Cover

Table of Contents

Cover

Title page

Copyright page

FOREWORD

PREFACE

CONTRIBUTORS

PART I: I  FUNDAMENTALS

1 IONIC LIQUIDS: DEFINITION, APPLICATIONS, AND CONTEXT FOR BIOTRANSFORMATIONS AND ORGANOCATALYSIS

1.1 IONIC LIQUIDS: DEFINITION, DEVELOPMENT, AND OVERVIEW OF CURRENT MAIN APPLICATIONS

1.2 ON THE GREENNESS OF ILs: TOWARD THE THIRD GENERATION OF ILs AND DES

1.3 CONTEXT OF ILs IN BIOTRANSFORMATIONS AND ORGANOCATALYSIS

2 IONIC LIQUIDS AND PROTEINS: ACADEMIC AND SOME PRACTICAL INTERACTIONS

ABBREVIATIONS FOR IONIC LIQUID CATIONS

ABBREVIATIONS FOR IONIC LIQUID ANIONS

ABBREVIATIONS FOR AMMONIUM IONIC LIQUIDS

OTHER ABBREVIATIONS

2.1 INTRODUCTION

2.2 IONIC LIQUIDS, WATER, AND PROTEINS

2.3 HOFMEISTER EFFECTS ON BIOCATALYSIS

2.4 IMPACT OF IONIC LIQUIDS ON ENZYMES AND PROTEINS

2.5 PROTEIN EXTRACTION BY MEANS OF IONIC LIQUIDS

2.6 PROPER SELECTION OF IONIC LIQUIDS FOR BIOCATALYSIS

2.7 CONCLUDING REMARKS

PART II: IONIC LIQUIDS IN BIOTRANSFORMATIONS

3 IONIC LIQUIDS IN BIOTRANSFORMATIONS: MOTIVATION AND DEVELOPMENT

3.1 FIRST USES OF IONIC LIQUIDS IN BIOTRANSFORMATIONS

3.2 MOTIVATION TO USE IL IN BIOTRANSFORMATIONS

3.3 CHALLENGES FOR THE USE OF IL IN BIOTRANSFORMATIONS

4 IONIC LIQUIDS AND OTHER NONCONVENTIONAL SOLVENTS IN BIOTRANSFORMATIONS: MEDIUM ENGINEERING AND PROCESS DEVELOPMENT

4.1 INTRODUCTION: TOWARD GREENER CATALYTIC PROCESSES

4.2 THE IMPORTANCE OF THE MEDIUM ENGINEERING IN BIOTRANSFORMATIONS

4.3 BIOCATALYSIS IN MONOPHASIC ILs SYSTEMS

4.4 (BIO)CATALYTIC PROCESSES IN SCFs

4.5 MULTIPHASE BIOTRANSFORMATIONS

4.6 PROSPECTS

ACKNOWLEDGMENTS

5 IONIC LIQUIDS AS (CO-)SOLVENTS FOR HYDROLYTIC ENZYMES

NOMENCLATURE OF ILs

5.1 INTRODUCTION

5.2 STATE-OF-THE-ART: LIPASES, ESTERASES, PROTEASES IN ILs AS (CO-)SOLVENTS

5.3 USE OF ILs FOR (DYNAMIC) KINETIC RESOLUTIONS ((D)KRs)

5.4 HYDROLASE-CATALYZED ESTERIFICATIONS OF SACCHARIDES AND CELLULOSE DERIVATIVES IN ILs

5.5 ILs FOR GLYCOSIDASES

5.6 PROSPECTS

ACKNOWLEDGMENTS

6 IONIC LIQUIDS AS (CO-)SOLVENTS FOR NONHYDROLYTIC ENZYMES

NOMENCLATURE OF ILs

6.1 IONIC LIQUIDS AND NONHYDROLYTIC ENZYMES

6.2 USE OF ILs IN OXIDOREDUCTASE-CATALYZED ENZYMATIC REACTIONS

6.3 ILs IN LYASE-CATALYZED REACTIONS

6.4 PROSPECTS

7 IONIC LIQUIDS AND WHOLE-CELL–CATALYZED PROCESSES

ABBREVIATIONS

7.1 IONIC LIQUIDS COMPATIBLE WITH WHOLE-CELL BIOCATALYSIS: FUNDAMENTALS AND DESIGN

7.2 BIOCOMPATIBILITY, TOLERANCE, AND ACCUMULATION IN THE CELL

7.3 STATE OF THE ART

7.4 PROSPECTS

8 NONSOLVENT APPLICATIONS OF IONIC LIQUIDS IN BIOTRANSFORMATIONS

8.1 INTRODUCTION

8.2 IONIC LIQUIDS AS ADDITIVES IN BIOTRANSFORMATIONS

8.3 IONIC LIQUIDS FOR COATING ENZYMES: THE ILCE CONCEPT

8.4 IONIC LIQUIDS COMBINED WITH MEMBRANES AND BIOTRANSFORMATIONS

8.5 IONIC LIQUIDS ANCHORING SUBSTRATES

8.6 IONIC LIQUIDS AND BIOELECTROCHEMISTRY

PART III: IONIC LIQUIDS IN ORGANOCATALYSIS

9 IONIC LIQUIDS AS (CO-)SOLVENTS AND CO-CATALYSTS FOR ORGANOCATALYTIC REACTIONS

9.1 NONTRADITIONAL MEDIA IN ORGANOCATALYSIS

9.2 EARLY ORGANOCATALYTIC REACTIONS IN IONIC LIQUIDS

9.3 IONIC LIQUIDS AS SOLVENTS FOR ORGANOCATALYTIC REACTIONS

9.4 IONIC LIQUIDS AS CO-CATALYSTS FOR ORGANOCATALYTIC REACTIONS: TOWARD NEW REACTIVITIES AND SELECTIVITIES

9.5 KEY FACTORS IN CHOOSING IONIC LIQUIDS FOR ORGANOCATALYSIS AND PROSPECTS

10 “NONSOLVENT” APPLICATIONS OF IONIC LIQUIDS IN ORGANOCATALYSIS

10.1 INTRODUCTION

10.2 IMMOBILIZING IONIC LIQUIDS AND ORGANOCATALYSTS

10.3 ANCHORING OF ORGANOCATALYST TO IONIC LIQUIDS

10.4 IONIC LIQUIDS AS ORGANOCATALYSTS

10.5 CONCLUSIONS

Index

Title page

FOREWORD

When Pablo Domínguez de María invited me to contribute a chapter to a book that he proposed on biocatalysis and organocatalysis in ionic liquids, I had to decline the offer owing to other pressing commitments, but I agreed to write a foreword to the book. Now that I see the impressive result of his endeavors I am rather sorry that I am not a contributor.

My introduction to the subject dates back to June 1996 when I attended an inspiring lecture on ionic liquids presented by Ken (“Mr. Ionic Liquids”) Seddon of the Queen’s University Belfast at the Clean Tech ’96 conference in London. I was immediately hooked. I was fascinated by the possible benefits to be gained by using ionic liquids as reaction media for catalytic processes. While listening to the lecture it occurred to me that it would be very interesting to try ionic liquids as solvents for conducting biocatalytic processes. I was motivated by the notion that ionic liquids, by virtue of their anticipated compatibility with enzymes, could possibly exert a rate enhancing and/or stabilizing effect, resulting in an improved operational performance compared with that observed in organic solvents. Afterward I asked Ken if he knew whether anybody had tried to use an enzyme in an ionic liquid. His answer was: “No, but why don’t we try it? I can supply the ionic liquids.” So we decided to try reactions with Candida antarctica lipase B (CaLB), as this robust enzyme was known to be thermally very stable and tolerant toward organic solvents under essentially anhydrous conditions. It took a while to find a Ph.D. student, Rute Madeira Lau, to perform the experiments, but the results were gratifying. We observed that Novozyme 435 (an immobilized form of CaLB) was able to catalyze various reactions—esterification, amidation, and perhydrolysis—under anhydrous conditions in the second-generation ionic liquids, [bmim] [BF4] and [bmim] [PF6], with rates at least as high as those in organic solvents.

Following the publication of our results, in Organic Letters in 2000, the use of ionic liquids as reaction media for catalysis in general and biocatalysis in particular has undergone exponential growth. It was soon recognized that the use of second-generation ionic liquids on a large scale was seriously hampered by their high price coupled with ecotoxicity and poor biodegradability. Consequently, attention was devoted to the development of a third generation of ionic liquids that are greener, more sustainable, and less expensive than the second generation. In particular, ionic liquids derived from natural raw materials, such as carbohydrates and amino acids, are emerging as green solvents potentially suitable for large-scale applications. Furthermore, it is possible to design task specific ionic liquids, for example, bio-based chiral ionic liquids, that meet not only environmental requirements but are also eminently suited to particular tasks.

Pablo is to be complimented on bringing this group of knowledgeable authors together to review the state of the art in biocatalysis and organocatalysis in ionic liquids. The subjects covered are wide-ranging, from fundamental aspects of interactions between proteins and ionic liquids to their use as reaction media with both hydrolytic and nonhydrolytic enzymes, whole cell bioconversions, and, as a bonus, organocatalytic reactions. Importantly, practical aspects are highlighted, including process development issues such as downstream processing. Why use ionic liquids as reaction media in the first place? An important motivation for their use as reaction media was that, based on their negligible vapor pressure, they would be environmentally acceptable alternatives to volatile organic solvents. However, the question still remained of how to separate the product from the ionic liquid. An elegant solution to this problem was found in continuous product extraction with supercritical carbon dioxide.

In addition to the enhanced operational performance through increased stability and/or selectivity another important motivation for using ionic liquids as reaction media was their ability to dissolve large amounts of highly polar substrates, such as carbohydrates and nucleosides. In particular, their ability to readily dissolve biopolymers such as cellulose and lignin has become an important asset in the current drive toward the bio-based economy, in which there is a need for effective and sustainable methods for the primary conversion of renewable lignocellulosic raw materials. The challenges of using ionic liquids as reaction media for biotransformations are also addressed. In order to be sustainable they must meet stringent requirements regarding the greenness and economic viability of their synthesis and their environmental footprint, which is governed by properties such as bioaccumulation, biodegradability, and ecotoxicity. In addition to the various chapters on the use of ionic liquids as reaction media, there is an extra treat for the reader: two chapters on nonsolvent applications, in biotransformations and organocatalytic conversions, respectively. This includes interesting concepts such as the use of ionic liquid–coated enzymes and the anchoring of organocatalysts to ionic liquids.

In short, I believe that this book is an important addition to the literature on ionic liquids as reaction media for biocatalytic and organocatalytic processes. In addition to its obvious value to practicing organic chemists in both industry and academia, its educational value should not be underestimated. It should prove to be of great value for advanced undergraduate and graduate students. Finally, I would like to thank Pablo for giving me the opportunity to air my views on the merits of this book. I wish him all the success that he has surely earned.

Roger A. Sheldon

Emeritus Professor of Biocatalysis and Organic Chemistry

Delft University of Technology

January 2012

PREFACE

When I was approached by Wiley to edit a book on ionic liquids in biotransformations and organocatalysis, the spontaneous question that quickly came to my mind was, is there a gap for such a book? The field of ionic liquids applied to biotransformations and organocatalysis has developed enormously during the last two decades. Therefore, the realization of a book that could gather, categorize, and provide an updated and complete state-of-the-art in these areas was clearly a demand. There are obviously several comprehensive reviews in the field, but I think none of them can cover the topic(s) in their widest extent. Thanks to the outstanding chapters of many world-class experts in the area, this book is now a reality that I hope will be a useful contribution for researchers in the field, both in academia and industry.

Since the beginning of my work as editor, I have made it clear in my mind that I do not want a book just covering uses of ionic liquids as solvents, albeit, of course, this topic is broad and very important (Chapters 3–7 and 9), nor a book regarding ionic liquids as “green solvents”—an unfortunate label that has surely brought more problems than advantages to ionic liquids (Chapters 1 and 7). In fact, many ionic liquids are not green, but their versatility and tunability makes us optimistic that it will be possible to combine greenness with the acquired know-how on advantages that ionic liquids may bring, for example, leading to the third generation of ionic liquids. Likewise, emerging deep-eutectic-solvents represent a promising option, and first uses in biotransformations are briefly discussed herein (Chapters 1, 5, and 7). In addition, an extensive updated state-of-the-art on toxicity and (bio)degradability of commonly used ionic liquids, together with protocols and rules applied for assessing these parameters, is provided in Chapter 7.

Quite remarkably, ionic liquids are more than mere solvents. They represent a fantastic academic tool for studying and understanding interactions with proteins, enzymatic mechanisms, and so on (Chapters 2 and 5); there are also a number of “nonsolvent” approaches for practical applications, such as catalyst immobilization or activation, downstream processing, and catalyst grafting or coating (Chapters 8 and 10). Ionic liquids can also be smartly combined with other nonconventional solvents, such as supercritical fluids, or with innovative process design concepts (Chapter 4). Finally, some ionic liquids can be employed in whole-cell biotransformations, providing novel and promising approaches, including proof-of-principle for deep-eutectic-solvents and whole cells (Chapter 7).

I want to acknowledge a number of people who have made this book a reality. First of all, the greatest credits go obviously to the authors of this book, the actual and unique protagonists of this work (together with the ionic liquids!). Without their outstanding efforts, professionalism, and excellent and readily updated chapters, this project would have never been possible. Furthermore, I wish to thank Dr. Daniela Gamenara, Dr. Fabrizio Sibilla, and Dr. Andreas Buthe for many fruitful and stimulating discussions. Likewise, thanks are given to Prof. Dr. Roger Sheldon for writing the Foreword of this book. I am also indebted to Ms. Anita Lekhwani, Senior Acquisitions Editor at Wiley, for the interest and patience she has had and the hard work she has done throughout the editing process. And my thanks go as well to Dr. Edmund H. Immergut, Consulting Editor for Wiley and Wiley-VCH, for inviting me to edit this book and his trust and support during this time.

I must say that, overall, this project has been for me a fascinating and unforgettable adventure. I really hope that readers will find this book an attractive and useful tool for working in the field of ionic liquids, biotransformations, and organocatalysis. Suggestions for further improvements, data treatment, new topics, and so on are of course welcome for future editions of this work.

Pablo Domínguez de María

Aachen, Germany, January 2012

CONTRIBUTORS

Paola Agrigento, Dipartimento Chimica Organica “E. Paternò”, Università di Palermo, Viale delle Scienze, Palermo, Italy

Danielle Dennewald, Lehrstuhl für Bioverfahrenstechnik, Technische Universität München, Garching, Germany

Pablo Domínguez de María, Institute of Technical and Macromolecular Chemistry (ITMC), RWTH Aachen University, Aachen, Germany

Daniela Gamenara, Physical-Organic Chemistry and Bioprocesses Group, Organic Chemistry Department, Facultad de Química, Universidad de la República (UdelaR), Montevideo, Uruguay

Eduardo García-Verdugo, Instituto de Catálisis y Petroleoquímica, CSIC, Campus de la UAM, Cantoblanco Madrid, Spain

Francesco Giacalone, Dipartimento Chimica Organica “E. Paternò”, Università di Palermo, Palermo, Italy

Lasse Greiner, Institute of Technical and Macromolecular Chemistry (ITMC), RWTH Aachen University, Aachen, Germany and DECHEMA e.V. Karl-Winnacker-Institut, Frankfurt am Main, Germany

Michelangelo Gruttadauria, Dipartimento Chimica Organica “E. Paternò”, Università di Palermo, Palermo, Italy

Christina Kohlmann, Institute of Technical and Macromolecular Chemistry (ITMC), RWTH Aachen University, Aachen, Germany and Cognis GmbH, Düsseldorf, Germany

Pedro Lozano, Departamento de Bioquímica y Biología Molecular “B” e Inmunología, Facultad de Química, Universidad de Murcia, Murcia, Spain

Patricia Saenz Méndez, Physical-Organic Chemistry and Bioprocesses Group, Organic Chemistry Department, Facultad de Química, Universidad de la República (UdelaR), Montevideo, Uruguay and Computational Chemistry and Biology Group, DETEMA, Facultad de Química, Universidad de la República (UdelaR), Montevideo, Uruguay

Renato Noto, Dipartimento Chimica Organica “E. Paternò”, Università di Palermo, Palermo, Italy

Radovan Šebesta, Faculty of Natural Sciences, Comenius, University Bratislava, Bratislava, Slovakia

Gustavo Seoane, Physical-Organic Chemistry and Bioprocesses Group, Organic Chemistry Department, Facultad de Química, Universidad de la República (UdelaR), Montevideo, Uruguay

Štefan Toma, Faculty of Natural Sciences, Comenius, University Bratislava, Bratislava, Slovakia

Dirk Weuster-Botz, Lehrstuhl für Bioverfahrenstechnik, Technische Universität München, Garching, Germany

Zhen Yang, College of Life Sciences, Shenzhen University, Shenzhen, Guangdong, China

Hua Zhao, Chemistry Program, Savannah State University, Savannah, GA, USA

PART I
FUNDAMENTALS

1

IONIC LIQUIDS: DEFINITION, APPLICATIONS, AND CONTEXT FOR BIOTRANSFORMATIONS AND ORGANOCATALYSIS

Pablo Domínguez de María

1.1 IONIC LIQUIDS: DEFINITION, DEVELOPMENT, AND OVERVIEW OF CURRENT MAIN APPLICATIONS

Ionic liquids (ILs) (low-temperature molten salts) are simply mixtures of cations and anions that do not pack well among them, and therefore remain liquid at low to moderate temperatures. The low melting points are often achieved by incorporating bulky asymmetric cations into the structure, together with weakly coordinating anions. Arbitrarily it has been established that ILs that melt below 100°C fall into the category of “ionic liquids.” On the other hand, those that are liquid at room temperature are often regarded as “room-temperature ionic liquids” (RTILs). Although some IL compositions have been known for a long time, it has been in the last decades when an impressive development in the field has emerged, providing innovative applications in many areas of chemistry. This interest is driven by the fact that by changing the cation or the anion of a certain IL, the physicochemical properties of that IL can be finely tuned. Thus, novel solvents can be defined and used for a specific tailored application. Obviously this wide tunability cannot be reached with conventional organic solvents. For instance, IL polarities can be modulated to design ILs that are immiscible with either low-polarity organic solvents or high-polarity solvents. This facilitates conventional extraction methods to be employed in product separation and furthermore provides promising entries in many areas of chemistry. Likewise, combinations of ILs with other solvent systems, for example, supercritical fluids, have provided promising synergies for chemical process setups since properties of both systems can be easily modulated.

Not without discussion, it is usually assumed that the first “true” IL was described in 1914 by Walden. The IL was ethylammonium nitrate (EAN), [EtNH3][NO3], with a melting point (m.p.) of 12.5°C. However, the finding attracted rather little attention at that time.1 Two decades later, in 1934, a patent reported on some pyridinium-based molten salts that were able to dissolve certain amounts of cellulose.2 Again, in this case, the importance, potential, or utility of this finding was underestimated. Remarkably, nowadays cellulosic biomass pretreatment by means of a wide number of ILs is an important topic of research since some ILs enable the dissolution of different lignocellulosic materials. Once dissolved in these ILs, cellulose can be subsequently depolymerized by, for instance, different hydrolytic enzymes (see also Chapter 5, Sections 5.4 and 5.5).3

In a broad sense, ILs started to attract interest in the 1960s. During several decades on (1960–1990), the first generation of ILs appeared and was widely described and chemically characterized. Typical cations for first-generation ILs were dialkylimidazolium and alkylpyridinium derivatives. As anions, chloroaluminate and other metal halide structures were used. As an important drawback for practical applications, first-generation ILs were found to be sensitive to water and air. These features clearly hampered further applications of first-generation ILs in different fields of chemistry. In the 1990s, the second generation of ILs emerged. Herein, anions were substituted for weakly coordinating anions such as BF4 or PF6. These new ILs were air- and water-stable and therefore led to much research and efforts in the area, as the enhanced stability of ILs provided a much wider frame for operating with them under many different processing conditions. More recently, the third generation of ILs has emerged. This third generation comprises biodegradable and readily available ions, such as natural bases (e.g., choline), amino acids, and naturally occurring carboxylic acids.4,5 Together with this third generation of ILs, so-called deep eutectic solvents (DES) represent a promising alternative because they are simple to prepare, biodegradable, and more economical, compared with other ILs. In general, DES are mixtures of a solid salt with a hydrogen-bond donor in different proportions. An example of DES is represented by the combination of choline chloride (solid salt at room temperature, m.p. 302°C) with urea (solid at room temperature, m.p. 132°C), which leads to a DES with a melting point of 12°C.5–7 Yet it is not clear if DES can be regarded as “IL” since some of the structures (e.g., urea) are not charged and therefore subsequently produced solvents are not entirely ionic. Despite this, it is believed that many properties of ILs can also be more or less extrapolated to DES. In Figure 1.1 some selected milestones in the IL history are depicted.

Figure 1.1. Some selected milestones in the history of ILs.4,5

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Until now, second-generation ILs have been the subject of enormous fundamental research, providing interesting and novel applications in many areas of chemistry. Yet their use at commercial scale is still limited to a few cases, presumably due to economic aspects related to ILs. However, along with the development of the third generation of ILs, which are more sustainable, biodegradable, and cheaper derivatives, it is anticipated that novel IL-based applications will reach the commercial level in the coming years. A significant number of companies already commercialize some ILs and perform R&D-related activities aimed at identifying new market niches and business opportunities.

The enormous potential of ILs is driven by their intrinsic feature (previously mentioned), which is that ILs can be finely tuned by carefully selection of anions and cations. Thus, ILs can be tailored for a specific application, leading to the concept of task-specific ionic liquid (TSIL). By choosing anions and cations, relevant examples of protic ILs, chiral ILs, multifunctional ILs, supported ILs, and so on have been reported. Some general applications for ILs have been put forward (see overview in Figure 1.2). More information on the general applications of ILs can be found in recent reviews and books devoted to various IL areas.8–16

Figure 1.2. Overview of possible applications of ILs in different areas.8–16

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1.2 ON THE GREENNESS OF ILs: TOWARD THE THIRD GENERATION OF ILs AND DES

Apart from the ample tunability of ILs (previous section), probably another aspect that has triggered significant interest and research in the field of ILs is the common claim that ILs are “green solvents.” This general assumption is based on several important properties commonly attributed to ILs, namely that ILs pose negligible vapor pressure and that they are nonflammable. In this section aspects related to the greenness of ILs will be briefly discussed.

First of all, it is usually reported that ILs do not exert measurable vapor pressure since they are entirely composed of ions. Hence, they cannot be distilled without decomposition and thus are nonvolatile. An obvious conclusion that may be drawn from these postulates is that environmental advantages would be achieved by using ILs instead of volatile organic compounds (VOCs). This nonvolatility statement has been challenged by Seddon and coworkers, who demonstrated that some ILs can in fact be distilled at low pressures.17 However, at ambient pressures most of the ILs indeed show a negligible vapor pressure, and therefore from that viewpoint they may still be considered environmentally advantageous compared with VOCs.

The second important property to categorize ILs as environmentally-benign solvents is their nonflammability compared again with VOCs. However, this statement has also been challenged by Wilkes, Rogers et al., who showed that a wide number of commonly used ILs were actually combustible since products formed during thermal decomposition of ILs were found to be combustible. Experiments thus showed that it is not safe to operate with ILs close to fire or heat sources.18 Therefore, although the low flammability of ILs may certainly provide advantages compared with VOCs, it is obvious that ILs should not be regarded as “green solvents” by the mere fact that they are ILs. Traditionally, in publications dealing with ILs, there are not many distinctions among ILs, and usually all ILs are generically regarded as “green solvents” or as “nonflammable” solvents. This trend, however, is starting to change.

Apart from the two above-mentioned IL properties (low vapor pressure and nonflammability), there are other aspects—surely more important in assessing the greenness of ILs—that definitely challenge the “green label” of many often used ILs. These aspects are related to the environmental impact that IL syntheses may have (e.g., the E-factor of producing ILs), as well as to the eco-toxicity and biodegradability of the ions composing the ILs, and of metabolites formed thereof, when ILs are (accidentally) spoiled in the milieu. These topics have only recently started to receive the attention that they actually deserve.19–22 In this chapter a brief discussion of these issues is given. Furthermore, a detailed and updated discussion of topics such as biocompatibility, toxicity, and biodegradability of ILs is also available in Chapter 7 (Sections 7.1 and 7.2).

As any other chemical or solvent, the production of ILs clearly involves a synthetic process in which some chemical steps are conducted. Therefore, during IL syntheses some reagents are used and some wastes or by-products are formed together with the IL. These waste and by-product formation is crucial from an environmental viewpoint—green chemistry and green engineering—23,24 and are often not mentioned or even considered when ILs are claimed as “green solvents.” In Table 1.1, the principles labeled “PRODUCTIVELY” (green chemistry) and “IMPROVEMENTS” (green engineering) are summarized.24

TABLE 1.1. Principles of Green Chemistry (“PRODUCTIVELY”) and Green Engineering (“IMPROVEMENTS”), as Reported in the Literature24

“PRODUCTIVELY”“IMPROVEMENTS”
Green chemistryGreen engineering
Prevent wastesInherently nonhazardous and safe
Renewable materialsMinimize material diversity
Omit derivatization stepsPrevention instead of treatment
Degradable chemical productsRenewable material and energy inputs
Use safe synthetic methodsOutput-led design
Catalytic reagentsVery simple
Temperature, pressure ambientEfficient use of mass, energy, space, and time
In-process monitoringMeet the need
Very few auxiliary substancesEasy to separate by design
E-factor, maximize feed in productNetworks for exchange of local mass and energy
Low toxicity of chemical productsTest the life cycle of the design
Yes, it is safeSustainability throughout the product life cycle

Despite the importance of these green chemistry principles, it has not been until recently that studies focusing on the environmental concerns of IL syntheses were reported.20 Therein, the widely used alkylimidazolium-based ILs were taken as a model, and critical studies regarding their syntheses (E-factor and atom economy), purification steps, discoloration, and source of energy applied were carried out. Overall it was concluded that the production of those ILs is far less green than what is usually claimed in the literature dealing with ILs. At laboratory-scale processes, quaternization synthetic approaches may still provide some green footprints if processes are conducted with either microwave or conduction as the energy source.24 However, in the other cases, conclusions clearly challenged the environmental label that ILs usually have in the literature. It is clearly expected that more environmental studies on the ILs syntheses will be carried out in the coming years and therefore a better picture will emerge.

Moreover, when assessing the greenness of ILs other important aspects include IL release, eco-toxicity, biodegradability, bioaccumulation, and spatiotemporal range in the milieu.22 Although it can be expected that environmental release of ILs could be easily controlled compared with VOCs—by virtue of the almost negligible vapor pressure and volatility of ILs—it is clear that sooner or later some appreciable amounts of ILs will reach the environment (e.g., in wastewater effluents). Therefore, it is crucial to assess how these ILs are going to interact with living organisms. To this end, a number of standardized tests and protocols have been established. They include studies on inhibition of acetylcholinesterase enzymes, luminescence inhibition of the marine bacterium Vibrio fisheri, growth rate inhibition of the freshwater green alga Pseudokirchneriella subcapitata, cell viability of IPC-81 cells, growth inhibition of duckweed, Lemna minor, and an acute test with zebrafish, Danio rerio.21 In addition, products formed during the environmental degradation of ILs must also be considered. It has been reported that some of these degradation products may be even more toxic than the original ILs.21 In Chapter 7 of this book (Sections 7.1 and 7.2), detailed information on the state-of-the-art of these aspects is provided.

A general conclusion that can be set herein is that commonly used ILs are far less green than what they are usually claimed in publications. However, once again it has to be mentioned that the huge versatility of ILs (tunability, tailored properties) might be used to provide greener ILs than the current ones. In general, these environmental concerns are starting to shift research in the field to the production of more sustainable ILs. An envisaged future challenge will be to design ILs that maintain their promising physicochemical properties and potential applications while providing greener footprints, both in terms of E-factors and in terms of degradability, toxicity, and so on.19 In this respect, an alternative that has emerged is the production of ILs starting from natural sources as substrates such as amino acids, carboxylic acids, and sugar-based structures.25 Herein, natural amino acids have been used extensively26 because of their interesting tunable chemical properties, greater affordability, and high compatibility for living organisms. In addition, amino acids incorporate chiral centers into the IL, which may add other interesting properties with promising applications. Thus, amino acid-based ILs represent interesting examples of chiral bio-based ILs.27 Another alternative is to use amino acids as starting materials for the synthesis of ILs. Herein, albeit substrates are obviously environmentally friendly, attention to subsequent synthetic procedures to afford the final derivatives should be taken into account in a case-by-case scenario. In Figure 1.3 some examples of ILs derived from amino acids are depicted.

Figure 1.3. Some examples of chiral ionic liquids using amino acids (or derivatives thereof) as substrates.27

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In the quest for ILs that could deserve the label “green solvents,” another important approach is represented by designing ILs that can be not only entirely composed of biomaterials, but also involve derivatization steps that may add limited environmental concerns to IL production. An example of this strategy is the use of available and inexpensive choline hydroxide as staring material. The production of choline-based ILs are conducted simply by substituting choline hydroxide with the correspondent (naturally occurring) carboxylic acid at ambient temperature, producing water as the only by-product of the process (Figure 1.4).28,29

Figure 1.4. Choline-based ionic liquids. Some of the carboxylic acids are naturally occurring, thus providing a 100% bio-based approach for the production of neoteric solvents.28,29

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Therefore, the design of ILs provides an enormous possibility for tailored ILs, even when environmental concerns are considered, and a useful but green solvent is envisaged. In conclusion, although ILs cannot be generally regarded as safe (green) solvents, it is possible to design ILs that can meet environmental requirements. Given the current trends in environmental processes and green chemistry, it is clear that this will be the most important and sustainable line of development for ILs in the coming years. Furthermore, the design of ILs that can be used for certain applications while maintaining acceptable environmental footprints will be crucial. Some examples of these combinations have just appeared in the field of biocatalysis, including the design of enzyme-friendly choline-based ILs that are able to dissolve cellulose at the same time (AMMOENG 110™, Figure 1.5).30 This combination provides a promising frame to undertake biocatalytic reactions in reaction media that can be compatible with the substrates/products employed. This approach is discussed more extensively in Chapter 2 (Section 2.6) and Chapter 5 (Sections 5.4 and 5.5).

Figure 1.5. Structure of AMMOENG 110™ recently reported as an enzyme-friendly solvent for cellulose dissolution.30

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As stated in the previous section, together with bio-based ILs, another important field in the third generation of ILs are represented by DES.5–7,9 DES are a combination of a room-temperature salt (e.g., choline chloride) together with a hydrogen-bond-forming molecule (e.g., urea, glycerol, and carboxylic acids). When these structures are mixed in different proportions, melting points drop, thus providing liquid solvents at different temperatures (even at room temperature). Herein, combinations of choline chloride with urea, malonic acid, ethylene glycol, or glycerol have been successfully reported as DES, showing that a broad range of new solvents can be produced. Because of the ease of their synthesis (a simple mixing of components is often enough) together with the complete biodegradability of their components, it is clear that DES represent a promising entry in the field of tunable green solvents (see also Chapter 5, Section 5.2.3.6, and Chapter 7, Section 7.4). Furthermore, prices for DES are expected to be much lower than those for ILs. Although much more research is needed, it is often considered that many of the observed properties of second-generation ILs will also be valid for both third-generation ILs and DES solvents.

1.3 CONTEXT OF ILs IN BIOTRANSFORMATIONS AND ORGANOCATALYSIS

The fields of biotransformations and organocatalysis have emerged in the last decades as promising alternatives for the environmental-friendly production of different chemicals, not only in the fine-chemical or pharmaceutical arena, but also in the production of other important low-added value commodities.31–34 Enzymes and many organocatalysts are benign and nontoxic catalysts, which enable the production of relevant compounds, building blocks, and commodities with reduced environmental concerns. These catalysts usually display high enantio-, regio-, or chemoselectivities, operating under mild reaction conditions. As an extension of these fields, ILs have also been largely considered useful alternatives for many applications in biotransformations and organocatalysis.

The first reported combination of enzymes and ILs was published in 1984.35 In that contribution, the stability and activity of alkaline phosphatase in water solutions, in which different amounts of the fused salt EAN, [EtNH3][NO3], had been added, was studied. The article showed an unexpectedly high stability of the enzyme under different proportions of EAN. Decades later, the enzyme-catalyzed formation of Z-aspartame in [BMIM][PF6], catalyzed by thermolysin, was reported, demonstrating that ILs may be excellent reaction media for biocatalysis, in terms of enhanced activity, stability, or selectivity.36 Since then, an impressive number of applications dealing with ILs and biocatalysis have been reported either as patents or as publications. Both types of biocatalysts, free enzymes and whole cells, have been studied. ILs have been used as solvents or co-solvents for biocatalytic reactions, as additives to enhance stability, activity, or selectivity of enzymes, or even as reaction (biphasic) media for whole-cell processes. Most of the applications in this area deal with second-generation ILs. Interestingly, first assessments of biocatalytic reactions using third-generation ILs or DES have started to appear.5,37–40 Therefore, it is expected that ILs will continue to make an impact in the field of enzyme catalysis since the enormous knowledge being developed with second-generation ILs will be a proper starting point to set up biocatalytic applications with more sustainable and economically accessible third-generation ILs and DES. Chapters 2–8 of this book deal in detail with the use of ILs in biocatalysis, covering in a broad extent all the applications, options, and synergies that the use of ILs may bring the field of enzyme catalysis and biotechnology.

On the other hand, the use of ILs in organocatalysis has also been reported, as documented by several recent reviews.41,42 The first applications of ILs in organocatalysis were as solvents for organocatalytic reactions. Later on other interesting applications, such as the use of ILs as support for organocatalyst immobilization, were reported. The combination of properties of ILs—finely tuned by selection of cations and anions—with exquisite catalysis that organocatalysts may bring may be a powerful synergy for envisaging new applications. The topics are well covered in Chapters 9 and 10, which deal exclusively with ILs and organocatalysis.

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