Volume 72, Issue 7

The evolving face of contemporary chemistry is characterized by unprecedented societal demand for the goods and services of the chemical industry, tempered by growing awareness that finite resources must be conserved and their exploitation optimized. At the same time, environmental protection has become a global concern, and the chemical industry is increasingly obliged to reexamine conventional methodologies, and to seek ways of developing and applying more efficient and environmentally benign strategies for future sustainable growth. The tandem concepts of discovery and exploitation are obviously as old as the industry itself, but there is new urgency in the quest for solutions that will halt and reverse some of the negative effects of historical development and, at the same time, seize the opportunities offered by the extraordinary advances in chemical sciences during recent years. The twin challenges of increasing synthetic efficiency in chemical transformations, and minimizing environmentally hostile waste offer irresistible opportunities for new-age ingenuity. It is in this climate that new approaches to these problems have coalesced into a distinctive discipline, which has been variously described and named but has, as its central thrust, the strategic objectives of increased efficiency, sustainability, and, ultimately, societal benefit. These objectives identify closely with the vision of IUPAC, which is eloquently expressed in two of the goals defined in the current strategic plan, namely to contribute to the advancement of research in the chemical sciences throughout the world and to assist chemistry-related industry in its contributions to sustainable development, wealth creation, and the improvement of the quality of life. A Working Party on Synthetic Pathways and Processes in Green Chemistry was established in 1996, under the auspices of the Commission on Physical Organic Chemistry (Commission III.2) of the IUPAC Organic and Biomolecular Division, with a mandate to promote and disseminate awareness of environmentally compatible synthetic pathways (green chemistry), throughout the academic and industrial scientific research community. In 1999 this group, in close collaboration with the IUPAC Subcommittee on Organic Synthesis, initiated a project to publish a Symposium-in-Print on Green Chemistry, and undertook to compile a collection of expert reviews on aspects of the topic, underpinned by an introductory account of the evolution of the project, its rationale, and its interfaces with complementary initiatives and organisations. This volume represents the culmination of that undertaking, and the introductory overview, comprising contributions by members of the Working Party, gives a detailed account of the role and interest of IUPAC in promoting this initiative, and sets the scene for the ensuing Symposium-in-Print, with an interpretation of the meaning of the term "green chemistry" and an account of the historical emergence of the concept. This is followed by a synoptic preamble, in which the content and purpose of individual reviews in the Symposium-in-Print are summarized. Although the preamble adopts a sequence of presentation based upon the logic imposed by the title theme of synthetic pathways and processes, the influential role of the Organization for Economic Cooperation and Development (OECD) is recognized by adoption of their recommended delineation of topics for grouping the ensuing reviews. The Symposium-in-Print sets out to capture the current status of the discipline and to project the boundless opportunities and challenges confronting contemporary organic synthesis and its practice in a changing world, increasingly sensitized to the finite bounds of natural resources and the vulnerability of the biosphere. It offers evidence that current problems are being addressed and can be solved, and engenders expectations that future problems can be anticipated and prevented. Most importantly, the collective expertise and commitment of the contributors is expected to furnish inspirational guidance to practicing scientists and students of chemistry, to participate in shaping a more environmentally benign future, in which the synthetic pathways and processes in chemistry are fully reconciled with societal expectations for ever-improving quality of life. J. R. Bull IUPAC Special Topics Editor

Modern chemistry is one of the essential tools in pursuing better medical care, more efficient telecommunications and informatics, and increased agricultural production. However, certain chemicals produced and used in large quantities might cause various hazards in environmental sectors, owing to their global (trans-boundary) translocation, as well as their intrinsically hazardous properties. To reduce environmental risk of such chemicals, international regulatory measures have already been taken [e.g., in response to the initiatives of the Intergovernmental Forum in Chemical Safety (IFCS)], including legally binding implementations and national capacity building in developing countries. Herein lies the urgent need for promoting worldwide research into green chemistry (sustainable chemistry), in which the invention and application of chemical products and processes are designed to reduce or to eliminate the use and generation of hazardous substances. Indeed, green chemistry should encompass a variety of disciplines of fundamental chemistry in IUPAC, to encourage new trends of chemical research. Moreover, results of these researches could be effectively applied for solving environmental problems related to the production and use of chemicals and to create a new chemical industry in the future. As such, green chemistry research conforms completely to the mission-oriented activity of IUPAC to meet regulatory requirements for achieving environmentally sound management of chemicals. We sincerely hope that the present special issue highlighting the state of the art and future prospects of green chemistry research will encourage all chemists who intend to serve society through their research efforts. J. Miyamoto Past-President of IUPAC Chemistry and the Environment Division The increasing knowledge in natural sciences and the application of this knowledge are the driving forces for the development and welfare of mankind. Chemistry plays a central role in this development. Chemistry provides the molecular understanding of physical properties of materials and other matters and thus closely interacts with physics. Chemistry also provides the molecular understanding of living systems and is the basis for modern biology and medicine. The development and opportunities of synthetic chemistry have opened a new dimension for tailor-made materials and compounds for specific purposes. The driving forces for developments in chemistry have been very strong, and there is a demand for new and efficient processes and chemicals. Aspects of sustainable and environmentally friendly processes and chemicals have sometimes been lagging behind this demand. Fortunately, chemistry also provides the tools for a green and sustainable development. Knowledge in this general area has to be integrated into the planning of all research and development in chemistry. There are specific research topics related to the development of green and sustainable processes, which need the input of new technology and novel chemistry. The present Symposium-in-Print provides an overview of recent research and development in the field. We hope that it will stimulate further activities in the field. It is planned as a first step in an IUPAC action on this subject. The IUPAC Organic and Biomolecular Chemistry Division is grateful to its Subcommittee on Organic Synthesis and particularly Professor Pietro Tundo for initiating and engaging in this action, and to him and Profs. David StC. Black and Sofia Memoli for editing the Symposium-in-Print. Torbjörn Norin President of IUPAC Organic and Biomolecular Chemistry Division

Contents Green Chemistry in the International Context The Concept of green Chemistry Definition of green chemistry | Green chemistry: Why now? | The historical context of green chemistry | The emergence of green chemistry The Content of Green Chemistry Areas of green chemistry | Preliminary remarks | Alternative feedstocks | Benign reagents/synthetic pathways | Synthetic transformations | Solvents/reaction conditions Green Chemistry in the International Context It has come to be recognized in recent years, that the science of chemistry is central to addressing the problems facing the environment. Through the utilization of the various subdisciplines of chemistry and the molecular sciences, there is an increasing appreciation that the emerging area of green chemistry 1 is needed in the design and attainment of sustainable development. A central driving force in this increasing awareness is that green chemistry accomplishes both economic and environmental goals simultaneously through the use of sound, fundamental scientific principles. Recently, a basic strategy has been proposed for implementing the relationships between industry and academia, and hence, funding of the research that constitutes the engine of economic advancement; it is what many schools of economics call the "triple bottom line" philosophy, meaning that an enterprise will be economically sustainable if the objectives of environmental protection, societal benefit, and market advantage are all satisfied 2 . Triple bottom line is a strong idea for evaluating the success of environmental technologies. It is clear that the best environmentally friendly technology or discovery will not impact on the market if it is not economically advantageous; in the same way, the market that ignores environmental needs and human involvement will not prosper. This is the challenge for the future of the chemical industry, its development being strongly linked to the extent to which environmental and human needs can be reconciled with new ideas in fundamental research. On the other hand, it should be easy to foresee that the success of environmentally friendly reactions, products, and processes will improve competitiveness within the chemical industry. If companies are able to meet the needs of society, people will influence their own governments to foster those industries attempting such environmental initiatives. Of course, fundamental research will play a central role in achieving these worthy objectives. What we call green chemistry may in fact embody some of the most advanced perspectives and opportunities in chemical sciences. It is for these reasons that the International Union of Pure and Applied Chemistry (IUPAC) has a central role to play in advancing and promoting the continuing emergence and impact of green chemistry. When we think about how IUPAC furthers chemistry throughout the world, it is useful to refer to IUPAC's Strategic Plan. This plan demonstrates the direct relevance of the mission of IUPAC to green chemistry, and explains why there is growing enthusiasm for the pursuit of this new area as an appropriate activity of a scientific Union. The IUPAC Strategic Plan outlines among other goals: IUPAC will serve as a scientific, international, nongovernmental body in objectively addressing global issues involving the chemical sciences. Where appropriate, IUPAC will represent the interests of chemistry in governmental and nongovernmental forums. IUPAC will provide tools (e.g., standardized nomenclature and methods) and forums to help advance international research in the chemical sciences. IUPAC will assist chemistry-related industry in its contributions to sustainable development, wealth creation, and improvement in the quality of life. IUPAC will facilitate the development of effective channels of communication in the international chemistry community. IUPAC will promote the service of chemistry to society in both developed and developing countries. IUPAC will utilize its global perspective to contribute toward the enhancement of education in chemistry and to advance the public understanding of chemistry and the scientific method. IUPAC will make special efforts to encourage the career development of young chemists. IUPAC will broaden the geographical base of the Union and ensure that its human capital is drawn from all segments of the world chemistry community. IUPAC will encourage worldwide dissemination of information about the activities of the Union. IUPAC will assure sound management of its resources to provide maximum value for the funds invested in the Union. Through the vehicle of green chemistry, IUPAC can engage and is engaging the international community in issues of global importance to the environment and to industry, through education of young and established scientists, the provision of technical tools, governmental engagement, communication to the public and scientific communities, and the pursuit of sustainable development. By virtue of its status as a leading and internationally representative scientific body, IUPAC is able to collaborate closely in furthering individual national efforts as well as those of multinational entities. An important example of such collaboration in the area of green chemistry is that of IUPAC with the Organization for the Economical Cooperation and Development (OECD) in the project on "Sustainable Chemistry", aimed at promoting increased awareness of the subject in the member countries. During a meeting of the Environment Directorate (Paris, 6 June 1999), it was proposed that United States and Italy co-lead the activity, and that implementation of five recommendations to the member countries be accorded the highest priority, namely: research and development awards and recognition for work on sustainable chemistry exchange of technical information related to sustainable chemistry guidance on activities and tools to support sustainable chemistry programs sustainable chemistry education These recommendations were perceived to have socio-economic implications for worldwide implementation of sustainable chemistry. How IUPAC and, in particular, its Divisions can contribute to this effort is under discussion. IUPAC is recognized for its ability to act as the scientific counterpart to OECD for all recommendations and activities. Although the initiatives being developed by the OECD are aimed primarily at determining the role that national institutions can play in facilitating the implementation and impact of green chemistry, it is recognized that each of these initiatives also has an important scientific component. Whether it is developing criteria or providing technical assessment for awards and recognition, identifying appropriate scientific areas for educational incorporation, or providing scientific insight into the areas of need for fundamental research and development, IUPAC can play and is beginning to play an important role as an international scientific authority on green chemistry. Other multinational organizations including, among others, the United Nations, the European Union, and the Asian Pacific Economic Community, are now beginning to assess the role that they can play in promoting the implementation of green chemistry to meet environmental and economic goals simultaneously. As an alternative to the traditional regulatory framework often implemented as a unilateral strategy, multinational governmental organizations are discovering that green chemistry as a nonregulatory, science-based approach, provides opportunities for innovation and economic development that are compatible with sustainable development. In addition, individual nations have been extremely active in green chemistry and provide plentiful examples of the successful utilization of green chemistry technologies. There are rapidly growing activities in government, industry, and academia in the United States, Italy, the United Kingdom, the Netherlands, Spain, Germany, Japan, China, and many other countries in Europe and Asia, that testify to the importance of green chemistry to the future of the central science of chemistry around the world. Organizations and Commissions currently involved in programs in green chemistry at the national or international level include, for example: U.S. Environmental Protection Agency (EPA), with the "Green Chemistry Program" which involves, among others, the National Science Foundation, the American Chemical Society, and the Green Chemistry Institute; European Directorate for R&D (DG Research), which included the goals of sustainable chemistry in the actions and research of the European Fifth Framework Programme; Interuniversity Consortium "Chemistry for the Environment", which groups about 30 Italian universities interested in environmentally benign chemistry and funds their research groups; UK Royal Society of Chemistry, which promotes the concept of green chemistry through a "UK Green Chemistry Network" and the scientific journal Green Chemistry; UNIDO-ICS (International Centre for Science and High Technology of the United Nations Industrial Development Organization) which is developing a global program on sustainable chemistry focusing on catalysis and cleaner technologies with particular attention to developing and emerging countries (the program is also connected with UNIDO network of centers for cleaner production); and Monash University, which is the first organization in Australia to undertake a green chemistry program. Footnotes: 1. The terminology "green chemistry" or "sustainable chemistry" is the subject of debate. The expressions are intended to convey the same or very similar meanings, but each has its supporters and detractors, since "green" is vividly evocative but may assume an unintended political connotation, whereas "sustainable" can be paraphrased as "chemistry for a sustainable environment", and may be perceived as a less focused and less incisive description of the discipline. Other terms have been proposed, such as "chemistry for the environment" but this juxtaposition of keywords already embraces many diversified fields involving the environment, and does not capture the economic and social implications of sustainability. The Working Party decided to adopt the term green chemistry for the purpose of this overview. This decision does not imply official IUPAC endorsement for the choice. In fact, the IUPAC Committee on Chemistry and Industry (COCI) favors, and will continue to use sustainable chemistry to describe the discipline. 2. J. Elkington, < http://www.sustainability.co.uk/sustainability.htm

The key to waste minimization in fine chemicals manufacture is the widespread substitution of classical organic syntheses employing stoichiometric amounts of inorganic reagents with cleaner, catalytic alternatives. The E factors (by waste per kg product) of chemical processes increase dramatically on going downstream from bulk to fine chemicals and pharmaceuticals, mainly owing to the use of "stoichiometric" methods. The concept of atom efficiency is a useful tool for rapid evaluation of the amount of waste generated by alternative processes. The general theme of atom-efficient, catalytic processes is illustrated with industrially relevant examples. These include catalysis by solid acids and bases, catalytic reductions and oxidations, catalytic C_C bond formation, asymmetric catalysis, biocatalysis, and catalysis in novel media (aqueous and fluorous biphasic systems, supercritical fluids, and ionic liquids).

Green chemistry not only emphasizes the central production process of the "green" chemical, but it ultimately requires a life-cycle conceptual approach for each chemical product. A life-cycle conceptual approach comprises the consideration of all stages along the life cycle of a chemical (i.e., raw material extraction, pre-production, production, use, recycling, and disposal) as well as the consideration of environmental impacts caused by by-products and auxiliaries (such as solvents and additives, but also technical facilities which have to be provided to produce the green chemical). A significant improvement in the evaluation of green chemical products can be approached by the complementary use of the methodologies of life-cycle assessment (LCA) and risk assessment. The use and combination of both methodologies can be performed by a separate use of the instruments (depending on the scope, definition, and application of LCA), an iterative use of LCA and risk assessment, or a complete integration of both instruments. Pros and cons of these approaches are discussed.

Vegetable oils and fats are important constituents of human and animal foodstuffs. Certain grades are industrially used and, together with carbohydrates and proteins, are important renewable resources compared to fossil and mineral raw materials, whose occurrence is finite. In concepts for new products, the price, performance, and product safety criteria are equally important and have a correspondingly high importance right at the start of product development. To ensure a high degree of product safety for consumers and the environment, renewable resources have often been shown to have advantages when compared with petrochemical raw materials and can therefore be regarded as being the ideal raw material basis. Results from oleochemistry show that the use of vegetable fats and oils allows the development of competitive, powerful products, which are both consumer-friendly and environment-friendly. Recently developed products, which fit this requirement profile, are the anionic surfactants cocomonoglyceride sulfate and the nonionic sugar surfactant alkyl polyglycoside. These products are used especially as mild surfactants in cosmetic formulations. In polymer applications derivatives of oils and fats, such as epoxides, polyols, and dimerizations products based on unsaturated fatty acids, are used as plastic additives or components for composites or polymers like polyamides and polyurethanes. In the lubricant sector fatty acid-based esters have proven to be powerful alternatives to conventional mineral oil products.

Environmental pollution and destruction on a global scale have drawn attention to the vital need for totally new environmentally friendly, clean chemical technologies and processes, the most important challenge facing chemical scientists in the field of green chemistry. Strong contenders as environmentally harmonious catalysts are photocatalysts that operate at room temperature and in a clean manner, while applications of such safe photocatalytic systems are urgently desired for the purification of polluted water, the decomposition of offensive atmospheric odors as well as toxins, the fixation of CO 2, and the decomposition of NOx and chlorofluorocarbons on a huge global scale. To address such enormous tasks, photocatalytic systems that are able to operate effectively and efficiently not only under UV light but also under the most environmentally ideal energy source, sunlight, must be established. To this end, we are moving in a positive direction with various practical applications already at hand, as is described. The present report involves 1) new approaches in the design and development of second-generation titanium oxide photocatalysts which can operate effectively under visible light and/or solar beam irradiation, 2) practical industrial applications of titanium oxide photocatalysts in Japan, and 3) recent advances in green chemistry in Japan.

This review outlines several approaches for designing new and environmentally friendly heterogeneously catalyzed oxidation processes for the synthesis of fine and intermediate chemicals. Environmentally benign oxidants such as molecular oxygen, hydrogen peroxide or nitrous oxide can be activated on suitable heterogeneous catalysts showing high activity and selectivity toward the desired oxygenated products. Several examples illustrate that features known from the synthesis of bulk chemicals can successfully be applied for manufacturing intermediate and specialty chemicals applying conventional industrial reactor systems. Direct oxidation of isoprenol, b-picoline, and benzene are chosen as examples for continuous gas-phase processes, oxidation of pinene and propylene as examples for semi-continuous or batchwise processes in the liquid phase.

Recent research progress in catalytic systems for potential use with hydrogen peroxide in industrial chemical synthesis is reviewed, with special focus on work published in the last five years. The main types of chemistry employed are critically appraised regarding their suitability for industrial exploitation. The most significant catalyst types are discussed in terms of the positive features identified to date, and the obstacles yet to be surmounted in order to become more widely adopted. It is believed that fully inorganic systems have more scope for commercialization than those containing organic ligands or supports, however robust. Critical targets are larger-pore analogs of titanium silicalite TS-1, more exploration of smectite-based materials, effective immobilization of activated metal peroxo systems, and improvements in design and manipulation of polyoxometallate compounds. Cooperation between branches of chemistry that have not traditionally worked closely together is advocated.

Basic characteristics of heteropolyacids as green catalysts are overviewed, focusing on the various reaction fields in which the heteropolyacid catalysts function as acid and oxidation catalysts, and then two industrial processes which were made very green by the use of heteropolyacid catalysts in liquid biphase systems are described. In this context an interesting new reaction field formed at the interfacial layer of a solid heteropolyacid and liquid has also been reported.

Tightening environmental legislation is driving the fine and speciality chemicals industries to consider alternative processes that avoid the use of conventional mineral acids. The use of heterogeneous catalysts in these processes would vastly simplify catalyst removal, minimizing the amount of waste formed. However, diffusion limitation of liquids within porous solids dictates that effective solid acids for liquid-phase reactions require the use of mesoporous materials <20_100Å. Recent developments in materials chemistry has led to the discovery of a family of ordered mesoporous silicas which opens up new possibilities for preparing solid-acid catalysts for liquid-phase reactions. This review concentrates on recent developments in the synthesis of new mesoporous solid acids for liquid-phase organic synthesis.

Photochemical reactions are expected to have an increasing role in organic synthesis with the drive towards environment-friendly reactions. Some examples illustrating the scope and versatility of radical alkylation of electrophilic alkenes via photoinduced electron transfer are presented. A few applications in special fields are mentioned.

Neurotoxic organotin reagents currently play a key role in radical chemistry. As a result, this is an important area for development of new clean replacement reactions. The pharmaceutical industry in particular has had to avoid use of radical methodology for the formation of carbon_carbon bonds for this reason. With the current dawn in green chemistry, a host of new clean radical methods is beginning to flourish. Our aim has been to develop new nontoxic methodology for carbon_carbon bond formation by radical chemistry, which would provide either reductive termination (giving a hydrogen atom to the ultimate radical, as happens with tributyltin hydride), or oxidative functionalization, installing a useful polar group at the site of the ultimate radical. Two methods for effecting radical reactions in an environmentally friendly way are presented: (i) The tetrathiafulvalene (TTF)-mediated radical-polar crossover reaction converts arenediazonium salts to aryl radicals, which have sufficient lifetime to cyclize onto alkenes—the resulting alkyl radicals couple with TTF +• to afford sulfonium salts which, in turn, undergo solvolysis to alcohols, ethers or amides. The method provides the key step in a synthesis of (±)-aspidospermidine. (ii) Hypophosphite salts and hypophosphorous acid, on the other hand, form C_C bonds with reductive termination. These economical reagents afford radicals efficiently, starting from aryl iodides, alkyl bromides, and alkyl iodides, and give very easy separation of products from by-products.

Biocatalysis harnesses the catalytic potential of enzymes to produce building blocks and end-products for the pharmaceutical and chemical industry. Located at the interface between fermentation processes and petrol-based chemistry, biotransformation processes broaden the toolbox for bioconversion of organic compounds to functionalized products.

We describe two methodologies for dissolving ionic/polar species in scCO 2 . Both lead to a broadening of the range of applications for scCO 2 . Fluorinated surfactants may be used to prepare water in carbon dioxide microemulsions to allow solubilization of ionic and biological species. We outline also the preparation of scCO 2 soluble metal precursors that can be impregnated efficiently into polymeric substrates. Further processing by heat or UV light leads to metallic particles distributed throughout a polymer substrate. The clean synthesis of such composites can be applied to the development of improved medical implants.

In the last ten years, there has been incredible growth in research involving the use of carbon dioxide as an environmentally benign solvent. This article will highlight polymer synthesis, characterization, and applications in CO 2 and place this research in the context of both green chemistry and the latest developments in CO 2 technology.

This review illustrates how water, as an environmentally friendly solvent, can have significant additional benefits when it is used as a solvent for the Diels_Alder reaction. The mechanism by which the unique properties of water enhance the rate and selectivity are discussed. Also, possibilities for the achievement of further increases in rate and enantioselectivity of aqueous Diels_Alder reactions through Lewis-acid and micellar catalysis are reviewed.

New types of Lewis acids as water-stable catalysts have been developed. Metal salts such as rare earth metal triflates can be used in carbon_carbon bond-forming reactions in aqueous media. These salts can be recovered after the reactions and reused. Furthermore, Lewis acid_surfactant-combined catalysts, which can be used for reactions in water without using any organic solvents, have been also developed. Finally, Lewis acid catalysis in supercritical carbon dioxide has been successfully performed. These investigations will contribute to development of environmentally friendly Lewis acid catalysis.

The recent developments in the field of polyolefin technologies is reviewed in the light of the positive impact that they will have on several aspects of environmental issues.

Ionic liquids, being composed entirely of ions, were once mainly of interest to electrochemists. Recently, however, it has become apparent that, inter alia , their lack of measurable vapor pressure characterizes them as green solvents, and that a wide range of chemical reactions (reviewed here) can be performed in them.

Basic concept of phase-transfer catalysis (PTC), its field of applications and specific features as the most general, efficient, and environment-friendly green methodology of organic synthesis, particularly for industrial processes, is discussed.