Fluid Phase Behaviour of Ionic Liquid-Based
Systems of Interest for Green Processes:
Measurements and Modelling
Fluid Phase Behaviour of Ionic Liquid-Based
Systems of Interest for Green Processes:
Measurements and Modelling
Proefschrift
ter verkrijging van de graad van doctor
aan de Technische Universiteit Delft,
op gezag van de Rector Magnificus Prof. dr. ir. J. T. Fokkema,
voorzitter van het College voor Promoties,
in het openbaar te verdedigen op 4 juni 2008 om 15:00 uur
door
Eliane KÜHNE
Master of Science in Chemical Engineering,
State University of Campinas, Brazilië
Dit proefschrift is goedgekeurd door de promotor: Prof. dr. G.J. Witkamp
Toegevoegd promotor: Dr.ir. C. J. Peters
Samenstelling promotiecommissie:
Rector Magnificus Voorzitter
Prof. dr. G.J. Witkamp Technische Universiteit Delft, promotor
Dr. ir. C.J. Peters Technische Universiteit Delft, toegevoegd promotor Prof. dr. I.W.C.E. Arends Technische Universiteit Delft
Prof. dr. S.B. Bottini Universidad Nacional del Sur – CONICET, Argentina Prof. dr. W. Buijs Technische Universiteit Delft
Dr. S. Raeissi Shiraz University, Iran
Dr. G. Meima Dow Benelux B.V.
ISBN 978-90-9023156-3
Copyright 2008 by Eliane Kühne
All rights reserved. No part of the material protected by this copyright notice may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording or by any information storage and retrieval system, without written permission from the publisher.
IIII
IIII
n
n
n
n
n
n
n
n
d
d
d
d
d
d
d
d
e
e
e
e
e
e
e
e
x
x
x
x
x
x
x
x
Summary... I
1. Introduction...1
1.1 The need for Green Chemistry...2
1.2 The principles and definition of green chemistry ...7
1.3 Motivation - Study of phase behaviour...9
1.4 Selection of the ionic liquid ...11
1.5 Model Reactions ...12
1.5.1 Mirtazapine...13
1.5.2 Acetophenone ...14
1.5.3 S-naproxen...15
1.5.4 Ibuprofen ...16
1.6 Aim and Outline of this thesis...17
1.7 References ...19
2. Background ...23
2.1 Ionic Liquids ...24
2.1.1 Properties of ionic liquids...26
2.1.2 Toxicity of ionic liquids ...27
2.2 Supercritical fluids ...29
2.3 Ionic liquids – carbon dioxide systems ...31
2.4 The Miscibility Switch...33
2.5 Brief Description of phase diagrams...34
2.5.1 The Gibbs Phase Rule ...34
2.5.2 Phase diagrams: binary mixtures...35
2.5.3 Phase diagrams: systems with ionic liquids ...37
2.6 References ...39
3. Experimental ...45
3.1 Synthesis of the ionic liquid bmim[BF4]...46
3.1.1 Chemicals ...46
3.1.2 Procedure and yield ...46
3.2 Synthesis of the ionic liquid emimdca ...47
3.3 Phase behaviour measurements ...49
3.3.3 The Cailletet Apparatus...51
3.3.4 Sample Preparation...53
3.3.5 Measuring Procedure...54
3.4 References ...55
4. Phase Behaviour Results: Selection of the Ionic Liquid ...57
4.1 Solubility of CO2 in bmim[BF4] ...58
4.2 Solubility of CO2 in emimdca ...60
4.2.1 Mercury cyanamide and mercury cyanide ...66
4.3 Conclusions...67
4.4 References ...69
5. Phase Behaviour Results: Model Reaction on the Synthesis of Mirtazapine...71
5.1 The system bmim[BF4] + 2-chloro-nicotinonitrile + CO2...72
5.2 The system bmim[BF4]+1–methyl–3-phenylpiperazine + CO2...74
5.2.1 Carbamates ...76
5.3 The system bmim[BF4] + KF + CO2...79
5.3.1 Stability of the BF4- anion ...80
5.4 The system bmim[BF4] + PCN + CO2...81
5.5 Reaction in bmim[BF4] ...82
5.6 Conclusions...83
5.7 References ...85
6. Phase Behaviour Results: Model Reaction on the Synthesis of s-naproxen ...87
6.1 The system bmim[BF4] + s-naproxen + CO2...88
6.2 Synthesis and extraction of s-naproxen in bmim[BF4] ...91
6.3 Conclusions...92
6.4 References ...93
7. Phase Behaviour Results: Model Reaction on the Hydrogenation of Acetophenone .95 7.1 The system bmim[BF4] + acetophenone + CO2...96
7.2 The system bmim[BF4] + 1-phenylethanol + CO2...96
7.3 Comparison between both ternary systems...97
7.4 Comparison with binary systems ...99
7.7 References ...103
8. Phase Behaviour Results: Model Reaction on the Synthesis of Ibuprofen ...105
8.1 The system bmim[BF4] + 4-isobutylacetophenone + CO2...106
8.2 The system bmim[BF4] + 1-(4-isobutylphenyl)-ethanol + CO2...110
8.3 Comparisson with other binary and ternary systems ...115
8.4 Conclusions...118
8.5 References ...119
9. Overview: The Miscibility Switch and Hydrogenations...121
9.1 The miscibility switch in ionic liquid – CO2 systems ...122
9.2 Catalyst selection ...125
9.3 Drawbacks...127
9.4 Conclusions...129
9.5 References ...129
10. Modelling the Phase Equilibria of Ternary Systems with Ionic Liquids...131
10.1 Introduction ...132
10.1.1 Criteria for Phase Equilibria...134
10.2 The GC-EOS ...135
10.3 Results and Discussion...138
10.3.1 Parameterization ...138
10.3.2 Results ...141
10.4 Conclusions ...147
10.5 References ...147
11. Conclusions and Outlook ...151
11.1 Conclusions ...152
11.2 Outlook...153
Abbreviations and Symbols ...155
Appendices ...159
Acknowledgements ...181
Curriculum Vitae...185
S
Industry is facing nowadays a hard challenge: how to achieve more environmentally benign and sustainable technology in order to reduce or eliminate the environmental impact of their processes. A reduction in the use of volatile organic solvents (VOS’s) is one of the most important issues to be overcome. In the last years, ionic liquids have emerged as promising candidates for the effective replacement of VOS’s. Their insignificant vapour pressure and the fact that they can be designed according to a specific need make ionic liquids great candidates for green chemistry. When associated with supercritical fluids in reaction and extraction processes, the new environmentally friendly process can ensure similar or higher efficiencies than the currently used ones, with the advantage of less hazardous substances involved as well as less loss of solvents and catalyst leaching.
The use of ionic liquids in combination with supercritical fluids has unlimited advantages; it is already known that supercritical carbon dioxide can be applied for a switch in the miscibility of mixtures of organic solvents or water with ionic liquids, as well as for extraction of organic compounds from the ionic liquid phase. It has been also proved that carbon dioxide is highly soluble in ionic liquids, and that no significant traces of ionic liquids can be found in CO2. It means that, when
scCO2 is used to extract products from an ionic liquid medium, the desired product
will be free from solvent contamination. The product can be recovered from the supercritical phase by simply decreasing the pressure, and depending on the solubility of reactants and catalysts in scCO2, no further purification is necessary.
The ionic liquid, together with the catalyst, can be then recycled and reused for another few batches.
Such a process has been conceived and patented by M.C. Kroon and co-workers in 2004. However, the capabilities of the process, i.e., the applicability of the miscibility switch in diverse systems and the conditions in which homogeneous and heterogeneous regions are found must be investigated and well understood.
Initially, the subject of this thesis was the performance of reactions and extractions using ionic liquids and carbon dioxide as combined solvents. The goal was to prove the concept of the processes developed and patented by Kroon and co-workers using the miscibility switch to perform reactions in one phase, and efficiently extract the product under heterogeneous conditions. However, the applicability of this process proved to be intimately related to molecular interactions between solute-ionic liquid, solute-carbon dioxide and solute-ionic liquid-carbon dioxide, as well as to the composition of each one of the substances in the system. Therefore, a better insight on the phenomenon of the miscibility switch and its dependence on pressure and temperature were necessary.
The focus of this study was then switched to the investigation of phase diagrams of ternary mixtures ionic liquid + organic solute + carbon dioxide, since the number of publications on the phase behaviour of multi-component mixtures based on ionic liquids was until a few years ago very scarce and the systems were poorly explored.
Due to its low viscosity, the ionic liquid 1-ethyl-3-methylimidazolim dicyanamide, emimdca, was considered a good candidate for investigation of the phase behaviour of ternary mixtures. However, a precipitation occurred during measurements of CO2 solubility, from which instability of the dicyanamide anion in presence of
mercury (used in the Cailletet equipment) has been proposed. After that, it was decided to continue the investigations with 1-butyl-3-methylimidazolim tetrafluoroborate, bmim[BF4], which was a known ionic liquid from previous
studies done in our group and which physical and chemical properties were better known in comparison with other ionic liquids.
Four reactions of interest of the pharmaceutical and fine chemical industry, among them three hydrogenations, were selected as model reactions to provide the organic solutes used in phase behaviour measurements. The main focus on the model reactions has been pharmaceutical processes, since this is one of the industry branches that frequently require products of extremely high purity and produce valuable products, conditions that make them good candidates for adopting new processes with ionic liquids.
The first model reaction, a nucleophilic substitution that is a reaction step in the synthesis of Mirtazapine (the active ingredient in the anti-depressant Remeron), was not successful in providing information on the miscibility switch phenomenon. Two of the four components involved in the model reaction interacted with the ionic liquid bmim[BF4] and with carbon dioxide, reducing the reliability on the data
obtained for the phase behaviour of the system. Although the miscibility switch could not be performed, the reaction was successfully carried out in bmim[BF4],
proving that ionic liquids are indeed able to efficiently replace VOS’s as solvents in reactions.
The second model reaction was the hydrogenation of 2-(6-methoxy-2-naphthyl)acrylic acid giving (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid, or s-naproxen, a non-steroidal anti-inflammatory drug (NSAID). The reactant of this model reaction was not available commercially neither could be supplied by industry. Therefore, only the phase behaviour of the system bmim[BF4] +
s-naproxen + CO2 was measured. In this system, it has been shown that extraction by
possible, considering that the solubility of this drug in supercritical CO2 is relatively
low for an economically attractive and efficient supercritical extraction.
The third selected model reaction was the hydrogenation of acetophenone into 1-phenylethanol. The hydrogenation of this simplest aromatic ketone is an important step in the production of various products in the fine chemicals industry. Measurements were performed for CO2 compositions up to 50 mol%, and under the
experimental conditions of this work, only liquid-vapour phase boundaries were found. The solubility of carbon dioxide in the ternary system with the ketone was found to be higher than in the system with the alcohol, what can be explained by the interactions ionic liquid-solute and ionic liquid – CO2 that take place in the
mixture.
The last model reaction studied was the hydrogenation of 4-isobutylacetophenone giving 1-(4-isobutylphenyl)-ethanol, which is a reaction step in the synthesis of Ibuprofen, another common NSAID. For compositions below 50 mol% CO2, the
same effect was observed as in the previous model reaction: lower solubility of CO2
in the mixture bmim[BF4] + alcohol than in bmim[BF4] + ketone. However, for CO2
compositions above 50 mol%, the complexity of the phase diagram increased significantly. Not only liquid-vapour but also liquid-liquid phase transitions were found, as well as a very narrow three-phase liquid-liquid-vapour region was detected. By a close investigation of the conditions under which the second liquid phase appeared, it was found to be a consequence of partial condensation of CO2
from the vapour phase instead of a new organic-rich phase as desired. In other words, the three-phase system was composed by a dense ionic liquid-rich liquid phase, an intermediary carbon dioxide-rich liquid phase and a carbon dioxide-rich vapour phase. For extraction purposes, the desired system should be composed basically by an ionic liquid-rich phase, an organic-rich liquid phase and a carbon dioxide-rich vapour phase.
Since measurements of phase behaviour are time consuming and the visualization of phase transitions may be sometimes cumbersome, the use of a model to predict the phase behaviour of mixtures based on ionic liquids and CO2 is highly desirable.
Therefore, the applicability of a group contribution equation of state, GC-EOS, for modelling the ternary systems measured in this work was also investigated. Excellent agreement has been found for vapour to liquid as well as liquid-liquid to liquid-liquid phase transitions, and reasonable agreement between experimental and predicted values for the bubble point curve in the ternary system bmim[BF4] +
acetophenone + CO2 was obtained. According to the results presented in this thesis,
the GC-EOS can be considered suitable for prediction of phase equilibria in ternary systems based on an ionic liquid and carbon dioxide.
1
1
IIII
IIII
N
N
N
N
N
N
N
N
T
T
T
T
T
T
T
T
R
R
R
R
R
R
R
R
O
O
O
O
O
O
O
O
D
D
D
D
D
D
D
D
U
U
U
U
U
U
U
U
C
C
C
C
C
C
C
C
T
T
T
T
T
T
T
T
IIIIO
IIII
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
Due to environmental, safety and economical concerns, worldwide industries are searching for greener processes with less or no use of VOC’s (Volatile Organic Compounds). The development of more benign, environmentally friendly processes with less hazardous solvents is currently a major focus of a wide variety of research activities. Reduction of VOC’s can be achieved with a very promising technology: processes based on ionic liquids and carbon dioxide as combined solvents for reactions and extractions. In this chapter the need for green chemistry and the importance of phase behaviour studies are justified, the reaction models which have been investigated are presented, and finally, an outline of this thesis is found in the end of this
1.1
THE NEED FOR GREEN CHEMISTRY
Earth’s environment is changing. Since the industrial revolution in the late 18th
century, human activities are changing the composition of the atmosphere through the burning of fossil fuels, land-use and emission of volatile organic compounds (VOC’s) and greenhouse gases (such as CO2), submitting our planet to a process of
environmental degradation. Although features of the climate also vary naturally, it is very difficult to determine what fraction of climate changes is exclusively a consequence of human activities. In order to reduce or eliminate threats such as climate change, depletion of ozone layer, global warming, acid precipitation, and many others, an increasing number of regulations and taxations have been created to reduce as much as possible the impact of human activities in the delicate equilibrium of our planet. As an example, some of the regulations that address the use and control of VOC emissions in Europe can be cited as:
-
REACH – Registration, Evaluation and Authorization of Chemicals, under development-
Environmental Protection Act 1990-
Pollution Prevention and Control Regulations 2000-
EU Solvents Directive (1999/13/EC)-
Health and Safety at Work Act 1974-
Control of Substances Hazardous to Health (COSHH) regulationsWorth mentioning is the implementation of IPPC (Integrated Pollution Prevention and Control) regulations to industry (IPPC Online). These regulations are based on the application of the “Best Available Techniques”, and the non-compliance with these techniques results in a cancellation of the permit for the company in question. Without this permission, production is not allowed.
To comply with the increasing number of rigorous governmental regulations, industry is under considerable pressure to reduce environmental pollution and implement more environmentally friendly processes. Additionally, companies that reduce costs by decreasing energy consumption or mass intensity will be more profitable, and therefore, more competitive.
This rising concern with the environment added to public awareness of ecological problems are driving the efforts of the scientific community towards the development of novel processes based on greener and more efficient technologies. The quest for atom-efficient synthesis (B.M. Trost, 1991), benign solvents, and sustainable technology combined in highly efficient synthesis-extraction processes is of interest for all types of industry.
Particularly pharmaceutical companies are facing substantial challenges to replace their troublesome processes to more environmentally friendly ones. The syntheses of drugs quite often are based on multi-step reactions involving large amounts of organic solvents and generating undesirable by-products as well. The Environmental factor (E-factor) developed by R.A. Sheldon (R.A. Sheldon, 1992 and 2000) measures the amount of waste (kg) generated per kilogram of product. It shows that pharmaceutical companies are the ones producing the most waste from all industry branches, from 25 to 100 kg of waste per kg of product (see table 1.1). Part of this waste is the release of volatile organic solvents into the atmosphere.
Table 1.1: The E-factor (R.A. Sheldon, 2000).
Industry Product Tonnage E-factor
Oil Refining 106-108 0.1
Bulk Chemical Industry 104-106 1-5
Fine Chemical Industry 102-104 5-50
Pharmaceutical Industry 10-103 25-100
In the USA, for instance, solvents emission can be estimated as 2/3 from all industrial emissions and 1/3 of all VOC emission (J.F. Brennecke and E.J. Maginn, 2001), and according to Allen and Shonnard 20 million ton of volatile organic compounds are estimated to be discharged into the atmosphere each year as a result of industrial processing operations (D.T. Allen and D.R. Shonnard, 2002). Although in the UK solvent emissions reduced 58% between 1990 and 2005 reaching 1 million tones per year (figure 1.1), the use of VOC’s as solvents remained unchanged considering other sources of emissions in the same period (Defra, environmental statistics website), as can be seen in figure 1.2.
Specifically for Europe, the emission of non-methane VOC’s in 2001 and 2004 can be followed on the website of the European Pollutant Emission Register (EPER), http://www.eper.cec.eu.int/eper/. This information has not been presented here since data is not fully complete for all activities and pollutant in the countries.
Figure 1.2: Sources and respective progress of VOC emissions in the UK (Source: Defra).
The use of VOC’s present not only health risks (many VOC’s act as irritants or carcinogens), but also environmental (VOC’s contribute to atmospheric pollution, to the formation of low-level ozone, causing respiratory diseases, damage to crops and plant life) and financial risks (most solvents are very expensive to buy, to recover or dispose of as they are classified as “special waste”). The use of VOC’s as solvents, however, can not be seen as completely detrimental, since there are also advantages in its industrial use. A comparison of the advantages and disadvantages in solvent use is presented in table 1.2.
As it is known, most active pharmaceutical ingredients are manufactured by chemical synthesis in which fine chemicals and intermediates undergo significant chemical change through a series of multi-step processes. These synthesis processes typically include the use of organic solvents and, therefore, traditionally require organic solvents for process cleaning. A growing trend exists in the industry to move away from solvent-based cleaning to aqueous cleaning whenever possible, driven by safety, regulatory and economic factors.∝ It has been estimated by GlaxoSmithKline that almost 85% of the total mass of solvents used in the production of pharmaceuticals is comprised by solvents, with recovery around 50 to 80% (D.J.C. Constable et al., 2002). Since the E-factor of pharmaceutical companies is
the largest found among all different industrial sectors, a reduction in the use of VOC’s as solvents in drug synthesis would lead to a more efficient, less pollutant and less harmful process.
Table 1.2: Advantages and disadvantages in the use of solvents (A.S. Matlack, 2001).
Advantages Disadvantages
-
Place reagents into a common phase where they can react;-
Dissolve solids so they can be pumped from place to place;-
Lower viscosity and facilitate mixing;-
Regulate temperatures of reactions byheating at reflux;
-
Moderate the vigour of exothermic reactions;-
Allow recovery of solids by filtration or centrifugation;-
Extract compounds from mixtures;-
Purify compounds by recrystallization;-
Convert pyrophoric materials tononpyrophoric solutions (as for
aluminum alkyls);
-
Remove azeotrope compounds fromreactions;
-
Clean equipments and clothing.-
Loss of 10–15 million tons of solvents (with a fuel value of 2 billion dollars) each year;-
Reaction of lost solvents in air with nitrogen oxides in sunlight to produce ground level ozone;-
Destruction of upper atmosphereozone by chlorofluorocarbons
(CFC);*
-
Toxicity of chlorinated and other solvents to workers;-
Miscarriages caused by ethers of ethylene glycol;-
Birth defects from exposure to solvents;-
Fires and explosions may result from use;-
Monetary cost: purchase, recovery and displacement of solvents (in comparison with no use of it).To reduce the amount of volatile organic solvents (VOS’s) used in industry, ionic liquids are emerging as an attractive alternative in synthesis and extraction processes. Ionic liquids are calling attention due to their notable properties like their negligible vapour pressure, the possibility of designing the ionic liquid according to one’s need, their non-flammability, large liquidus range and high thermal stability, to mention only a few (P. Wasserscheid and T. Welton, 2002).
Besides ionic liquids, supercritical fluids are also good candidates for replacing VOS’s. Among the most studied supercritical fluids is carbon dioxide: it is cheap, easily available, non-flammable, non-toxic and has mild critical pressure, Pc=7.38
MPa and temperature, Tc=304.25 K (P.G. Jessop and W. Leitner, 1999).
Consequently, it is not surprising that there is an increasing interest in environmentally benign processes based simultaneously on ionic liquids and supercritical carbon dioxide (scCO2). An article published by Blanchard et al. (L.A.
* After the global CFC ban, the rate of ozone depletion has been slowing down, as a strong evidence
Blanchard et al., 1999)is one of the landmarks that showed scientists how profitable a process based on ionic liquids and CO2 could be. It was shown that when scCO2 is
used to extract compounds from the ionic liquid medium, no detectable amount of ionic liquid will be present in the supercritical phase, i.e., the finally extracted product will be free of any contamination of both the ionic liquid and scCO2.
Moreover, it is known that ionic liquids can be used as an excellent reaction medium or even act as an immobilized catalyst. Furthermore, carbon dioxide can be used to control the number of fluid phases of a system, as well as acting as a solvent to extract the product from the ionic liquid rich phase.
Recently, Kroon and co-workers (M.C. Kroon et al., 2006) showed that it is possible to perform reactions in ionic liquids and extract the products with very high purity using supercritical carbon dioxide. This combined approach offers unique advantages: there is no solvent release into atmosphere, both the ionic liquid and CO2 can be recycled during the process, recovery of the product is easily done by
simply decreasing the pressure and the product is obtained without any contamination by the solvent and / or the catalyst.
Therefore, it is clear that the use of ionic liquids and CO2 as combined solvents for
reactions and separations is a potential solution for the replacement of VOS’s in industry.
Industrial applications with new technology, however, are more likely to be applied if economic motivators exist. If economical advantages drive the adoption of neoteric solvents in industry, then environmental advantages can be expected as consequences, including reduced evaporative losses, reduced reliance on petrochemical-derived solvents, reduced hazardous waste and increased solvent recycling. The pay off for the implementation of new processes based on ionic liquids, therefore, is most likely to be attractive for industries with products that have high added values, as it is the case of medicines. The high purity of the final product frequently required in the synthesis of drugs is another reason to justify the implementation of ionic liquids – CO2 based processes.
Therefore, the focus of this work has been driven to the study of reactions which are interesting for the production of pharmaceuticals, and therefore, could be an example for the successful implementation of processes based on ionic liquids and carbon dioxide.
1.2
THE PRINCIPLES AND DEFINITION OF GREEN CHEMISTRY
The term “green chemistry” has become very popular in the last years. Since it is frequently used in this thesis, it deserves proper introduction.
By definition, green chemistry is the design of chemical product and processes that reduce or eliminate the use and generation of hazardous substances (P.T. Anastas, J.C. Warner, 1998). The 12 principles of green chemistry according to Anastas and Warner are as follows:
-
Prevention: It is better to prevent waste than to treat or clean up waste after it has been created.-
Atom Economy: Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product.-
Less Hazardous Chemical Syntheses: Wherever practicable, synthetic methods should be designed to use and generate substances that possess little or no toxicity to human health and the environment.-
Designing Safer Chemicals: Chemical products should be designed to preserve their desired function while minimizing toxicity.-
Safer Solvents and Auxiliaries: The use of auxiliary substances (e.g., solvents, separation agents, etc.) should be made unnecessary wherever possible and innocuous when used.-
Design for Energy Efficiency: Energy requirements of chemical processes should be recognized for their environmental and economic impacts and should be minimized. If possible, synthetic methods should be conducted at ambient temperature and pressure.-
Use of Renewable Feedstocks: A raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable.-
Reduce Derivatives: Unnecessary derivatization (use of blocking groups, protection/ deprotection, temporary modification of physical/chemical processes) should be minimized or avoided if possible, because such steps require additional reagents and can generate waste.-
Catalysis: Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.-
Design for Degradation: Chemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment.-
Real-time analysis for Pollution Prevention: Analytical methodologies need to be further developed to allow for real-time, in-process monitoring and control prior to the formation of hazardous substances.-
Inherently Safer Chemistry for Accident Prevention: Substances and the form of a substance used in a chemical process should be chosen to minimize the potential for chemical accidents, including releases, explosions, and fires.A question that may arise is why should companies consider having a green process, especially from the economical point of view, and how to do that? To address this question, one may reflect on the risks for business derived from unsustainable practices: green house gas emission taxes, pollutants and toxic release, shipment of highly hazardous materials, new and increasingly restrictive regulations (air, water, land, and hazardous waste). Also, the desire for competitive advantage may play an important role in the decision for implementation of more benign processes: reducing costs by decreasing energy consumption or mass intensity (amount of raw material required to produce something) is more profitable than sticking to unsustainable practices. The potential increase of rate and selectivity in reactions, facilitated solvent and catalyst recycling and reduced waste disposal costs are also attractive points.
In any process, green chemistry can be applied from the early stages of pre-manufacturing up to the end-of-life of the product in question. Recently, J.H. Clark (J.H. Clark, 2006) has pointed out where green chemistry can be used in the global design of a “greener” process. The so-called cradle to grave lifecycle is represented in scheme 1.1.
Scheme 1.1: “Cradle to grave” application of Green Chemistry (J.H. Clarck, 2006).
In order to apply metrics of green chemistry in industry, GlaxoSmithKline developed an approach to assess whether the chemistry and the processes applied are green (A.D. Curzons et al., 2001). Various categories related to subjects like
Pre-Manufacturing
Manufacturing
Product Delivery
Product Use
End-of-Life
Alternative feedstocks Waste Minimization
Degradable Packing
Environmentally Benign
Chemicals Safer Chemicals
Biodegradable Products Recyclable Products
Catalyst
environmental tool kit, as they called it, showed that effective management of solvents use result in the largest gains for reducing life cycle impacts in batch chemical operations.
It is now the task of the scientific community and industry to work together and focus on each one of these steps, aiming the development of more sustainable and environmentally benign processes.
1.3
MOTIVATION - STUDY OF PHASE BEHAVIOUR
Despite all the interest in ionic liquids, studies on phase behaviour are still scarce, especially regarding multicomponent systems. When the design of a new process or improvement of the existing one is considered, knowledge on the phase behaviour of the system is of fundamental importance.
When performing reactions such as hydrogenations, it is still a challenge to decide whether homogeneous or heterogeneous catalysis is the best one for the process. Both types of catalysis have advantages and disadvantages, as it can be seen in figure 1.3. When carbon dioxide is used to tune the miscibility of the system, the new process will profit from the positive characteristics of both types of catalysis without their disadvantages.
Figure 1.3: Comparison between homogeneous and heterogeneous catalysis.
The use of carbon dioxide to tune the miscibility of a system for reactions and separations was already successfully applied by K. Buchmüler et al. (K. Buchmüler et al., 2003) using CO2 as tuneable solvent (and reactant). By changing pressure and
temperature conditions, the coupling of butadiene and carbon dioxide catalyzed by palladium was performed in one-phase system with moderate conversions. Solinas
hydroformylation of 1-octene. Instead of using CO2 for reaching one homogeneous
phase during the reaction, it was used to precipitate the rhodium catalyst from the reaction mixture, allowing the product to be recovered in a separate phase with low levels of catalyst leaching.
Earlier research done by Peters and Gauter (C.J. Peters and K. Gauter, 1999; K. Gauter et al., 2000) described the generally applicable phenomenon in ternary systems based on organic compounds and CO2 that CO2 is able to force two immiscible
liquid phases into a homogeneous phase. Based on this phenomenon, Scurto and co-workers (A.M. Scurto et al., 2002) found that CO2 could be used to change the
miscibility of an ionic liquid with organic solvents. The possibility of extending this switch in miscibility to mixtures with other types of organic compounds resulted in the development of a novel synthesis and extraction process. An application of the miscibility switch phenomenon is that reactions can be carried out in one single phase and products can be extracted from the heterogeneous system. Such a process has been conceived and patented by Kroon and co-workers (M.C. Kroon et al., 2006) and is illustrated in figure 1.4.
Figure 1.4: Simplified scheme of a green synthesis and extraction process in an ionic liquid-CO2
medium. The red-dashed box indicates the part of the process where the miscibility switch plays an important role, and where knowledge of the phase behaviour of the system is of fundamental importance.
In order to replace an existing synthesis of pharmaceutical compounds by an ionic liquid – CO2 based process, knowledge on the phase behaviour is of crucial
importance. Especially this holds when there is an interest in applying the miscibility switch phenomenon, as identification of the location of homogeneous and heterogeneous regions is necessary to select optimum pressure and temperature conditions for the process.
Up to now, various articles have been published on the solubility of carbon dioxide in ionic liquids. For instance, our group has been measuring the phase behaviour at high pressures of systems composed by imidazolium-based ionic liquids (mainly with [BF4]- and [PF6]- anions) and supercritical carbon dioxide (A. Shariati and C.J.
Peters, 2003 and 2004; M.C. Kroon et al., 2005) but yet the number of publications regarding the investigation of the phase behaviour in ternary systems with ionic liquids is scarce. For utilisation of ionic liquid - CO2 systems in industrial
applications, scale-up of the process is based on the knowledge of thermodynamic properties and behaviour of the system, which as discussed, are usually poorly studied.
Therefore, the phase behaviour of the system is of great importance. Understanding when homogeneous conditions are achieved, as well as how each one of the compounds involved affect the phase equilibrium, will maximize the efficiency of the reaction and provide a cleaner, environmentally friendly and economically attractive production process. At the same time, splitting phases is a powerful tool to improve extraction of compounds from ionic liquids.
1.4
SELECTION OF THE IONIC LIQUID
When selecting a solvent for a specific process, one may consider aspects such as physical-chemical properties (boiling point, volatility, and so on), hazards to human health and to the environment, price, biodegradability, etc. Ionic liquids may be considered ideal solvents when their negligible vapour pressure, tuneable properties, non-flammability and other peculiarities are considered. However, the lack of information regarding their toxicology, environmental fate, physical-chemical properties and the optimal selection among the enormous options of cations and anions - about 1 billion, according to Earle and Seddon (M.J. Earle and K.R. Seddon, 2000) - are issues that still need to be addressed.
In this study, two ionic liquids were selected as candidates for synthesis-extraction processes based on the miscibility switch phenomenon: 1-butyl-3-methylimidazolium tetrafluoroborate (bmim[BF4]) and
1-ethyl-3-methylimidazolium dicyanamide (emimdca). Figure 1.5 shows their molecular structure.
Figure 1.5: Molecular structure of the ionic liquids bmim[BF4] (left) and emimdca (right).
The ionic liquid bmim[BF4] was chosen because by the time this work was started, it
was one of the most studied ionic liquids, with physical-chemical properties better defined in comparison with other new ionic liquids. Additionally, this ionic liquid
phase equilibrium measurements due to its stability, relatively low viscosity and ease of synthesizing. As it will be shown later, bmim[BF4] also has higher solubility
of carbon dioxide in comparison with most other ionic liquids.
On the other hand, the ionic liquid emimdca was emerging as a promising ionic liquid, with interesting properties such as its low viscosity (M. Yoshida et al., 2004; D.R. MacFarlane et al., 2001). The dicyanamide anion is a ligand having Lewis basic properties, while the BF4- anion is a very weak Lewis base (D.R. MacFarlane et al.,
2002). Moreover, the dicyanamide anion does not hydrolyse in presence of water, as it is the case of the PF6 anion and BF4 (R.P. Swatloski et al., 2003).
An overview of the properties of these two ionic liquids is presented in table 1.3.
Table 1.3: Summary of some properties of bmim[BF4] and emimdca. N.A.: not available.
Properties bmim[BF4] ξ emimdca ∝∝∝∝
CAS number 174501-65-6 448245-52-1
Molecular weight (g/mol) 226.02 205.26
Melting Point (oC) -81.0 -21
Decomposition temperature (oC) 403 275
Water Miscible? Yes Yes
Viscosity (cP) 154 (20oC) 21 (25oC)
Density @ 25oC (g/cm3) 1.12 1.06
Toxicity (LC50-Daphnia Magna 48h, mg/L) 10.68 a N.A.
ξ bmim[BF4]: dried conditions (A.D. Curzons et al., 2001)
∝ D.R. MacFarlane et al., 2001
a R.J. Bernot et al., 2005
1.5
MODEL REACTIONS
This work started with the study of a nucleophilic substitution which is a reaction step in the synthesis of Mirtazapine, the active ingredient of the anti-depressant Remeron of Organon B.V. Due to chemical interactions that occurred between some of the compounds involved in this reaction and the solvents ionic liquid and carbon dioxide, other reactions were selected for investigation of the phase behaviour of ternary systems.
Three other reactions were selected, all of them hydrogenations. This choice is justified by the fact that hydrogenations are one of the most important types of reactions performed by industry. A variety of valuable substances can be obtained by hydrogenation of, for instance, double carbon-carbon or carbon-oxygen bonds present in less valuable compounds. Also in pharmaceutical industries, hydrogenations play an important role in all kind of intermediate reaction steps in the synthesis of medicines.
Especially when the hydrogenation is the last step in the synthesis of a drug, contamination of the product by traces of solvent or catalyst leaching is very problematic. Most of the catalysts for hydrogenations can be toxic for humans, and the high degree of final purity required for most pharmaceutical drugs would demand a costly and time-consuming purification of the final product.
In order to solve the problem of drug contamination by solvent and/or catalyst and to design a benign medium to produce drugs in compliance with the principles of green chemistry, processes based on ionic liquids and supercritical fluids as solvents for reactions and extractions emerged as an alternative for the replacement of common volatile organic solvents (VOS’s).
The three hydrogenations chosen as model reactions are as follows:
− The hydrogenation of acetophenone giving 1-phenylethanol was selected as one of the simplest, most extensively aromatic ketone hydrogenation that has been studied so far;
− The hydrogenation of 2-(6-methoxy-2-naphthyl)acrylic acid giving (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid, or s-naproxen, a non-steroidal anti-inflammatory drug (NSAID);
− The hydrogenation of 4-isobutylacetophenone giving 1-(4-isobutylphenyl)-ethanol, which is a reaction step in the synthesis of Ibuprofen, a common NSAID.
The last two reactions were intended to be practical examples of hydrogenations performed nowadays by the pharmaceutical industry, since they are the ones to obtain the most profit from greener processes as seen previously in this chapter. Due to the commercial importance of these products, they were considered good examples for investigation of the miscibility switch.
A brief review of all model reactions is given in the next sections.
1.5.1
Mirtazapine
The consumption of the anti-depressant Remeron, one of the biggest products from Organon B.V., has increased on the last years. In 2002 over 700 million euros of this drug were sold, justifying its commercial importance and the concern on the environmental impact that its production may have.
Currently, this reaction is performed in DMF, dimethylformamide, which is a very toxic and flammable solvent. Moreover, the boiling point (around 426 K) is
condition. The replacement of DMF by bmim[BF4] represents a significant
improvement in the environmental and safety aspects of this process.
The complete synthesis of Mirtazapine can be seen in figure 1.6, with emphasis on the reaction step studied.
Figure 1.6: Synthesis of Mirtazapine, including solvents and catalysts used in industrial production. (A. Kleemann and J. Engel, 2000)
Performing the reaction in an ionic liquid would eliminate the solvent problem, and the possibility of using supercritical carbon dioxide to perform the reaction in one homogeneous liquid phase with further extraction of the product under heterogeneous condition, is very attractive for this system. Therefore, the phase behaviour of the components of this reaction together with CO2 and bmim[BF4] was
studied. The results are presented in Chapter 5.
1.5.2
Acetophenone
The hydrogenation of acetophenone is one of the most widely studied model reactions when one refers to carbonyl hydrogenation. Various solvents and catalysts have been investigated for this specific reaction, and the knowledge obtained with this simple aromatic ketone is usually extended to more complex carbonyl hydrogenations.
Acetophenone is the simplest aromatic ketone, with melting point around 20oC. It is
used as an intermediate for pharmaceuticals, agrochemicals and other organic compounds. (Encyclopaedia Britannica Online). Acetophenone and its derivatives – among them 1-phenylethanol - are products of interest of the pharmaceutical and perfume industry. They are ingredients of flavour and fragrance in soaps, detergents, cosmetics and perfumes as well as in foods, beverages, and tobacco (Chemical Land 21 Online).
The importance of this reaction lays on the relatively simple chemistry behind the asymmetric hydrogenation of the C=O bond in aromatic ketones. Due to the simplicity of the molecule, hydrogenations studied with acetophenone allow a better understanding of the reaction mechanism and evaluation of catalyst performance. Moreover, acetophenone is a moisture- and air-stable compound, cheap and available from different suppliers.
The results of the investigation of ternary systems for this model reaction are presented in Chapter 7.
1.5.3
S-naproxen
(S)-(+)-2-(6-Methoxy-2-naphthyl) propionic acid (in this thesis simply referred to as s-naproxen) is a non-steroidal anti-inflammatory drug (NSAID) widely used. Recent researches suggest that some NSAID can be used in cancer prevention (C.M. Ulrich, et al., 2006), which might increase its production. Therefore, improving the synthesis of this compound will not only contribute to the benefit of health conditions of our society, but also offers advantages by increasing environmental protection and reducing pollution.
The synthesis of s-naproxen is composed by diverse reaction-steps, involving different organic solvents, catalysts and compounds. About five different routes are known for its production (A. Kleemann, J. Engel, 2000). Of particular interest, is the synthesis shown in figure 1.8.
In comparison with C=O bonds, hydrogenations of C=C bonds catalyzed by transition metal complexes are one of the most studied reactions in hydrogenation catalysis. In this respect, various publications can be found on the synthesis of naproxen, most of them based on organic solvents (with methanol being the most preferable of them).
Figure 1.8: Synthesis of s-naproxen, with the hydrogenation step studied in this thesis in detail. (A. Kleemann, J. Engel, 2000).
Recently, the synthesis of s-naproxen has been investigated in the biphasic system bmim[BF4]/isopropanol (A.L. Monteiro et al., 1997). The air sensitive ruthenium
catalyst [RuCl2-(S)-BINAP]2.NEt3 was synthesized in situ and immobilized in the
ionic liquid. The product was isolated in the organic phase, which could be easily separated from the reaction mixture by decantation. However, the process can be modified and improved by complete elimination of the use of organic solvents, for instance, replacing isopropanol by CO2 and developing an air stable catalyst.
Unfortunately, the reactant was not available commercially and could not be supplied by industry. Therefore, only the extraction of s-naproxen from the reaction mixture ionic liquid / CO2 has been considered. Chapter 6 presents the results for
the phase behaviour of the ternary system bmim[BF4] + s-naproxen + CO2.
1.5.4
Ibuprofen
The synthesis of Ibuprofen is a good example on how chemistry can be efficiently used to reduce waste, production costs and develop a more elegant, environmentally friendly process.
The original synthesis of Ibuprofen (N.J. Stuart, A.S. Sanders, 1968), was based on 6 steps with an atom economy of 40%, generating yearly millions of kilograms of unwanted, unutilized and unrecycled chemical by products that have to be treated or disposed.
Known as the BHC (Basf-Hoechst-Celanese) process, a more efficient and greener synthesis has been applied since 1992 (V. Elango et al., 1991; D.D. Lindley et al., 1991). The new technology involves only three catalytic steps with 77% atom economy
anhydrous hydrogen fluoride as both catalyst and solvent offers important advantages in reaction selectivity and waste reduction. Virtually all starting materials are either converted to product or reclaimed by-product or are completely recovered and recycled in the process. The generation of waste has been practically eliminated. This process won the Presidential Green Chemistry Award in 1997.
The third model reaction chosen for this work is a reaction step in the synthesis of Ibuprofen based on the BHC process, which is described in figure 1.9.
Figure 1.9: Complete synthesis of ibuprofen, with detail to the studied hydrogenation step reaction. (A. Kleemann, J. Engel, 2000).
This model reaction has been chosen not only due to the commercial importance of Ibuprofen, but also due to the similarity of the reactant and product molecules with respectively, acetophenone and 1-phenylethanol. The only difference between them is the substitution of the hydrogen at the C4 position in the aromatic ring by an isobutyl group. Useful information can be obtained from a comparison of the phase diagrams of ternary systems with the ketones (or the alcohols) on the effect that the addition of an alkyl group in the solute molecule has on the phase behaviour of the ternary system.
1.6
AIM AND OUTLINE OF THIS THESIS
This work aims a better insight on the behaviour of mixtures of an ionic liquid, an organic compound and carbon dioxide. For this purpose, four reactions of interest for the pharmaceutical industry were selected to provide the organic compounds which were studied in the ternary systems. The focus on the model reactions involved in pharmaceutical processes is due to the fact that this is one of the industrial branches that frequently require products of extremely high purity and which are commercially valuable, conditions that make them good candidates for
adopting new processes with ionic liquids. Additionally, from the four model reactions, three of them are hydrogenations, which is one of the most widely applied types of reactions in industry. These four model reactions were described previously in Section 1.5.
In order to get acquainted with the terms and subject of this thesis, a review on the theoretical background of ionic liquids, supercritical fluids and phase diagrams for binary mixtures is presented in Chapter 2. The miscibility switch phenomenon is introduced and a brief overview on the recent discoveries regarding phase diagrams with ionic liquids is given.
All equipments and experimental procedures used for phase behaviour measurements and synthesis of the ionic liquid 1-butyl-3-metylimidazolium tetrafluoroborate, bmim[BF4], and 1-ethyl-3-metylimidazolium dicyanamide,
emimdca, are reported in Chapter 3.
In order to select the ionic liquid with the highest CO2 solubility, and as
consequence, the best one for investigation of the miscibility switch, Chapter 4 presents a comparison of the solubility of CO2 in bmim[BF4] collected from
literature and in emimdca, which was investigated in this work. In this last system, a precipitation occurred during measurements, from which instability of the dicyanamide anion in presence of mercury (used in the Cailletet equipment) has been proposed.
From Chapter 5 until 8, the ternary systems with components from the model reactions are presented. Except for Chapter 8, only results for CO2 compositions
lower than 50 mol% in the ternary systems are shown.
Chapter 5 presents the phase diagrams obtained experimentally for ternary systems of the type ionic liquid + organic solute + CO2 with the organic compounds
involved in the reaction step for the synthesis of Mirtazapine, described in Section 1.5.1. During experiments, interactions between the components of the system occurred, and therefore, a discussion is made on the origin of these interactions and attempt of identification of the new formed compounds.
The possibilities for extraction of s-naproxen from the reaction mixture bmim[BF4] +
CO2 are discussed in Chapter 6, where the phase diagrams for the ternary system
bmim[BF4] + s-naproxen + CO2 with different CO2 compositions are presented.
In Chapter 7, the hydrogenation of acetophenone is investigated. The phase behaviour of ternary systems bmim[BF] + acetophenone + CO and bmim[BF] +
1-phenylethanol + CO2 are presented and compared with the binary system
bmim[BF4] + CO2. The extraction of 1-phenylethanol by supercritical CO2 is also
discussed.
Chapter 8 contains the phase behaviour of ternary systems with the organic compounds that are intermediaries in the synthesis of Ibuprofen, and which were presented in Section 1.5.4. CO2 compositions up to 70 mol% were investigated, and
different phase transitions were found. A comparison is made between the effect of the molecular structure of the solutes on the solubility of CO2 in the mixture
bmim[BF4] + solute. An elaboration is made on the appearance of a second liquid
phase resulting in L1+L2+V and L1+L2 equilibria.
Since the application of the miscibility switch in synthesis of drugs is considered in this thesis, a brief discussion on the general conditions under which hydrogenations may be carried out, the diversity of catalysts that can be used and the effect of the addition of carbon dioxide to the reaction mixture is presented in Chapter 9. A summary of the effect of solute addition to the binary system bmim[BF4] + CO2 is
given, and the similarities of the phase behaviour of the systems studied are discussed. Finally, some assumptions on the occurrence of the miscibility switch in different systems together with its limitations are presented.
Due to the fact that phase behaviour measurements are cumbersome, time consuming and sometimes involving toxic or harmful substances, the use of prediction models is of high interest. Therefore, the use of a Group Contribution Equation of State (GC-EOS) to model data experimentally obtained for the phase diagrams of ternary mixtures studied in this thesis is presented in Chapter 10.
Finally, conclusions are drawn in Chapter 11, where recommendations are given for the better understanding of the complex behaviour of ionic liquids in mixtures.
1.7
REFERENCES
A.D. Curzons, D.J.C. Constable, D.N. Mortimer, V.L. Cunningham, Green Chemistry, 2001, 3, 1-6.
A. Kleemann, J. Engel, “Phamaceutical Substances: syntheses, patents, applications”. 3rd
edition, Thieme, 2000.
A.L. Monteiro, F.K. Zinn, R.F. de Souza, J. Dupont, Tetrahedron: Asymmetry, 1997, 8(2), 177-179.
A.M. Scurto, S.N.V.K. Aki, J.F. Brennecke, J. Am. Chem. Soc. (Communication), 2002, 124(35), 10276-10277.
A. Shariati, C.J. Peters, The Journal of Supercritical Fluids, 2003, 25(2), 109-11.
A. Shariati, C.J. Peters, The Journal of Supercritical Fluids, 2004, 30(2), 139-144.
A.S. Matlack, Introduction to Green Chemistry, New York Marcel Dekker, Inc., 2001. ISBN: 9780824704117.
B.M. Trost, Science, 1991, 254, 1471-1477.
Chemical Land 21 Online, http://chemicalland21.com/industrialchem /organic/ACETOPHENONE.htm
C. J. Peters and K. Gauter, Chem. Rev., 1999, 99, 419-431.
C.M. Ulrich, J. Bigler, J.D. Potter, Nature Reviews Cancer, 2006, 6, 130-140.
D.D. Lindley, T.A. Curtis, T.R. Ryan, E.M. de la Garza, C.B. Hilton, T.M. Kenesson, “Process for the production of 4’-isobutylacetophenone”, U.S. Patent 5,068,448. 1991.
Defra (Department for Environment, Food and Rural Affairs), e-digest environmental statistics website, http://www.defra.gov.uk/environment/statistics/airqual/ aqemvoc.htm
D.J.C. Constable, A.D. Curzons, V.L. Cunningham, Green Chem., 2002, 4, 521-527.
D.R. MacFarlane, J. Golding, S.A. Forsyth, M. Forsyth, G.B. Deacon, Chem. Commun., 2001, 1430-1431.
D.R. MacFarlane, S.A. Forsyth, J. Golding, G.B. Deacon, Green Chemistry, 2002, 4, 444-448.
D.T. Allen, D.R. Shonnard, Green Engineering. Prentice Hall, Upper Saddle River, NJ, 2002.
Encyclopaedia Britannica Online, http://www.britannica.com/eb/article-9003508/acetophenone
G. Vince, NewScientist.com news service, http://www.newscientist.com/article/ dn4010-earths-ozone-depletion-is-finally-slowing.html, 30 July 2003.
IPPC Online, http://www.ippc-info.co.uk/
J.F. Brennecke, E.J. Maginn, AIChE Journal, 2001, 47(11), 2384 – 2389.
J.H. Clark, Green Chemistry, 2006, 8, 17-21.
K. Buchmüller, N. Dahmen, E. Dinjus, D. Neumann, B. Powietzka, S. Pitter, J. Schön, Green Chemistry, 2003, 5, 218–223.
K. Gauter, C.J. Peters, A.L. Scheidgen, G.M. Schneider, Fluid Phase Equilibria, 2000, 171(1-2), 127-149.
L.A. Blanchard, D. Hâncu, E.J. Beckman and J.F. Brennecke, Nature, 1999, 399, 28-29.
M.C. Kroon, A. Shariati, L.J. Florusse, C.J. Peters, J. van Spronsen, G-J. Witkamp, R. A. Sheldon, K.E. Gutkowski, “Process for Carrying Out a Chemical Reaction”, International Patent WO 2006/088348 A1 (2006).
M.C. Kroon, A. Shariati, M. Costantini, J. van Spronsen, G-J. Witkamp, R.A. Sheldon, C.J. Peters, J. Chem. Eng. Data, 2005, 50(1), 173-176.
M.C. Kroon, J.v. Spronsen, C.J. Peters, R.A. Sheldon and G.J. Witkamp, Green Chem., 2006, 8, 246-249.
M.J. Earle and K.R. Seddon, Pure Appl. Chem., 2000, 72, 1391-1398.
M. Solinas, J. Jiang, O. Stelzer, W. Leitner, Angew. Chem. Int. Ed., 2005, 44, 2291-2295.
M. Yoshida, K. Muroi, A. Otsuka, G. Saito, M. Takahashi, T. Yoko, Inorganic Chemistry, 2004, 43, 1458-1462.
N.J. Stuart, A.S. Sanders, “Phenyl propionic acids”. U.S. Patent 3385886, 1968.
P.G. Jessop and W. Leitner, “Chemical synthesis using supercritical fluids”. 1st Edition,
Wiley-VCH, Weinheim, 1999. ISBN: 3-527-29605-0.
P. T. Anastas, J.C. Warner. “Green Chemistry: Theory and Practice”. Oxford University Press, Oxford, 1998. ISBN: 0-19-850234-6.
P. Wasserscheid, and T. Welton, “Ionic Liquids in Synthesis”. 1st Edition. Wiley-VCH,
Weinheim, 2002. ISBN 3-527-30515-7
R.A. Sheldon, Chem. Ind. (London), 1992, 903-906.
R.A. Sheldon, Pure Appl. Chem., 2000, 72(7), 1233–1246.
R.J. Bernot, M.A. Brueseke, M.A. Evans-White, G.A. Lamberti, Environmental Toxicology and Chemistry, 2005, 24(1), 87–92.
R.P. Swatloski, J.D. Holbrey, R.D. Rogers, Green Chemistry, 2003, 5, 361-363.
V. Elango, M.A. Murphy, B.L. Smith, K.G. Davenport, G.N. Mott, E.G. Zey, G.L. Moss, “Method for producing Ibuprofen”, U.S. Patent 4,981,995. 1991.
2
2
B
B
B
B
B
B
B
B
A
A
A
A
A
A
A
A
C
C
C
C
C
C
C
C
K
K
K
K
K
K
K
K
G
G
G
G
G
G
G
G
R
R
R
R
R
R
R
R
O
O
O
O
O
O
O
O
U
U
U
U
U
U
U
U
N
N
N
N
N
N
N
N
D
D
D
D
D
D
D
D
Ionic liquids (ILs) and carbon dioxide (CO2) are emerging as candidates to
replace VOC’s in synthesis and extraction processes. Ionic liquids are a relatively new class of substances composed only of ions and liquid at temperatures below 100oC. As a major attractive characteristic, they have
negligible vapour pressure and could, therefore, eliminate solvent loss by evaporation and reduce environmental pollution. They are called designer solvents, because anions and cations can be selected for a specific need. When used simultaneously with carbon dioxide for reactions and extractions, the process will be based on non-toxic, non-flammable solvents and it will be applicable for a wide variety of compounds. Moreover, it has been recently shown that carbon dioxide can be used to split phases in homogenous one-phase systems with ILs. The miscibility switch, as it is known, allows reactions to be carried out in one phase, and by simply changing CO2
pressure, extractions can be carried out more efficiently under heterogeneous conditions. In order to be introduced to this work, the reader will find in this chapter an overview on ionic liquids and carbon dioxide. Since it is the basis of this research, the phenomenon of miscibility switch is explained, and the chapter ends with a brief explanation on phase diagrams.
2.1
IONIC LIQUIDS
Ionic liquids (ILs) are organic salts composed solely of ions, and by definition, their melting point is found at or below the convenient, arbitrary temperature of 100oC
(373 K). Usually, cations are large organic molecules and anions, small inorganic ions. Due to their high degree of asymmetry, packing of the molecules in the crystal lattice is very difficult and therefore crystallization is prevented; this is one of the reasons why ionic liquids have lower melting point in comparison with other inorganic salts which have extremely high melting point (for instance, sodium chloride has a melting point of 801oC).
The number of cations and anions that can be selected for the design of an ionic liquid is enormous. Since anions and cations can be selected for a specific need, ionic liquids became known as “designer solvents”. However, the task of choosing the best combination of cation and anion is very hard: as estimated by Earle and Seddon, there are at least one million types of binary ionic liquids (M.J. Earle and K.R. Seddon, 2000) and 1018 ternary ionic liquids are potentially possible to be
selected. For comparison, about 600 molecular solvents are in use today (R.D. Rogers, K.R. Seddon, 2003).
Some of the most studied cations and anions are shown in figure 2.1.
Figure 2.1: Some examples of the most popular anions and cations that can be selected for the design of an ionic liquid.
Up to now, three different generations of ionic liquids are known. The 1st generation
is comprised by chloroaluminate ionic liquids (J.S. Wilkes et al., 1982). The 2nd
generation is made of air and moisture stable ionic liquids (J.S. Wilkes and M.J. Zaworotko, 1992), including bmim[BF4]. Finally, the recently discovered task-specific
ionic liquids belong to the 3rd generation (J.H. Davis Jr. et al., 1998; A.E.Visser et al.,
2001).
Ionic liquids called attention from industry and scientists due to some especial features, such as:
− They are known as “designer solvents” (they can be designed to have acid or basic characteristics, to be hydrophilic or hydrophobic, etc.);
− They have a large liquidus range of about 300oC (-96 to +200oC);
− They are excellent solvents for organic, inorganic and polymeric materials;
− They have negligible vapour pressure, detected only at extreme conditions of vacuum and at relatively high temperature (P. Wasserscheid, 2006; M.J. Earle et al., 2006);
− They have suitable density and viscosity;
− They are thermally stable;
− They can be designed to be non-flammable;
− They have wide electrochemical window;
− They are relatively simple to synthesize, and nowadays commercially available - although still expensive (from 106 up to 2400 euros/kilo of imidazolium-based ionic liquids, Solvent Innovation product list) in comparison with organic solvents.
However, ionic liquids are not intrinsically green, as they are commonly referred to. Toxic or flammable ionic liquids can be synthesised by the correct (or better said, wrong) combination of the cation and anion. Moreover, the synthesis of ionic liquids is also not performed at its best. It still resembles the traditional synthesis of most compounds, where litters of organic solvents are used and by-products are obtained. The development of more sustainable processes for synthesizing ionic liquids is necessary to completely evaluate the greenness of their use. In that respect, significant improvements have been done by synthesizing ionic liquids from renewable sources (G. Imperato et al., 2007), by solvent-free anion exchange (P.D. Vu et al., 2007) and in supercritical CO2 media (Z. Zhou, T. Wang, H. Xing,
2006). Also biodegradable ionic liquids were recently synthesized (N. Gathergood, P.J. Scammells, 2002).
One of the key features of ionic liquids is that physical-chemical properties can be tailored by a suitable combination of cations and anions. The major problem is that “the perfect” ionic liquid may not exist; with the improvement of some properties,
other ones may be compromised. The effects of the different types of cations and anions on the final properties of the ionic liquids are presented in the next Section.
2.1.1
Properties of ionic liquids
Most of the intrinsic properties of ionic liquids derive from the Coulombic attraction forces between the ions. They determine not only the vanishingly low vapour pressure that is characteristic of ionic liquids, but for instance, also the melting point temperature. However, other effects such as van der Waals and hydrogen bond interactions and rotation of the alkyl chain length of the cation also influences the properties of ionic liquids. They are all closely related with the combination of cations and anions.
Computation of the melting point of ionic liquids is problematic, since glass transitions are sometimes wrongly reported as melting points (K.N. Marsh et al., 2004). Usually, an increase in the alkyl chain length of the cation from methyl to butyl or hexyl is responsible for a decrease on the melting point, and further increase results in a proportional increase of the melting point, since the asymmetry of the system also increases.
Water solubility, for instance, is strongly influenced by the anion. Considering the same cation, water miscibility increases in the following order: PF6-, [(CF3SO2)2N]- <
BF4-, CF3SO3- < CH3CO2-, CF3CO2-, NO3-, Br-, Cl- (K.R. Seddon et al., 2000).
The viscosity of ionic liquids is still a problem to be overcome. It is several times higher than water and the most common VOC’s, being comparable to some oils. This is a considerable disadvantage when mass and heat transfers are considered, as well as chemical processing (for instance, pumping and mixing). However, ionic liquids based on the dicyanamide anion (N(CN)2-) are very low viscous compounds,
with viscosity at 20oC in the order of 21 cP (emimdca) up to 50 cP
(N-butyl-N-methylpyrrolidinium dca) (D.R. MacFarlane et al., 2002). For comparison the viscosity of water at the same temperature is 1.002 cP, and the one of bmim[PF6] is
430 cP (K.N. Marsh et al., 2004).
The solvation and solubility characteristics of ionic liquids are also dependant on cations and anions (P. Wasserscheid, W. Keim, 2000). A good example of anion influence in the solubility of a certain compound in ionic liquids is water miscibility. While some ionic liquids are extremely hygroscopic and therefore water miscible (for instance, IL’s with the NO3- anion), other ones present miscibility gaps. When
