Eco-Friendly Synthesis of Fine Chemicalsby Chiappe Cinzia (Contribution by), Roberto Ballini (Editor), Janet L Scott (Contribution by), James H Clark (Editor), Claudio Trombini (Contribution by)
The 20th century has seen a phenomenal growth in the global economy and continuous improvement in the standard of living in the industrialized countries. Sustainable development has become an ideal target in recent years and in the early 1990s the concept of "Green chemistry" was launched in the USA as a new paradigm, and since 1993 it has been promoted by the
The 20th century has seen a phenomenal growth in the global economy and continuous improvement in the standard of living in the industrialized countries. Sustainable development has become an ideal target in recent years and in the early 1990s the concept of "Green chemistry" was launched in the USA as a new paradigm, and since 1993 it has been promoted by the National Science Foundation (NSF) and the Environmental Protection Agency (EPA). The success of the pharmaceutical industry is, in large part, due to the towering achievement of organic chemistry, a mature science which emerged as a distinct discipline well over 150 years ago, however this has been both a blessing and a curse. Many of our most reliable strategies for assembling target molecules employ reactions which are fifty to one hundred years old and are often named in honour of their discoverers. During these early years, the chronic toxicological properties of chemicals were often completely unknown and many unwittingly became indispensable tools of the trade. Early pioneers in green chemistry included Trost (who developed the atom economy principle) and Sheldon (who developed the E-Factor). These measures were introduced to encourage the use of more sustainable chemistry and provide some benchmarking data to encourage scientists to aspire to more benign synthesis. Green chemistry is essentially the design of chemical processes and procedures that reduce or eliminate the use, or the generation, of hazardous substances. Green chemistry is a growing area of research and an increasing number of researchers are now involved in this field. The number of publications has dramatically increased and new recognition of advances made is necessary with respect to other research areas. The synthesis of "Fine Chemicals" represents one of the main goals in organic synthesis and this new book extensively examines the main processes and procedures for their preparation under eco-friendly conditions.
The book is a collection of selected research topics delivered by scientists involved in some of the more prominent fields of green chemistry. It is devoted to the synthesis of fine chemicals by the use of alternative eco-friendly solvents (ionic liquids, polyethylene glycol, water, etc.), supported organic catalysis, microwave irradiation or high pressure as contributors to more efficient processes, photochemistry as a green procedure and solvent-free processes. Each chapter gives an introduction to the various methods or procedures and their contribution to green chemistry and a variety of the most representative examples of the eco-friendly synthesis of fine chemicals are reported and discussed. In addition, there is a chapter dedicated to the application of simple reaction to the synthesis of complex molecules.The chapters are all written by authors who are experts in their field and are exhaustively referenced and the book will be invaluable for researchers and industrialists as well as academia.
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Eco-Friendly Synthesis of Fine Chemicals
By Roberto Ballini
The Royal Society of ChemistryCopyright © 2009 Royal Society of Chemistry
All rights reserved.
Catalysis in Non-conventional Reaction Media
1.1.1 The Context
The concept of green or sustainable chemistry was born around 1990 thanks to a small group of chemists who, ahead of the times, clearly saw that the need for more environmentally acceptable processes in chemical industry had to become a top priority in R&D activities. In 1990, the Pollution Prevention Act was the spark that ignited awareness of the need for innovative chemical technologies that accomplished pollution prevention in a scientifically sound manner. In 1991 Paul Anastas coined the term and defined the field of "Green Chemistry". In the same year the first "Green Chemistry" program, the "Alternative Synthetic Pathways" research program, was launched. From a theoretical viewpoint, concepts like "atom economy" proposed by Trost and the "E factor" introduced by Sheldon, gave impetus to the creation of a new way of thinking about chemistry and to the development of a green metric able to provide quantitative support to compare the "greenness" of alternative products and processes. From a functional point of view, several endeavours aimed to promote green chemistry activities got under way. In 1995 the Presidential Green Chemistry Challenge Award, proposed by Anastas to the White House, was approved. Since then, every year the Presidential Green Chemistry Challenge Awards highlight successes in research, development and industrial implementation of technologies that prevent pollution at source while contributing to the competitiveness of the innovators. In 1997 Anastas co-founded the Green Chemistry Institute, which worked closely with industries and universities on environmental issues, and expanded its international network to consortia in 27 nations. Other initiatives in the green chemistry field rapidly spread throughout the world, e.g. in Italy, Canada, UK, Australia and Japan. The Green Chemistry journal was launched in 1999 by the Royal Society of Chemistry, and it was accompanied in 2008 by ChemSusChem published by Wiley-VCH. Less than two decades after its beginnings, green chemistry issues are providing an enormous number of challenges and are the central concern of those who practice chemistry in industry, education and research. In Europe the SusChem Technology Platform and in the US the Technology Vision 2020 of the Chemical Industry are turning their chemistry research agenda into new goals, jobs and business through innovation directed towards sustainability and environmental stewardship.
1.1.2 The 12 Principles of Green Chemistry
In 1998, Anastas and Warner teamed up to write the best selling and most cited book in the field of Green Chemistry, Green Chemistry: Theory and Practice, which explicated the 12 principles of Green Chemistry. The principles, intended as guidelines for practical chemistry, provided a road map for chemists both of academia and industry to promote pollution prevention through environmentally conscious design of chemical products and processes. The 12 principles are:
1. It is better to prevent waste than to treat or clean up waste after it is formed.
2. Synthetic methods should be designed to maximise the incorporation of all materials used in the process into the final product.
3. Wherever practicable, synthetic methodologies should be designed to use and generate substances that possess little or no toxicity to human health and the environment.
4. Chemical products should be designed to preserve efficacy of function while reducing toxicity.
5. The use of auxiliary substances, e.g. solvents, separation agents, should be made unnecessary wherever possible and innocuous when used.
6. Energy requirements should be recognised for their environmental and economic impacts and should be minimized. Synthetic methods should be conducted at ambient temperatures and pressure.
7. A raw material feedstock should be renewable rather than depleting, whenever technically and economically practical.
8. Unnecessary derivatization (blocking group, protection/deprotection, temporary modification of physical/chemical processes) should be avoided wherever possible.
9. Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.
10. Chemical products should be designed so that at the end of their function they do not persist in the environment and break down into innocuous degradation products.
11. Analytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances.
12. Substances and the form of a substance used in a chemical process should be chosen so as to minimize the potential for chemical accidents, including releases, explosions and fires.
The 12 guidelines essentially fall into four groups: efficient use of energy, hazard reduction, waste minimization and the use of renewable resources. Although each heading clearly indicates a proficient solution toward sustainability, the more guidelines or green technologies a master plan meets the greater is its intrinsic value. An example could be offered by a process involving the addition reaction (100% atom economy) of two starting materials derived from renewable feed-stocks (rule no. 7) taking place in a perfect stereoselective way (waste minimization) at room temperature (energy efficient) in water (a prototypical green solvent) under the action of a low amount of a recyclable catalyst (rule no. 9).
The present chapter presents a few snapshots from the recent literature on the integration of the theme of catalysis with the topic of green solvents. The examples discussed witness how molecular design makes its own contribution to the breakthrough approach to innovative problem-solving, providing sustainable solutions to the chemical industry. Part of these cutting-edge results, suitably integrated by the state of the art process engineering, have the chance to evolve into low cost, robust, efficient and easy to operate sustainable technologies.
Adopting a K. B. Sharpless statement, catalysis is the engine that drives the development of chemistry. Everybody can easily recognize that top achievements in applied chemistry are focused on industrial applications of catalysis, rational design, serendipitous discovery or combinatorial identification of new ligands, catalysts, new solid supports (organic, inorganic, amorphous or mesoporous silica phases, metal organic frameworks, etc).
An ideal catalyst should approach 100% selectivity while reaching high levels of productivity. Selectivity refers first of all to (i) chemoselectivity, which means the catalyst must be able to select preferred reactants from complex mixtures, (ii) regioselectivity, which means selection of preferred sites of the reacting substrate and (iii) stereoselectivity, which means preferred formation of a single stereoisomer.
At the beginning of this decade Gladysz defined what should be an ideal catalyst. He proposed the following features: the rapid production (turnover frequency, TOF) of an infinite amount of product (turnover number, TON), preferentially at room temperature and under atmospheric pressure, which implies no deactivation and poisoning under the reaction conditions. This "ideal" catalyst does not require an inert atmosphere to operate, is insensitive to reactant impurities and affords product yields of 100%. Gladysz clearly noted that these unattainable limits can never be realized but help to focus attention on what we should strive for. The "infinite TON" limit, for example, would make catalyst recovery efforts unnecessary, a quest that is unrealistic. The design of recoverable catalysts has become, indeed, a central field of catalysis research. In fact, catalyst decomposition associated with leaching of the active species and decomposition itself have to be taken into account. In practice, design efforts for effective recoverable catalysts must address the removal of these catalyst impurities from solution.
Catalysis is generally hypothesis driven: the chemist uses experience to envisage candidate catalysts, which are then tested, investigated and optimized, including the use of high throughput and library technologies. There is an increased need for new paradigms of how catalysis research and rational design has to be done. But there is an even more urgent need: that of addressing in R&D activities both classic economy-linked problems (cost, yield, selectivity, time, resistance to poisoning and deactivation, minimization of product contamination by catalyst residues), and sustainability concerns. They focus on minimizing waste production, energy consumption and use of toxic and eco-toxic chemicals. An impressive example from the golden era of petrochemistry is the SOHIO ammoxidation of propane with ammonia, which replaced the IG FARBEN process based on acetylene and hydrogen cyanide. Particularly in the case of costly and highly specialized catalysts the optimization of catalyst recovery and reuse is a fundamental demand, too, for economic and environmental reasons. Moreover, from a practical viewpoint, an optimum catalytic process should be wide in scope, easy to perform and insensitive to oxygen and water, which could become the solvent of choice. This is what characterizes, for example, the Cucatalysed azide-alkyne cycloaddition, a reliable and practical reaction, which proved very useful, for example, for accelerating the drug discovery process. The reaction, work-up and purification should use benign solvents, avoiding chromatography or time-consuming distillation or crystallization unit operations.
Catalysis is traditionally divided into heterogeneous and homogeneous catalysis. In classic solid/liquid or solid/gas heterogeneous catalysis, the catalyst provides a surface on which the reactants are temporarily adsorbed. Bonds in the substrate are weakened sufficiently by adsorption or chemisorption for new bonds to be created. Syngas conversion, hydrogenation and oxidation processes are by far the most important industrial applications. Catalyst synthesis technology is applied to the manufacture of high surface area metal species, including nanoparticles, and metal oxides, usually supported in another metal oxide such as alumina, silica and zeolites. The chemical industry often favours heterogeneous catalysis for the easy recovery and good stability of the catalyst, the practical downstream separation processes involved, and the easier recycling of the catalyst. However, the role played by phase partitioning and transport phenomena make the kinetic interpretation of a catalytic process a tough task. Analogous difficulties are encountered in the rationalization of heterogeneous catalysis in terms of a molecular phenomenon with well-defined surface organometallic intermediates and/or transition states. An example of paradigms developed to support a rational catalyst design is offered by the seven principles, or "seven pillars", proposed by Grasselli for tailoring new selective oxidation catalysts. The lattice oxygen of the metal oxide, metal–oxygen bond strength, host structure, redox properties, multifunctionality of active sites, site isolation and phase cooperation are all essential aspects to be controlled for a successful design.
Homogeneous catalysis, on the other hand, has reached astonishing advanced levels in terms of molecular understanding of the elementary steps characterizing the catalytic cycle, bringing molecular insight to the design of new catalysts and even allowing the discovery of new reactions; examples are offered by Ziegler–Natta depolymerization and alkane metathesis. The pros of homogeneous catalysis are often the activity (TONs, TOFs) and selectivity, while cons are generally the poor stability, troublesome separation of the catalyst from the product, which is often contaminated by it, the quite difficult separation and reuse of the catalyst. Homogeneous asymmetric catalysis provides a powerful tool for the synthesis of optically active molecules that serve, for example, as Active Pharmaceutical Ingredients (APIs). Although numerous highly selective chiral catalysts have been developed over the past three decades, their practical applications in industrial processes are hindered by their high costs as well as difficulties in removing trace amounts of toxic metals from the organic product. In this case costly and time-consuming unit operations, such as crystallization, chromatography or distillation, are necessary to both purify the product and to recover and eventually reuse the catalyst.
To overcome these problems many different approaches have been employed to generate heterogenized asymmetric catalysts. The most frequently used approach makes use of solid/liquid biphasic chemistry; in this context the term "supported reagent" is currently used to describe a wide range of materials involving an inorganic or organic support onto which a "catalyst" species has been chemically or physically adsorbed.
Some of the key advantages of supported reagents compared to the unsupported homogeneous catalyst are:
good dispersion of active sites, and the concentration of sites within small pores can lead to significant improvements in activity,
the presence of molecular-sized pores and the adsorption of reactant molecules on the material surface can lead to improvements in reaction selectivity,
easier and safer storage, work-up and handling,
the opportunity to replace batch processes, as well as time- and solvent-consuming purifications (e.g. chromatography) with flow techniques exploiting a suitable immobilization strategy.
The heterogenized catalyst is, however, often less effective than their homogeneous counterparts. Thus there exists a need to develop new, innovative approaches toward the design of recoverable and reusable asymmetric catalysts with the aim of combining the advantages of heterogeneous and homogeneous catalysis.
Liquid/liquid biphasic, and sometimes gas/liquid/liquid triphasic heterogeneous conditions, provide an alternative way of achieving phase separation, the catalyst being eventually confined in an immiscible liquid solvent. In the ideal catalytic system operating under biphasic conditions the catalyst is immobilized in one solvent, which is immiscible with a second one in which the substrates/products are dissolved. Thus, the product is easily removed without being contaminated by the catalyst, and the catalyst can be simply recovered and reused. With metal-based catalysts, the efficient immobilization of the catalysts in a separate phase from that which contains the products is often performed by tailoring suitable ligands that confer the correct partition coefficient to the catalyst. One strategy adopted when the solvent of choice is water or an ionic liquid is based on the introduction of an ionic tag into ligands, transition metal complexes or organocatalysts, that confers the species of interest the right solubility in the reaction medium. A beautiful, and historically one of the first examples, is the Ruhrchemie/Rhône-Poulenc propene hydroformylation process, where sulfonated triarylphosphine ligands make rhodium catalysts water-soluble, allowing for an easy separation of the catalyst from the butanal product by decantation.
1.1.4 Green Solvents
Many of the traditional solvents that are favoured by organic chemists have been blacklisted by international regulations, for instance chlorinated hydro-carbon solvents have been severely curtailed. Thus, the question of the solvent requires a major rethink in terms of green chemistry issues; this need is driving the search for alternative reaction media. Such media are the basis of many of the cleaner chemical technologies that have reached commercial development. Typical non-conventional reaction media are supercritical carbon dioxide (31.1 °C, 73 atm) and supercritical water (374 °C, 218 atm), water under P/T standard conditions, room-temperature ionic liquids, up to and including solvent-free conditions.
Excerpted from Eco-Friendly Synthesis of Fine Chemicals by Roberto Ballini. Copyright © 2009 Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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Roberto Ballini is a Full Professor of Organic Chemistry at the Faculty of Sciences of the University of Camerino, Italy. His research interest is mainly dedicated to organic synthesis, with particular emphasis on the field of eco-friendly processes (green chemistry). Professor Ballini's group has developed a variety of collaborations with other Universities worldwide conducting similar research. Of particular interest to them all is the chemistry of aliphatic nitro compounds, employed for the generation of carbon-carbon single and multiple bonds and carbon-carbon double bonds as well as for the cleavage of the carbon-carbon bonds. The obtained products find widespread utilization as key building blocks in the synthesis of important targets such as natural products featuring enhanced biological activity. This scientific activity has resulted in more than 210 publications in the main scientific journals, including several Review articles, mainly in the fields of organic synthesis and eco-friendly processes (green chemistry). Professor Ballini has been invited to attend conferences in various national and international meetings and symposiums and has been a lecturer in several worldwide Universities.
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