / / / / 4 501.2 23.7 4.7 79 8.2 28.5 98.1 / / 0.02 0.54 0.13 0.02
5 504.5 23.7 4.7 99 8.2 28.3 99.2 / / <0.01 0.46 0.15 0.01
6 495.2 23.7 4.8 159 7.1 24.2 / 0.4 0.8 / / / /
7 501.5 20 4.0 130 7.0 24.1 94.5 0.4 0.8 / / / /
8 495.5 20 4.0 134 6.1 20.7 96.6 1.2 2.4 <0.01 0.49 0.50 1.30 9 500.5 23.7 4.7 118 7.0 23.8 93.2 0.5 1.0 / / / /
10 1000 47.4 4.7 124 8.3 23.7 93 / / / / / /
Chapter 5
112
5.2.3. Acid-catalysed esterification followed by base-catalysed
transesterification
To be able to compare our approach to the technique generally used on high
FFA feedstocks, acid esterification of the FFA followed by base
transesterification of the TG, we compared our optimal conditions with the
former approach, and performed a series of experiments using this strategy. This
is, in our opinion, a more complicated concept as the additional H2SO4 is needed
after the second step to neutralize the base. Also, it is assumed that the addition
of the base in the second step leads to a partial hydrolysis of the esters to FFA,
which interferes with the reaction work up and leads to an increase of the acid
value.
We performed the experiments in a parallel manner as the previous two sets
of experiments: the oil was in the first stage submitted to the esterification, and
in the second step, in the one-pot approach, the alkaline catalyst was added to
perform the transesterification. This approach allowed the use of less acid
catalyst in the first step (the quantities of the used acid were between 16 and 60
mass% of FFA). For the second step, we used between 0.9 and 2.5 mass% of
KOH (recalculated on commercial 85 % purity of KOH). The total methanol
quantity was between 5.7:1 and 12:1 molar ratio to the oil. After a series of
adjustments in the process, the relatively good yields (90 %) were obtained with
26 mass% of sulphuric acid (to FFA), 1.4 mass% KOH (to the oil content) and a
9:1 mol ratio methanol:oil. However, during the washing step we have
experienced difficulties in the separation of layers , due to the incomplete
conversion, which impedes the process and leads to lower reaction yields
(experiment 3, Table 21).
Table 21: Acid catalysed esterification, followed by the transesterification catalyzed by KOH
Exp. Feed
CPO
mass
(g)
H2SO4/ FFA
(mass
%)
MeOH
(ml)
T
(h)
KOH
(g)
KOH/oil
mass%
MeOH
(ml)
t
(°C)
T
(h)
Total
MeOH
mass%
Total
MeOH/
oil mol
%FFA
(as C 16:0)
Acid
no. (as
C 16:0)
NMR Yield
1 2 51.2 58.8 20 2 1.5 2.5 10 60 1 46.3 12.0 0.5 1.0 / 79.3
2 1 107.0 38.5 20 2 2.6 2.1 30 60 2 36.8 9.6 / / / 91.9
3 1 454.0 26.2 100 2 7.5 1.4 100 60 2 34.8 9.0 0.5 1.0 / 89.6
4 2 481.0 31.3 100 3 7.5 1.3 100 60 1.5 32.9 8.5 0.8 1.6 / / 5 1 102.0 15.9 15 1.5 1.0 0.9 25 60 1.5 31.0 8.0 1.1 2.2 / 87.6
6 1 506.0 37.7 80 2 12 2.0 60 Δ 2 21.9 5.7 / / TG, FFA 87.1
Chapter 5
114
5.2.4. One-step approach – transesterification
Having in mind that the FFA content is not extremely high (especially for
feedstock 2, 3.7 % FFA), and in an attempt to avoid a two-step process, making
the process simpler by the use of only one catalyst, it was decided to “neglect”
the FFA in the production procedure and to focus on the transesterification
catalyzed by KOH. In one of the set-ups, biodiesel was further purified by
distillation. This is possible as the palm oil FAME have a boiling point
between 185 and 212 °C at 10 mmHg.637 The main advantage of this method
was the high purity of the biodiesel, obtained after blending of the distilled
esters. A practical problem was, however, the solidification of the palmitic
fraction at room temperature (melting point of the palmitic methyl ester is 32-
35 °C). Due to the practical problems, the high energy consumption and
investment costs for the distillation equipment, it was decided to abandon this
approach. This procedure yielded 80 % of FAME, which was expected as only
two fractions were collected (oleate and palmitate account for about 85 mass%
of the fuel, due to the composition of the oil, see Table 16).
Further experiments focused on the removal of the FFA; this was done by
two different manners, prior or after the transesterification. In the f irst
approach, the FFA were saponified by addition of 10 % KOH in water and the
solid soaps were then removed from the feedstock. This procedure lowered
the amount of FFA to 0.4 %. The neutralized oil was then subjected to
transesterification. In the second approach, the KOH-catalysed
transesterification was performed on the untreated feedstock and the FFA
were subsequently washed out of the neutralized reaction mixture together
with the glycerol/water.
Both approaches gave biodiesel of very good quality. However, the yields
were moderate (around 70 %) due to the loss of material (FFA removal instead
of conversion to FAME and a difficult washing step); additionally, the volume
of the waste stream was significantly higher.
On the other hand, if the latter approach was applied on the MeOK-
catalysed reaction, due to the more complete conversions, the washing step
was remarkably improved, as described in § 5.2.2.; the losses were thus
Biodiesel production from crude palm oil
115
considerably reduced and the yields improved. For example, if the conditions
of the first step of the experiment 7, Table 20 were repeated, without the
second (esterification) step, followed by neutralisation and washing, the
biodiesel yield was 93 %. It was thus concluded that this method is feasible to
produce biodiesel starting from palm oil with a lower FFA content in the
starting material. Considering the straightforwardness of the method and the
saving in the chemicals (both acid catalyst and methanol), this method was
ultimately selected as optimal for the large scale production (vide infra, § 5.2.5).
5.2.5. Scale-up to one ton
To test the applicability of the method on pilot scale, two experiments were
performed in a one-ton reactor, following the initially tested two-step
procedure; one experiment using KOH as a catalyst and one using MeOK
(conditions of experiments 9 and 20). The equipment was tested in Belgium
and later transported to Ivory Coast and Cameroon. The reactor has been
mounted on a frame (see Figure 20) so that it could be simply made mobile by
mounting on a truck. In this manner, the transport from one production
facility to the other is made possible.
Figure 20: The one ton reactor in the production facility
The production was firstly performed analogously to the lab experiments
described in § 5.2.1 and § 5.2.3., with some smaller necessary adjustments
Chapter 5
116
considering the scale and the equipment. For example, the washing step was
performed in the reactor itself. In both cases, the methods were successful,
producing satisfactory yields and a good quality of biodiesel. However, in
comparison to the method from § 5.2.4, the two step procedure was assessed
as too complicated and not practical to run under technologically challenging
conditions. In addition, the process was expensive due to the large amount of
chemicals; especially methanol was critical, due to its price in Africa.
Therefore, the method suggested in § 5.2.4 was applied, i.e. removal of the FFA
with the aqueous layer after the transesterification. This approach was
economically acceptable for MeOK as catalyst, as it gave better conversions,
and for the feedstocks with lower FFA content –feedstock 2 (3.7 % FFA) was at
the higher limit of FFA content acceptability. Above this value, higher contents
of MeOK and methanol were needed, and the yields of biodiesel were not
satisfactory.
The reactor was then transported to Africa and the one-ton experiments
were repeated on the production site. With the advantage of avoiding the
transport of the CPO, the feedstocks with the lower FFA content (2 – 3.5 %)
were easily available. The process is nowadays still in use (five years of
continuous FAME production and use). Analogously to the experiment 7 from
the Table 20, the optimized biodiesel production method involves a
transesterification step with 3 to 4 mass% of MeOK (32 % solution in
methanol) and additional 16 to 20 mass% of MeOH (both in proportion with
the FFA content, as it was observed that a higher FFA content demands larger
quantities of catalyst and methanol). After this step, sulphuric acid was added
until neutralisation of the mixture (the quantity of the acid is determined by
titration because of its variable quality available on the spot). Subsequently
glycerol, the FFA and the extra methanol were washed out with the water
layer.
This procedure routinely gives 93 % yield of biodiesel of good quality. The
biodiesel is regularly tested for quality. Quality parameters from analysis
performed by ASG Analytic Service GmbH are shown in Table 22.
Considering the small amounts of waste, the eventual purification is
economically not interesting for the palm oil producer.
Biodiesel production from crude palm oil
117
Most of the quality parameters comply with the European standard DIN
EN 14214 specifications. The total contamination and the alkaline metal
content are slightly above the limits. This is due to the characteristics of the
feedstocks (unprocessed oil) and process (base catalysis). Water and
monoglyceride content are slightly above the limits as well, and oxidative
stability is slightly below the EU demands. This is, again, linked to the process
and the feedstock characteristics. However, the risk-benefit ratio of using this
plantation-made fuel is evaluated as positive. The fact that biodiesel is not
intended for commercial purposes, but to own drive, topped by avoiding of
costs and insecure availability connected to the fossil based fuels, was the
strong positive drives for use of this fuel. Even more interesting, unlike the
general use of palm biodiesel (in mixtures with fossil diesel), this biodiesel is
at the moment used pure (B100), without mixing with fossil diesel and without
additives. Until today, in five years of biodiesel production and use for the
own vehicle fleet, this biodiesel has proven to be a very satisfactory fuel .
Probably due to the lubricating properties of biodiesel, the engines reportedly
look even better than in the past.
Figure 21: Fueling the biodiesel into a car on the plantation
Chapter 5
118
Table 22: Quality of biodiesel produced on the palm oil plantation in Africa
Parameter Unit Method Result Specification DIN EN 14214:10-04
min. max
Ester content % m/m DIN EN 14103:2003 97.0 96.5 -
Density at 15 °C kg/m3 DIN EN ISO 12185 875.2 860 900
Viscosity at 40 °C mm2/s DIN EN ISO 3104 4.74 3.5 5.0
Flash point °C DIN EN ISO 3679 172.0 101 -
CFPP °C DIN EN 116 11 - *
Sulphur content mg/kg DIN EN ISO 20884 <1 - 10.0
Carbon residue (10 %) % m/m DIN EN ISO 10370 0.20 - 0.3
Cetane number - DIN EN 15195 62.5 51.0 -
Sulphated ash % m/m ISO 3987 <0.01 - 0.02
Water content mg/kg DIN EN ISO 12937 558 - 500
Total contamination mg/kg DIN EN 12662:1998 50 - 24
Copper strip corrosion Corr.de
gr. DIN EN ISO 2160 1 1
Oxidation stability at
110 °C h DIN EN 14112 5.2 6.0 -
Acid value mg
KOH/g DIN EN 14104 0.484 - 0.5
Iodine value g
I2/100g DIN EN 14111 38 - 120
Linolenic acid
methylester % m/m DIN EN 14103 0.2 - 12.0
Methylester ≥ 4 double bonds
% m/m DIN EN 15779 0.01 - 1.00
Methanol content % m/m DIN EN 14110 0.01 - 0.20
Free glycerol % m/m DIN EN 14105 <0.01 - 0.020
Monoglyceride content % m/m DIN EN 14105 1.02 - 0.80
Diglyceride content % m/m DIN EN 14105 0.26 - 0.20
Triglyceride content % m/m DIN EN 14105 0.01 - 0.20
Total glycerol % m/m DIN EN 14105 0.30 - 0.25
Phosphorus content mg/kg DIN EN 14107 <2 - 4.0
Metals I (Na + K) mg/kg DIN EN 14108/109 9.0 - 5.0
Metals II (Ca + Mg) mg/kg DIN EN 14538 <2 - 5.0
* Requirements : 15.04. - 30.09. max. 0 °C
01.10. - 15.11. max. -10 °C 16.11. - 28.02. max. -20 °C
01.03. - 14.04. max. -10 °C
Biodiesel production from crude palm oil
119
5.3. Experimental part
Potassium hydroxide (flakes/pellets, 85 % purity) and potassium
methoxide (32 % solution in methanol) were obtained from Acros Organics
and used as such. Sulphuric acid (96 % purity) and methanol (99.8 % purity)
were purchased from Fluka and used as such. Other solvents, reagents and
indicators used in analytical procedures were obtained from Acros or Fluka
and used as such.
Lab-scale reactions (50, 100, 500 and 1000 g oil) were performed in glass
round bottom flasks and Erlenmeyer flasks. Flasks were heated in oil baths,
stirred with magnetic stirrers, connected to water coolers and protected from
humidity by calcium chloride tubes.
Reactions on a 1 ton scale were performed in a large industrial reactor as
shown on Figure 20.
1H-NMR (300 MHz) and 13C-NMR (75 MHz) spectra were recorded on a
Jeol JNM-EX 300 NMR spectrometer with CDCl3 as solvent and TMS as
reference. NMR spectra were used for qualitative determination of glycerides
and FFA. FG, MG, DG and TG were quantified by a modified ISO method EN
14105 by gas chromatography. GC analysis was performed on a gas
chromatograph Varian 3380, with an on-column injector, oven and flame
ionisation detector, on a Supelco HT-5 fused silica capillary column. 1,2,4–
Tributanol was used as internal standard for glycerol, and tricaprine was used
as internal standard for glycerides. N-methyl-N-
trimethylsilyltrifluroroacetamide (MSTFA) was used for the silylation of the
samples.
Calibration solutions are prepared from glycerol, glycerides and their
internal standards. Calibration functions for glycerol and glycerides are used
for calculation of correlation coefficient and constants needed for calculation of
quantities of glycerol and glycerides (r, a, b). Sample preparation was as
follows: 100 mg of sample is weighed in a 10 ml vial. Internal standards 1 and
2, in quantities of 80 and 100 µl, respectively, and 100 µl MSTFA are added.
After the silylation, the mixture is dissolved in 8 ml heptane.
Chapter 5
120
The analysis protocol was as follows: column temperature: gradient 50 °C
– 180 °C, at 15 °C/min, then up to 340 °C at 7 °C/min, final temperature held
for 15 min; detector temperature: 380 °C; carrier gas: H2, carrier gas pressure:
80 kPa; injection volume: 0.5 µl.
FFA were determined by titration using the modified AOCS Official
Method Ca 5a-40, using 0.1 N NaOH (accurately standardized with acid
potassium phtalate, KHC8H4O4, AOCS Specification H12-52) as a titrating
solution and phenolphthalein indicator (1 % solution in isopropanol).
The FFA content was expressed as palmitic acid, by the following
equation:
% FFA as palmitic acid = (ml NaOH × N × 25.6)/mass of sample in g, where
N = M NaOH = 0.1
The acid value was calculated from the FFA content, as 1.99 × %FFA.
The moisture content was determined by the Karl Fischer titration
according to the AOCS official method Ca 2e-84, on a Metrochem 716 DMS
Titrino automated Karl-Fischer titration set.
5.3.1. Reaction setup – lab scale
Palm oil was preheated to melt, weighed into a flask and further heated in
an oil bath to approximately 60 °C. Potassium hydroxide was dissolved in
methanol and added to the oil while stirring (trials from Table 18).
Alternatively, methanolic solution of potassium methylate was added,
followed by the addition of methanol (trials from Table 20). The mixture was
then heated for a specific period. A water cooler with a drying tube was
connected to the reaction vessel. After the first step, sulphuric acid (pure or
dissolved in methanol) was added. It was noticed that addition of pure acid to
the reaction mixture gave an extremely exothermic reaction and produce d a
change of the FAME colour. The reaction was further refluxed for a specific
period. The reaction mixture was then cooled under running water and was
transferred into a separating funnel. Alternatively, the reaction mixture was
partially cooled and then washed with warm water. This approach resulted in
Biodiesel production from crude palm oil
121
better separation of the layers during the washing. The bottom layer,
containing glycerol, water and methanol, was separated and the top layer,
containing FAME, was washed with water (in three portions adding up to
approx. half of the weight of the oil) until neutral pH. For experiments with
the first feedstock (see Table 18 and Table 20), water was removed by drying
the FAME over magnesium sulphate. MgSO4 was filtered off, and the filter
washed with dichloromethane, which was then evaporated from the FAME.
With the second feedstock (see Table 18), water was removed by drying under
vacuum. Exact times and quantities of reagents for several experiments, as
well as the results of the experiments, are shown in Tables 18 and 20.
The opposite approach (esterification followed by transesterification) was
performed in the analogous manner, but in the reverse order of catalyst
addition. The exact quantities of reagents are shown in Table 21.
Alternatively, the esterification step was abandoned. Transesterification
was performed on a 500 g scale, with 10 g of KOH and 125 ml MeOH under
reflux for 1.5 h. The reaction mixture was submitted to fractional distillation
under reduced pressure (1 mm Hg). Two major fractions were collected:
methyl palmitate and methyl oleate at 140 - 155 °C at 1 mm Hg. Methyl
linoleate (167 °C/1 mm) was collected in a small quantity. After the distillation,
the esters were mixed to determine the yields and quality of the product.
In one more set up, before the transesterification, 134.5 g oil was submitted
to the saponification with 1.5 ml 10 % KOH in water. Reaction mixture was
refluxed for 90 min. After the reaction, the oil was dried and the soaps were
removed by filtration over Büchner funnel. After the FFA content
determination by titration, the oil was submitted to transesterification by
addition of 0.5 g KOH in 35 ml methanol for 2 h at 50 °C. The reaction was
then worked up as usual.
Alternatively, the transesterification step with the conditions from
experiment 9, Table 18, was performed. On a 100 g scale, 2 g of KOH in 40 ml
of MeOH was added to the preheated oil; the reaction was performed for 1.5 h
at 60 °C and it was followed by the usual work up after the neutralisation.
Chapter 5
122
5.3.2. Reaction setup – pilot scale
Two experiments are performed on the pilot set ups in Belgium, with KOH
and with KOMe as catalysts. One ton of crude palm oil is preheated to 60 °C in
a closed and stirred reactor. 21 kg of KOH was dissolved in 270 kg of methanol
and this solution was added to the preheated oil in the reactor. The oil was
stirred for 1.5 h at 65 °C. For the second step, 58 kg of H2SO4 was dissolved in
50 kg of methanol, then added to the reactor and the reaction was run for an
additional three hours at the same temperature. The stirrer was then stopped
and the vessel left for 30 minutes for the layers to separate. The lower layer
was discarded and the biodiesel washed three times with 150 kg of warm
water (60 °C). The FAME were dried in the reactor under vacuum at 70 °C for
1 hour.
If potassium methylate was used as catalyst, the procedure was performed
in the aforementioned manner, with different quantities of catalysts. 47 kg of
MeOK and 237 kg MeOH were added to the preheated oil in the first step, and
50 kg H2SO4 in 50 kg of methanol in the second step. The work-up was the
same as in the experiment with the KOH.
Alternatively, in the finally accepted and applied one-step
transesterification approach, 3 – 4 mass% of MeOK (32 % methanolic solution)
was added to the preheated oil, together with 16 – 20 % MeOH (both
proportionally to the FFA content, between 2 and 3.5 %). After the same
reaction time, a titration of the sample was performed with the locally
available sulphuric acid and the corresponding quantity was added to the
reaction mixture. Side products and unused methanol were washed out in the
lower layer, and the resulting FAME were dried at 70 °C.
5.4. Conclusions
A very robust and straightforward process was developed for the
production of biodiesel from crude palm oil. Two alkaline catalyst systems are
applicable: potassium hydroxide and potassium methylate. The latter, being a
stronger base, is preferred for the reaction, as it gives high conversions and an
Biodiesel production from crude palm oil
123
easier work up. A preliminary tested idea using a second esterification step of
the free fatty acids was abandoned after consideration of the cost benefit effect.
With a limit of applicability of 3.5 % FFA in the starting material, it is possible
to obtain a satisfactory yield of 93 mass% of good quality biodiesel.
The biodiesel quality parameters that are borderline (acid value and the
total contamination concentration) do not pose special problems in the
intended and actual application. The normal diesel engines of the cars and
trucks are run for five years on this biodiesel, without additives and without
blending with diesel fuel. No negative effect was noticed on the engines; on
the contrary, due to the better lubricating properties of the biodiesel, some of
the engines are even in an improved condition compared to the previous
period in which they were run on diesel fuel.
124
125
6. Summary
Sustainability as a trend is particularly important in the chemical
environment. Earth pollution, leading to fundamental environmental changes
on multiple levels on one hand, and the exhaustion of the petrochemical
sources on the other hand, are the main two drives for the policies of change in
the chemical industry. The research in alternative sources of energy is focusing
on renewable resources as well. As a part of the sustainability trend in
chemical industry, green chemistry principles define the design of chemical
processes and products in which the use and generation of hazardous
substances are eliminated, and the use of inherently safe materials is
encouraged. This involves the use of renewable and biodegradable materials,
reduce of use of solvents harmful for the health and environment, or their
replacement by more acceptable alternatives; furthermore, the use of
heterogeneous catalysis and biocatalysis is encouraged, as opposed to
homogeneous catalysis. Novel materials are explored (such as ionic liquids).
Microreactor technology is one of the manners to achieve process
intensification (PI) by reducing the reaction volume, linked to a sharp decrease
in the reagents and solvents use, and to the improved mixing linked to the
higher surface to volume ratio. The ease of control of reaction conditions and
the flexibility of a physically small set-up are joined by the enormous savings
in energy and time, and by an improved reaction safety, due to the smaller
scale. Closed systems reduce the exposure to the environment, and the
improved heat and mass transfer.
In this work, we submitted a range of bio-based molecules to chemical
transformations in order to obtain materials of importance to the chemical
community. Microreactor technology was successfully applied to improve the
output of the existing reactions, increasing the yields and opening the route to
the scale-up. We have also optimized a process for the obtaining a bio-based
fuel for the use on a pilot scale.
Symmary
126
In the first chapter, we have used ionic liquids as reaction media and
catalysts for the production of 5-(hydroxymethyl)furfural (HMF) from inulin,
a polysaccharide material found in nature and not used in the essential human
diet. HMF is a promising bio-based molecule for a wide range of chemical
conversions in fine and polymer chemistry for example. Solid heterogeneous
catalysts and ionic liquids showed a distinct activity for these conversions.
Separation of the HMF product remains a problem. Continuous extraction was
in our experience the most efficient manner of reaching a complete separation
from the reaction medium; however, this is a very energy-demanding process.
Technical improvements in order to minimize the energy losses and the loss of
solvent due to evaporation, combined with the strictly defined recycle patterns
of the solvents, might be the manner for an efficient separation of HMF from
the reaction mixtures. Alternatively, improved solvent systems (still to be
defined) might be of use in separation of HMF.
O
HO OO OH
HO
HO OH
OH
O OH
HO
HO OH
O
O OH
HO
HO
O
O OH
HOO OH
O
HOOH
OH
OH
n
H+ H+
O
HO NR
NH2R
NaBH4
O
HOHN
R
H
Scheme 19: Production of HMF and reductive amination to pharmaceutically
interesting molecules
As a continuation of this work, by a straightforward process of reductive
amination, HMF was converted to a range of derivatives with potential use as
starting materials for future conversions to pharmaceutically active
derivatives. Reactions were performed in water, traditionally the most
undesired compound in the reaction of reductive amination, being one of its
side products. Alternatively, methanol and ethanol, possibly renewable
solvents, were used as solvents and performed better than water. Reactions
were performed in the absence of catalysts. Some future interesting work on
this topic would be the development of actual bio-based pharmaceutically
active substances (for example, antihistaminics), as replacements to the
structures nowadays produced in energetically unfavourable manner.
Symmary
127
In the second part of the work, we have proven the advantages of
microreactor technology to the existing processes by performing Kiliani
reaction in flow. This reaction, addition of cyanide to the carbonyl group, is a
classical process in chemistry of monosaccharides for the prolongation of the
C-chain, amongst other; however, it was mostly reported on aldoses, with
unreliable yields and danger of accidental HCN release. Benefits of
microreactors (intensified process and increased safety by the use of a closed
system) have lead to the successful production of the hydroxynitriles from
ketoses. α-Hydroxycarboxylic acids, important building blocks in organic
chemistry, were obtained by in situ hydrolysis.
1a, R= CH2OH1b, R= (S)-CH(OH)-CH2OH1c, R= (S)-CH(OH)-(R)-CH(OH)-(R)-CH(OH)-CH2OH
CN- source
R
OH
OHR
OH
OH
N NH2O
R
OH
OH
OHO
R
O
OH
or or
Scheme 20: Kiliani reaction as a route to α-hydroxyacids performed in flow
Methanol was the main solvent in the solvent mixture for the Kiliani
conducted reactions in flow. Reaction was successful for the C3 and C4 ketoses
(respectively dihydroxyacetone and L-erythrulose); however, only trace
conversion was noticed in case of D-fructose (C6 carbohydrate) as substrate.
Seeing that the reaction time was clearly one of the factors in reaching the
good conversions, and that an increased retention time was needed for the
conversion of longer chain carbohydrates to the final products, it is possible a
that a prolonged retention (reaction) time could lead to better conversions.
This can be achieved by the modification of the reaction paths, for example by
the use of a larger volume/length RTU, or the conduction of the reaction in
another type of reactor (for example, a self-made system with flexible reaction
channels. The conduction of the reaction in a flexible system, under the
condition that a resistant polymer, such as Teflon (polytetrafluoroethylene
PTFE) is used, would additionally allow for the greater freedom in the choice
of reactants and concentrations (for example, mineral acids could not be used
in the CPC, made of stainless steel). It would also be interesting to combine the
Symmary
128
chiral solid catalysis (biocatalysis) with this process in order to obtain pure
product isomers.
In the third part of the work, we have shown that the microreactor
technology can be a successful replacement for the microwave-conducted
processes. Benzotriazole chemistry for the coupling of amino acids is largely
reported in batch, under microwave heating. The application of microreactor
technology opened the route to the scale-up of the reaction and allowed the
use of an environmentally friendlier solvent.
CbzHN
R1
Bt
O
Het-NH2
CbzHN
R1
O
HN
Het
NN
NBt =
Scheme 21: Production of (α-aminoacyl)amino-substituted heterocycles in flow
using microreactor technology
However, the weak point of this process remains the product purification,
consisting of the water quench, followed by the organic solvent extraction and
chromatographic purification. A possible further insight into different solvents
could potentially avoid the use of the high boiling solvents and result in a less
tedious product separation. Also, the benzotriazole activated N-protected
amino acids could potentially be produced in flow, under condition that the
clogging problem is efficiently solved. This can potentially be achieved by the
use of ultrasound in combination with an adapted solvent mixture and
quenching to avoid an extensive salt formation.
In the final part of this work, the optimisation of a biodiesel production
process from crude palm oil was performed. The initially considered two-step
acid-base catalysed process is ultimately replaced by a one-step procedure, a
base-catalysed esterification; this is made possible under the condition that the
oil is processed to biodiesel soon after the pressing cycle, while the FFA (free
Symmary
129
fatty acids) content is relatively low. A methanolic solution of potassium
methylate (MeOK) is used as catalyst in this process. The robust and
straightforward process is successfully applied, in technologically limited
conditions, on a one ton scale. The process is currently in use for the
production of the fuel, used by a palm oil producer, on the palm oil
production facility self. Biodiesel is used pure, without additives and without
mixing with petroleum diesel, for the run of own vehicles, in equatorial Africa.
OH
OH
OH
3 ROH
R1
O
O
R2
O
O
R3
O
O
R
R
R
R1
O
O
O
O
R2
O
O
R3
Scheme 22: Generic reaction of biodiesel production
A side product of this process is salt potassium sulphate (K2SO4, in this
case formed by neutralisation of the alkaline catalyst by sulphuric acid), with
potential use as a fertilizer. On a lab scale, this salt was successfully recovered.
However, during the current biodiesel production, the salt is not recovered
due to the relatively small production volume and waste stream. A possible
improvement of the process would be the separation of the salt before the
removal of the waste stream.
Symmary
130
131
7. Samenvatting
Duurzaamheid als trend is bijzonder belangrijk in de chemische wereld.
De vervuiling van onze planeet die leidt tot fundamentele veranderingen in
het milieu op verschillende niveaus enerzijds, en de uitputting van de
petrochemische bronnen anderzijds, zijn de twee belangrijkste drijfveren voor
het beleid van veranderingen in de chemische industrie. Het onderzoek naar
alternatieve energiebronnen is ook gericht op hernieuwbare grondstoffen. Als
onderdeel van de trend naar duurzaamheid in de chemische industrie,
bepalen groene uitgangspunten het ontwerp van chemische processen en
producten, waarbij het gebruik van schadelijke stoffen wordt geëlimineerd, en
het gebruik van intrinsiek veilige materialen wordt gestimuleerd. Dit omvat
het gebruik van hernieuwbare en biologisch afbreekbare materialen, het
verminderen van het gebruik van solventen die schadelijk zijn voor de
gezondheid en het milieu, of hun vervanging door meer acceptabele
alternatieven. Bovendien wordt het gebruik van heterogene katalyse en
biokatalyse aangemoedigd, in de plaats van homogene katalyse. Nieuwe
materialen worden onderzocht (zoals ionische vloeistoffen).
Microreactortechnologie is een van de manieren om procesintensificatie (PI) te
verwezenlijken; dit gebeurt door het reactievolume te verkleinen, gekoppeld
aan een sterk verminderd gebruik van reagentia en oplosmiddelen alsook
door de verbeterde menging als gevolg van een hogere oppervlakte -
volumeverhouding. De eenvoudige controle van de reactieomstandigheden en
de flexibiliteit van een fysiek kleine opstelling, leiden tot enorme energie -en
tijdsbesparingen, alsook een verhoogde reactieveiligheid vanwege de kleinere
schaal. Gesloten systemen verminderen de blootstelling aan het milieu, en
hebben een betere warmte- en massaoverdracht.
In dit werk werden een reeks biogebaseerde moleculen onderworpen aan
chemische transformaties, met het oog op het bekomen van waardevolle
producten voor de chemische industrie. Microreactortechnologie werd
succesvol toegepast om de resultaten van bestaande reacties te verbeteren, de
rendementen te verhogen en het pad te effenen naar schaalvergroting. Een
Samenvatting
werkwijze werd eveneens geöptimaliseerd om biobrandstof te produceren
voor het gebruik op pilootschaal.
In het eerste hoofdstuk werden de ionische vloeistoffen of vaste
heterogene katalysatoren, als reactiemedia en/of katalysatoren gebruikt voor
de productie van 5-(hydroxymethyl)furfural (HMF) uit inuline, een
polysacharide uit de natuur die niet gebruikt wordt in menselijke voeding.
HMF is een veelbelovende biologische grondstof molecule, voor een groot
aantal chemische omzettingen in fijn- en polymeerchemie. Deze stoffen
toonden een duidelijke aciviteit voor HMF vorming uit het substraat.
Efficiënte purificatie van de HMF product blijft een probleem in dit process.
Uit onze ervaring blijkt dat een continue extractie de meest efficiënte wijze
was om een volledige scheiding van HMF uit het reactiemedium te bereiken;
dit is echter een hoogenergetisch proces. Technische verbeteringen kunnen het
verlies van energie en solventen vermijden. Gecombineerd met een strikt
gedefinieerde recyclagepatroon van de solventen, kan dit tot een efficiënte
scheiding van HMF uit de reactiemengsels leiden.
O
HO OO OH
HO
HO OH
OH
O OH
HO
HO OH
O
O OH
HO
HO
O
O OH
HOO OH
O
HOOH
OH
OH
n
H+ H+
O
HO NR
NH2R
NaBH4
O
HOHN
R
H
Schema 1: Productie van HMF en reductieve aminering van farmaceutisch
interessante moleculen
Als een vervolg op dit bovenstaande werk, werd HMF door een eenvoudig
proces van reductieve aminering omgezet in een reeks derivaten voor
potentieel gebruik als startmaterialen voor toekomstige omvormingen naar
farmaceutisch actieve derivaten. De reacties werden uitgevoerd in water, de
traditioneel ongewenste verbinding in de reactie van reductieve aminering.
Als alternatief werden methanol en ethanol als solventen gebruikt. Reacties
werden uitgevoerd in afwezigheid van katalysatoren. Interessant toekomstig
onderzoek zou de ontwikkeling van de werkelijke bio-gebaseerde
Samenvatting
133
farmaceutisch actieve stoffen kunnen zijn, ter vervanging van de bestaande
structuren geproduceerd in energetisch ongunstige manier.
In het tweede deel van het werk werden de voordelen aangetoond van
microreactortechnologie in bestaande processen, met als voorbeeld het continu
uivoering van de Kiliani-reactie. Deze omzetting, waarbij cyanide aan de
carbonylgroep wordt geaddeerd, is een klassieke benadering voor de
verlenging van de C-keten van monosacchariden. Tot op heden werd dit
proces meestal uitgevoerd op aldoses, met onbetrouwbare opbrengsten en met
gevaar voor accidentele HCN-vrijstelling. De voordelen van microreactoren
(intensief proces en de verhoogde veiligheid door het gebruik van een gesloten
systeem) hebben geleid tot de succesvolle productie van hydroxynitriles van
ketoses. α-Hydroxycarbonzuren, belangrijke bouwstenen in de organische
chemie, werden verkregen door in situ hydrolyse.
1a, R= CH2OH1b, R= (S)-CH(OH)-CH2OH1c, R= (S)-CH(OH)-(R)-CH(OH)-(R)-CH(OH)-CH2OH
CN- source
R
OH
OHR
OH
OH
N NH2O
R
OH
OH
OHO
R
O
OH
or or
Schema 2: Kiliani reactie van sacchariden via een continuprocess
Methanol was de voornaamste solvent in het solventenmengsel van deze
reactie. Deze reactie was succesvol voor de C3 en C4 ketose (respectievelijk
dihydroxyaceton en L-erythrulose); anderzijds werden slechts sporen van de
vervorming waargenomen bij D-fructose (C6 koolhydraat) als substraat.
Aangezien de reactietijd duidelijk één van de factoren was bij het bereiken van
de goede omzettingen, is het aannemelijk dat een retentie (reactie) tijd tot
betere conversies kan leiden. Dit kan bereikt worden door de verlenging van
de reactiepaden, bijvoorbeeld door het gebruik van een groter volume (lengte)
RTU en/of de uitvoering van de reactie in een ander type reactor (bv. een
zelfgemaakte reactor met flexibele reactiekanalen). Indien een resistent
polymeer, zoals Teflon (PTFE), zou gebruikt worden, heeft men een grotere
keuze uit reactanten (zoals bv. de keuze van een zuur, gezien de minerale
zuren niet konden gebruikt worden in onze staalreactoren). Verder zou het
Samenvatting
interessant zijn als de geproduceerde α-hydroxyzuren getransformeerd
zouden worden tot farmaceutisch interessante producten.
In het derde deel van het werk werd aangetoond dat
microreactortechnologie een succesvol alternatief kan vormen voor processen
uitgevoerd onder microgolfverwarming. De benzotriazoolchemie voor het
koppelen van aminozuren wordt grotendeels uitgevoerd in batch bij
microgolfverwarming. De toepassing van microreactortechnologie maakte de
weg vrij voor schaalvergroting van de reactie en liet het gebruik toe van
milieuvriendelijkere solventen.
CbzHN
R1
Bt
O
Het-NH2
CbzHN
R1
O
HN
Het
NN
NBt =
Schema 3: Productie van (α-aminoacyl) aminogesubstitueerde heterocycli in flow met
microreactortechnologie
De product zuivering, een extractie met een organisch solvent en een
chromatografische zuivering, blijft het zwakke punt van dit proces. Een
verandering van het reactiemedium zou het gebruik van hoogkokende
solventen potentiëel vermijden en tot een eenvoudigere productscheiding
kunnen leiden. Ook de benzotriazool-geactiveerde aminozuren zouden
kunnen geproduceerd worden in flow onder voorwaarde dat het
verstoppingsprobleem efficiënt kan opgelost worden. Dit kan mogelijk bereikt
worden door het gebruik van ultrageluid in combinatie met aangepaste
solventencombinatie en quenching die de uitgebreide zoutvorming zouden
kunnen voorkomen.
In het laatste deel van dit werk werd de optimalisatie van een
biodieselproductieproces vanuit ruwe palmolie uitgevoerd. De aanvankelijk
overwogen twee-staps (zuur-base gekatalyseerde) procedure werd uiteindelijk
vervangen door een één-staps procedure: een base gekatalyseerde reactie. Dit
Samenvatting
135
is mogelijk onder voorwaarde dat de olie naar biodiesel verwerkt wordt direct
na het persen, wanneer de hoeveelheid van de vrije vetzuren relatief laag is.
Een methanoloplossing van kaliummethylaat (MeOK) wordt als katalysator in
dit proces gebruikt. Dit robuuste en eenvoudige proces wordt momenteel, in
moeilijke omstandigheden met succes toegepast op een één ton schaal, voor
brandstofproductie op de productiefaciliteit van een palmolieproducent in
equatoriaal Afrika. De bekomen biodiesel wordt als dusdanig gebruikt, zonder
toevoegingen en zonder vermening met fossiel-gebaseerde diesel, voor het
aandrijven van eigen voertuigen.
OH
OH
OH
3 ROH
R1
O
O
R2
O
O
R3
O
O
R
R
R
R1
O
O
O
O
R2
O
O
R3
Schema 4: Algemene reactie van de biodieselproductie
Een nevenproduct van dit proces is het zout, kaliumsulfaat (K2SO4, hier
gevormd door de neutralisatie van de alkalische katalysator met zwavelzuur),
potentieel te gebruiken als meststof. Op laboschaal werd dit zout met succes
recupereerd. In de toegepaste productie van biodiesel op grote schaal echter
wordt het zout niet recupereerd; dit is door de relatief kleine productievolumes
en afvalstromen. De afscheiding van het zout uit deze afwalstroom zou een
aanzienlijke verbetering zijn van dit proces.
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Curriculum vitae
° 29 October 1976
Vlasotince
Ana Ćukalović
Koningsdonkstraat 36
9050 Gentbrugge
0484 08 63 46
2007-2012 PhD student, Department of Sustainable Chemistry and
Technology, Faculty of Bioscience Engineering, Ghent
2007-2009 Research funded by the TESS project (EC-EF6)
2009-2012 Research funded by the Long Term Structural Methusalem
Funding by the Flemish Government (M2dcR2)
2006-2007 QC responsible, Actavis Pharmaceuticals Serbia
2004-2006 MSc Food Safety and Quality, Tempus program, Faculty of
Veterinary Medicine, Belgrade
Thesis title: “Dry fractionation of palm oil and physico-chemical
evaluation of fractions”
Promoter: Prof. Dr Dejan Smiljanić
1995-2004 MSc Pharmaceutical Sciences, Faculty of Pharmaceutical
Sciences, Belgrade
Thesis title: “Enzyme preparations in food production” (in Serbian)
Promoter: Prof. Dr Ivan Stanković
Curriculum
155
Publications
A. Cukalovic, J.-C. Monbaliu, Y. Eeckhout, C. Echim, R. Verhé, G.
Heynderickx, C. Stevens. Development, optimization and scale-up of biodiesel
production from crude palm oil and effective use in developing countries ,
Biomass Bioenerg., accepted
A. Cukalovic, J.-C. Monbaliu, G. Heynderickx, C. Stevens. User friendly
and flexible Kiliani reaction on ketoses using microreaction technology, J.Flow
Chem., 2(2012); 43-46
F. Van Waes, J. Drabowicz, A. Cukalovic, C. Stevens. Efficient and catalyst-
free condensation of acid chlorides and alcohols using continuous flow. Green
Chem., 14(2012)10; 2776-2779
A. Cukalovic, C. Stevens. Production of biobased HMF derivatives by
reductive amination. Green Chem. 12(2010)7;1201-1206.
J.-C. Monbaliu, A. Cukalovic, J. Marchand-Brynaert, C. Stevens.
Straightforward hetero Diels–Alder reactions of nitroso dienophiles by
microreactor technology. Tetrahedron Lett. 51(2010)44;5830-5833.
A. Cukalovic, C. Stevens. Feasibility of production methods for succinic
acid derivatives: a marriage of renewable resources and chemical technology.
BioFPR. 2(2008)6; 505-529.
Book chapters
A. Cukalovic, J.-C. Monbaliu, C. Stevens. Microreactor technology as an
efficient tool for multicomponent reactions. In: Synthesis of Heterocycles via
Multicomponent Reactions, R. Orru, ed. Top. Heterocycl. Chem. 23: (2010)
161–198, Springer, Berlin.
Poster presentations
A. Cukalovic, J.-C. Monbaliu, Y. Eeckhout, C. Echim, R. Verhé, G.
Heynderickx, C. Stevens. Development, optimization and scale-up of biodiesel
production from crude palm oil and effective use in developing countries .
Curriculum
Eighth International Conference on Renewable Resources and Biorefineries
(RRB 8), Toulouse, 4-8 June 2012.
A. Cukalovic, J.-C. Monbaliu, B. Roman, A. De Blieck, T. Heugebaert, J.
Thybaut, G. Marin, G. Heynderickx, C. Stevens. Application of microreactor
technology for cyanohydrin production: extending the scope towards
renewable resources. RRB 7, Brugge, 8-10 June 2011.
A. Cukalovic, C. Stevens. Reductive amination of carbohydrate derivatives
as a simple route to building blocks for biologically active compounds. RRB 6,
Düsseldorf, 7-9 June 2010.
A. Cukalovic, C. Stevens, S. Breeden, J. Clark. Specialty chemicals
manufacturing SMEs Toolbox to support Environmental and Sustainable
Systems (TESS). RRB 4, Rotterdam, 1-4 June 2008.
A. Cukalovic, C. Stevens, S. Breeden, J. Clark. TESS: supplying SMEs with
renewable building block information. RRB 3, Ghent, 4-6 June 2007.
Miscellaneous
A. Cukalovic, C. Stevens. A guide for the implementation of the REACH
regulation: small and medium enterprises (SMEs). BioFPR 2009, 3(6);579-579