ghent universitypromoters prof. dr. ir. christian stevens department of sustainable organic...

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,


Ghent University

Prof. Dr. ir. Wim Soetaert

Centre of Expertise for Industrial

Biotechnology and Biocatalysis,


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,


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


3.1.1. Kiliani reaction 59


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


3.3.1. 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



4.2.1. Production of starting materials, N-protected α-aminoacylbenzotriazoles 80

4.2.2. Production of α-aminoacylamino substituted heterocycles 81


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


5.1.1. Biodiesel as a transport fuel 94

5.1.2. Palm oil as biodiesel feedstock 99


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


5.3.1. 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


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).


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-


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).


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.


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.


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


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


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.


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).


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


2/98 Rf= 0.30

10’


2/98 Rf=0.18

12


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


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.


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.


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


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


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).


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


61

efficient agent but its high price limits its applicability. Viable alternatives

include alkaline cyanides, acetone cyanohydrin and cyanoformates.508


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


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


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


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.


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.


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.


3.3.1. 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.


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


4.2.1. 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


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.


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.


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.


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).


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).


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


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


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


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


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


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.


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.


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


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


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.


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


119


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


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


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.

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.


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.


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

[email protected]

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

mailto:[email protected]

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

ghent universitypromoters prof. dr. ir. christian stevens department of sustainable organic...

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