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www.rsc.org/greenchem Volume 9 | Number 12 | December 2007 | Pages 1261–1384
Sheldon The E Factor: fifteen years on Cozzi and Zoli Nucleophilic substitution of ferrocenyl alcohols
Fleckenstein and Plenio Aqueous cross-coupling Qi and Jiang Efficient synthesis of β-oxopropylcarbamates
nl This journal is ß The Royal Society of Chemistry 2007 . Netherlands. It soon became clear that tens of kg of waste per kg product was no exception in the fine chemicals industry.4.5-triaminobenzene. We conclude that the E Factor concept has played a major role in focusing the attention of the chemical industry world-wide.3.3 The idea was simple: the more atoms of the syn gas that ended up in the product the better. 2007. the process involved vintage 19th century organic chemistry: oxidation of 2. Sheldon Received 6th September 2007. 1. to address the environmental issues of both chemical products and the processes by which they are produced. NH4Cl. 9.4 At about the same time Trost published his elegant paper5 on the atom economy which became the widely accepted terminology. by analogy with the use of ‘syn gas utilisation’. The guiding principle is the design of environmentally benign products and processes Green Chem.1 2.Sheldon@. 1.tudelft.6-trinitrotoluene (TNT) with potassium dichromate in fuming sulfuric acid (oleum). by Anastas6–10 at the US Environmental Protection Agency (EPA). 1 Phloroglucinol manufacture from TNT.PERSPECTIVE www. 1. in the late 1980s. to propose what we called the E(nvironmental) Factor (kg waste/kg product) for assessing the environmental impact of manufacturing processes and the now well-known Table of E Factors was used to illustrate the problem of waste in different segments of the chemical industry (see later). 40 kg of solid waste containing Cr2(SO4)3. 2628 BL Delft.rsc.1039/b713736m The purpose of this perspective is to review the effect that the E Factor concept has had over the last fifteen years on developments in the (fine) chemical industry and pharmaceutical industry with regard to waste minimisation and to assess its current status in the broader context of green chemistry and sustainability. E-mail: R. at about the same time the concept of green chemistry was being formulated. more sustainable processes. Japan. Biocatalysis & Organic Chemistry. which we used to illustrate this concept. Enter green chemistry and sustainability Interestingly. This process generated ca. and they were subsequently published in 1992. while ethylene utilises only 44%. This led us. Introduction: origins of the E Factor concept The fifteenth anniversary of the publication of the E Factor concept1 seemed like a good moment in time to reflect on the effect it has had on process chemistry and process chemists and the role it may have played in promoting change. was a comparison of the traditional chlorohydrin route to ethylene oxide with the commercial process via oxidation of ethylene with molecular oxygen (see Fig.org/greenchem | Green Chemistry The E Factor: fifteen years on Roger A. 2). It provided. after in situ decarboxylation. followed by Bechamp reduction ´ with iron and hydrochloric acid to give. 1991. In the early 1980s our attention was drawn to the problem of waste in the (fine) chemicals industry by the closure of a phloroglucinol plant at Oce Andeno (later to become part of DSM Fine ´ Chemicals). Delft University of Technology. We presented our concepts at the International Symposium on Catalytic Chemistry for Global Environment in Sapporo. As is shown in Fig. We developed the latter in the late 1970s to roughly assess the commercial viability of various processes for the production of commodity chemicals from syn gas. on the problem of waste generation in chemicals manufacture. The concept was reported in an interview published in 1991. An example.2 Subsequent heating of the acidic solution of the latter afforded phloroglucinol. 1273–1283 | 1273 Fig. FeCl2 and KHSO4 for every kg of phloroglucinol. Accepted 2nd October 2007 First published as an Advance Article on the web 19th October 2007 DOI: 10. although it is also referred to as atom efficiency.A. The plant was shut down because the cost of disposing of the waste was rapidly approaching the selling price of the product. Methanol synthesis. the impetus for developing cleaner. At about the same time we also began using what we called the atom utilisation concept for quickly assessing the environmental acceptability of processes at an early stage. in July. for example. Based on this edifying experience we began an inventory of the amount of waste formed in processes for the manufacture of other fine chemicals and pharmaceutical intermediates and some bulk chemicals. and particularly the pharmaceutical industry. Extension of this concept afforded the idea of using atom utilisation to assess the (potential) environmental acceptability of processes.. involves 100% syn gas utilisation. and continues to provide.
It can be easily calculated from a knowledge of the number of tons of raw materials purchased and the number Table 1 E factors in the chemical industry Product tonnage 106–108 104–106 102–104 10–103 E Factor (kg waste/kg product) . There is one exception: we generally excluded water from the calculation of the E factor. An alternative term. PRODUCTIVELY. minus kilograms of desired product.1 . solvent losses.Fig. 1273–1283 This journal is ß The Royal Society of Chemistry 2007 . 9.9–14 Subsequently. E Factors and atom efficiency as green metrics It is now generally accepted that two useful measures of the (potential) environmental acceptability of chemical processes 1274 | Green Chem.e. in principle. defined as everything but the desired product. has been proposed by Poliakoff et al. Put quite simply. are the E factor.16 which captures the spirit of the twelve principles of green chemistry and can be presented as a single slide. i. all process aids and. According to this definition ‘raw materials’ includes the source of energy.. calculated by dividing the molecular weight of the desired product by the sum of the molecular weights of all substances produced in the stoichiometric equation..1. even fuel (although this is often difficult to quantify). For example. It takes the chemical yield into account and includes reagents. The enormity of the waste problem in chemicals manufacture is readily apparent from a consideration of typical E factors in various segments of the chemical industry (Table 1). The ideal E factor is zero. is sustainable development. when considering an aqueous waste stream only the inorganic salts and organic compounds contained in the water are counted.6. In the last fifteen years the concept of green chemistry has become firmly entrenched in both industrial and academic circles and several books have been devoted to the subject. but from an engineering viewpoint.18–21 defined as the mass ratio of waste to desired product. The E factor is the actual amount of waste produced in the process. One could say that sustainability is our ultimate common goal and green chemistry is the means of achieving it.0.13 A higher E factor means more waste and. Anastas and Zimmerman15 proposed the twelve principles of green engineering which embody the same underlying features—conserve energy and resources and avoid waste and hazardous materials—as those of green chemistry. it is primary pollution prevention rather than waste remediation (end-of-pipe solutions). Green chemistry eliminates waste at source. greater negative environmental impact. the water itself is excluded.1–5 5–50 25–100 Industry segment Oil refining Bulk chemicals Fine chemicals Pharmaceuticals 3. it is kilograms (of raw materials) in. Green chemistry efficiently utilises (preferably renewable) raw materials. divided by kilograms of product out. Prevention is better than cure (the first of the twelve principles of green chemistry). 2007. eliminates waste and avoids the use of toxic and/or hazardous reagents and solvents in the manufacture and application of chemical products. consequently.7. often more favoured by the chemical industry. More recently. and the atom efficiency. Inclusion of water used in the process can lead to exceptionally high E factors in many cases and can make meaningful comparisons of processes difficult. (benign by design) which is embodied in the 12 Principles of Green Chemistry. 2 Syn gas utilisation and atom utilisation. a concept which dates back to the late 1980s and can be defined as:17 Meeting the needs of the present generation without compromising the ability of future generations to meet their own needs. a mnemonic.6 the essence of which can be reduced to the following working definition.
that a paradigm shift was necessary to change from the traditional concepts of process efficiency and optimisation that exclusively focus on chemical This journal is ß The Royal Society of Chemistry 2007 yield of the desired product to one that assigns economic value to eliminating waste and avoiding the use of toxic and/or hazardous chemicals. elegantly promulgated by Trost. The stoichiometric equation for that process is shown in Fig. however. 3 Atom efficiency of stoichiometric versus catalytic oxidation of an alcohol. such as sodium chloride. is effectively the same as EMY. the atom efficiencies of stoichiometric (CrO3) versus catalytic (O2) oxidation of a secondary alcohol to the corresponding ketone are compared in Fig. It was abundantly clear. This is questionable as the environmental impact of such substances is very volumedependent. A theoretical E factor can be derived from the atom efficiency. The nature of the waste All of the metrics discussed above take only the mass of waste generated into account.. the larger E Factors in the fine chemical and pharmaceutical industries are also due to the widespread use of classical stoichiometric reagents rather than catalysts (see later). proposed the effective mass yield (EMY). 15 years ago. we introduced18 the term ‘environmental quotient’.of tons of product sold. The aim was to use this data to drive the greening of the pharmaceutical industry. to benchmark the environmental acceptability of processes used by its members (see the Green Chemistry Institute website). such as sodium chloride. what is important is the environmental impact of this waste. obtained by multiplying the E factor with an arbitrarily assigned unfriendliness quotient. 9. Atom for atom The atom utilisation. It was necessary that enviro-economics become a major driving force in technological innovation. which is the same as Mass Intensity. 2007. In contrast to the E factor. AstraZeneca.24 More recently. e. i. sodium sulfate and ammonium sulfate. The latter include several leading pharmaceutical companies (Eli Lilly. We also note that this method of calculation will automatically exclude water used in the process but not water formed..e. we felt that the lower absolute amounts. therefore. For example. It is perhaps surprising. Schering-Plough and Johnson & Johnson). hence. However.22 for example. 4. i. however.e. should not be used as an excuse for not doing anything to reduce the E Factor of processes in the fine chemicals and pharmaceuticals segments. are formed in the reaction or in subsequent neutralisation and other work-up steps. We hasten to point out. For example. etc. It is interesting to calculate the atom efficiency of the phloroglucinol process discussed above. 1273–1283 | 1275 .. that this situation is rapidly changing and the E factor is being widely adopted by the fine chemicals. Green Chem.. that many companies are not aware of the E factors of their processes. Fig. atom efficiency or atom economy concept. an atom efficiency of 40% corresponds to an E factor of 1. defined as the total mass used in a process divided by the mass of product. 5% which translates to a theoretical E Factor of ca.. These authors also suggest the use of so-called mass productivity. for a particular product or a production site or even a whole company. MI = E factor + 1. Constable and co-workers of GlaxoSmithKline23 proposed the use of mass intensity (MI). Hence. which more clearly reflects the ultimate goal of zero waste. acetic acid. Other metrics have been proposed for measuring the environmental acceptability of processes. the ideal (P)MI is 1 whereas the ideal E Factor is 0. 5. Attempts have also been made to unify the different green metrics. the E factor will generally be much higher since the yield is not 100%. 20. As proposed. i. As is clear from Table 1. it assumes a chemical yield of 100% and exactly stoichiometric amounts and disregards substances which do not appear in the stoichiometric equation. Q.g. As noted above. 3. the nature of the waste must be considered. enormous amounts of waste. Hudlicky and coworkers. and the ideal MI is 1 compared with zero for the E factor. an excess of reagent(s) is used and solvent losses and salt generation during work-up have to be taken into account.25 is an extremely useful tool for rapid evaluation of the amounts of waste that will be generated by alternative processes. 4. However. pharmaceutical and even the bulk chemical industries. whereas in reality it is 40. Merck. It is calculated by dividing the molecular weight of the product by the sum total of the molecular weights of all substances formed in the stoichiometric equation for the reaction involved. One of the reasons that the E factor increases dramatically on going downstream from bulk to fine chemicals and pharmaceuticals is that the latter involve multi-step syntheses and pharmaceutical companies have emphasised that the absolute amount of waste is lower than in bulk chemicals because of the much lower production volumes involved. EQ. it is a theoretical number. In practice. which is the reciprocal of the MI and. One kg of sodium chloride is obviously not equivalent to one kg of a chromium salt. Pfizer. In our opinion none of these alternative metrics offers any particular advantage over the E factor for giving a mental picture of how wasteful a process is. not just its amount. GlaxoSmithKline. Hence. which is defined as the percentage of product of all the materials used in its preparation. it does not include so-called environmentally benign compounds.5 (60/40). This affords an atom efficiency of ca. comprising primarily inorganic salts.e. compared with bulk chemicals. the Green Chemistry Institute Pharmaceutical Round Table has used the Process Mass Intensity (PMI).
possible. The role of catalysis As noted above. nitrations. diazotisations and Friedel–Crafts acylations. KOH. ZnCl2. such as NaOH. been widely applied in the manufacture of bulk chemicals. the waste generated in the manufacture of organic compounds consists primarily of inorganic salts. Examples which readily come to mind are stoichiometric reductions with metals (Na.. there are still some processes which use stoichiometric inorganic reagents 6. This is important when considering biocatalytic processes (see later). O. in propylene oxide manufacture via the chlorohydrin route. Zn. such as H2SO4. a multitude of reactions. It is also worth noting that Q for a particular substance can be both volumedependent and influenced by the location of the production facilities. BF3) are major sources of waste. sulfonations. 2007. 4 Stoichiometric equation of the TNT to phloroglucinol process. Ironically. importantly. The solution is 1276 | Green Chem. O2. evident: substitution of antiquated stoichiometric methodologies with cleaner catalytic alternatives. ease of recycling. low-salt processes. on the other hand. and could be given a Q of zero. NaBH4). 9. Fe) and metal hydride reagents (LiAlH4. depending on its toxicity. a major challenge in chemicals manufacture in general is to develop processes based on H2. C and N. which combines an oxidation with stoichiometric amounts of chromium(VI) with a stoichiometric reduction with Fe/HCl. when very large quantities of sodium chloride are generated the Q value could decrease again as recycling by electrolysis becomes a viable proposition. oxidation and carbonylation (Fig. This is a direct consequence of the use of stoichiometric inorganic reagents in organic synthesis. etc. This journal is ß The Royal Society of Chemistry 2007 . H2O2. CO. employing stoichiometric amounts of mineral acids (H2SO4. The generation of 10 000 tons per annum. oxidations with permanganate. 5) are good examples of highly atom efficient. e. 100–1000 to a heavy metal salt. HF. say.g. Catalytic hydrogenation.26 7. in our experience. one could arbitrarily assign a Q value of 1 to NaCl and. for economic reasons. We also mention that. Indeed. Although catalytic processes have. Similarly. generally speaking the Q value of a particular waste will be determined by its ease of disposal or recycling. manganese dioxide and chromium(VI) reagents. the generation of 100–1000 tons per annum of sodium chloride is unlikely to present a waste problem. organic waste is. such as chromium. The generation of copious amounts of inorganic salts can similarly be largely circumvented by replacing stoichiometric mineral acids. particularly in fine chemicals and pharmaceuticals manufacture. 1273–1283 Fig. halogenations. with recyclable solid acids and bases. Bulk chemicals: propylene oxide and caprolactam The waste problem is not limited to fine chemicals. CO2 and NH3 as the direct sources of H. H3PO4) and Lewis acids (AlCl3.. ‘quantitative assessment’ of the environmental impact of chemical processes is. For example. in principle. A classic example is the phloroglucinol process discussed above. The magnitude of Q is obviously debatable and difficult to quantify but. Mg. preferably in catalytic amounts. e.g.Fig.. Thus. may already present a disposal problem and would warrant assignation of a Q value greater than zero. generally speaking. 5 Atom efficient catalytic processes. more easy to dispose of than inorganic waste. and Lewis acids and stoichiometric bases.
7). The chlorohydrin route. 4. which involves combining the Enichem technology31 for ammoximation of cyclohexanone with NH3–H2O2 over the titanium silicalite catalyst (TS-1) with a novel vapour phase Beckmann rearrangement over a high-silica MFI zeolite. Headwaters Technology Innovation (HTI) received a 2007 Presidential Green Chemistry Challenge Award for the development of a palladium–platinum nanocatalyst. BASF. producing cyclohexanone oxime. it is essentially salt-free. 7 Sumitomo caprolactam process. It was gratifying.5 kg of ammonium sulfate per kg of caprolactam (Fig.. The conventional process involves the reaction of cyclohexanone with hydroxylamine sulfate (or another salt).1–5 in Table 1).e. The overall process generates ca. with water as the sole by-product (Fig. In contrast. 2007. This process is now being commercialised in partnership with Degussa (now Evonik). catalytic process (see Fig. which generates ca. Since such Fig. 7). in partnership with Dow Chemical. hydrogen and oxygen. Although catalytic oxidation is widely applied in the bulk chemicals industry27 there are still a few processes which use stoichiometric inorganic oxidants. It has been known since the mid-eighties that titanium silicalite. based on H2O2 (Fig. In the bulk chemicals arena it is used. that the Sumitomo scientist. 7). the raw material for nylon 6. This journal is ß The Royal Society of Chemistry 2007 Green Chem. 1273–1283 | 1277 . for the production of acetic acid by rhodium-catalysed carbonylation of methanol.28 is able to catalyse the epoxidation of propylene with the green oxidant hydrogen peroxide. for example. therefore. 2 kg of CaCl2. 6). the Sumitomo process generates two molecules of water as the sole co-product. 4 million tons of propylene oxide produced annually.and generate several kg of waste per kg of product (hence the range of .32 affording caprolactam in .30 Similarly. A case in point is propylene oxide manufacture. which is subjected to the Beckmann rearrangement in the presence of stoichiometric amounts of sulfuric acid or oleum. but the latter was too expensive for this application.. i. have similarly commercialized the Enichem epoxidation technology but without the added benefit of direct formation of hydrogen peroxide from hydrogen and oxygen.98% yield based on cyclohexanone and 93% Fig. However. Catalytic C–C bond formation C–C bond formation is a key transformation in organic synthesis and an important catalytic methodology for generating C–C bonds is carbonylation. developed by Enichem. 8. Sumitomo has commercialised a process for caprolactam. used the E Factor to illustrate the difference between the classical and the new. which enables the direct synthesis of hydrogen peroxide from hydrogen and oxygen in high selectivity below the flammability limit of hydrogen. accounts for more than half of the ca. Ichihashi. 9.29 Combination of this with the Enichem technology enables the direct synthesis of propylene oxide from propylene. 6 Different processes to propylene oxide. The rest is produced by so-called coproduct processes which use oxygen as the primary oxidant but generate tert-butanol or styrene as the co-product.
However. that olefin metatheses.38 Its importance was underpinned by the award of the 2001 Nobel Prize in Chemistry to Knowles.37 When a chiral molecule exhibits biological activity the desired activity almost always resides in one of the enantiomers and the other enantiomer is at best isomeric ballast that does not contribute to the desired effect. pharmaceuticals and pesticides. 1273–1283 9. i. 8 Hoechst–Celanese process for ibuprofen. 10 Olefin metathesis reactions. Fig. Following its discovery in the 1960s olefin metathesis was applied to bulk chemicals manufacture. for economic and environmental viability. Chirotechnology and asymmetric catalysis At roughly the same time that waste minimization was becoming an important issue enantiomeric purity of biologically active agents. it took about thirty years before sufficient regulatory pressure stimulated the shift towards marketing drugs in enantiomerically pure form. 100% atom efficient synthesis of a-amino acid derivatives from an aldehyde. 9. although this effect of chirality on biological activity was already known in the 1960s. chiral organocatalysts.. We noted in 1993 that ‘‘the current climate of ‘environmentality’ is precipitating a dramatic move towards enantiomeric purity in bioactive agents’’. are often not 100% atom efficient in that they produce an olefin co-product. 9 Palladium-catalysed amidocarbonylation. Another elegant example is the palladium-catalysed.33 This process replaced a more classical route which involved more steps and a much higher E factor. using enzymes (see later). Grubbs and Schrock for the development of the olefin metathesis reaction. 8) with 100% atom efficiency. in the last two decades there has been a marked trend towards marketing chiral pharmaceuticals and pesticides as pure enantiomers. Consequently. onestep. a prominent example being the Shell Higher Olefins Process (SHOP). was becoming the focus of regulatory attention. This has manifested itself in the last 15 years in increasing attention for enantioselective catalysis. Indeed. with an annual production of several thousands tons.. the most well-known example being the thalidomide tragedy in the 1960s. in turn. In this process ibuprofen is produced in two catalytic steps (hydrogenation and carbonylation) from p-isobutylacetophenone (Fig.g.35 It should be noted. In the worst case scenario it may exhibit toxic side-effects. e. The importance of olefin metathesis as a pre-eminent. that function in the presence of most functional groups. ibuprofen. in particular the ruthenium-based ones developed by Grubbs. Noyori and Sharpless for their contributions to enantioselective catalysis. as Noyori has recently noted. This journal is ß The Royal Society of Chemistry 2007 . 10). This. Fig. 9). generated a need for economically viable methods for their synthesis. reactions are 100% atom efficient they are increasingly being applied to fine chemicals manufacture.e. green methodology for the formation of C–C bonds under mild conditions was underpinned by the award of the 2005 Nobel Prize in Chemistry to Chauvin. paved the way for widespread application of olefin metathesis in the synthesis of complex organic molecules. however. CO and an amide (Fig.34 No discussion of catalytic C–C bond formation would be complete without a mention of olefin metathesis in its many forms: cross metathesis (CM).Fig.. more recently. ring opening metathesis (ROM). 1278 | Green Chem. Pregnant women who received this drug in racemic form gave birth to deformed babies as a result of the mutagenicity of the ‘‘wrong’’ enantiomer. An elegant example of this is the Hoechst–Celanese process for the manufacture of the analgesic. in contrast to carbonylations. ring closing metathesis (RCM). Here again. 2007. processes need to be atom efficient and have low E factors. chiral metal complexes or. According to the Swedish academy olefin metathesis is ‘‘a great step forward for green chemistry’’. they should employ catalytic methodologies.39 asymmetric hydrogenation is ideal green chemistry.36 In the succeeding decades the development of catalysts. ring opening metathesis polymerization (ROMP) and acyclic diene metathesis (ADMET) (Fig.
e. in contrast.. with a target for the future of 4 l kg21. have been blacklisted that the whole question of solvent use requires rethinking and has become a primary focus. i. a heterogeneous catalyst. This eliminated the need to use. not resulted in commercially viable processes. therefore. poor catalyst productivities. The question of solvents: non-conventional reaction media Another important issue in green chemistry is the use of organic solvents. The subject of alternative reaction media also touches on another issue that is important from both an environmental and an economic viewpoint: recovery and re-use of the catalyst.40. Attempts to heterogenise homogeneous catalysts by attachment to organic or inorganic supports have. 85% of the total mass of chemicals involved in pharmaceutical manufacture comprises solvents. The E Factor for the current process is 6. Two elegant examples of highly efficient asymmetric catalysis on a multi-thousand tons per annum scale. for a number of reasons. provide for their efficient removal from the product and re-use. Indeed. However.14 are the Takasago l-menthol process and the Syngenta (S)-metalochlor process. The conclusion is evident: we need to maintain the advantages of homogeneous catalysts while providing for facile separation of product and catalyst. tetrahydrofuran. It is also worth noting that in the redesign of the sertraline manufacturing process. Alternative solvents should. biomassbased raw materials. non-inflammable. if details were not known. ideally.43 for which Pfizer received a Presidential Green Chemistry Challenge Award in 2002. is easily separated by centrifugation or filtration. Similarly. toluene and hexane). Pfizer workers also reported44 impressive improvements in solvent usage in the process for sildenafil (Viagra) manufacture reducing the solvent usage from 1700 l kg21 of product used in the medicinal chemistry route to 7 l kg21 in the current commercial process. polar aprotic solvents have stimulated the fine chemical and pharmaceutical industries to seek more benign alternatives. the catalyst solution remains in the reactor and is re-used with a fresh batch of reactants without further treatment or. Inexpensive natural products such as ethanol have the added advantage of being readily biodegradable and ethyl lactate. such as chlorinated hydrocarbons. abundantly available and inexpensive.41 In our original studies of E factors of various processes we assumed. 11 Enantioselective catalysis in (S)-metolachlor and l-menthol manufacture. There is a marked trend away from hydrocarbons and chlorinated hydrocarbons towards lower alcohols. presents more of a problem and a serious shortcoming of homogeneous catalysis is the cumbersome separation of the catalyst from reaction products and the quantitative recovery of the catalyst in an active form. among other improvements a three-step sequence was streamlined by employing ethanol as the sole solvent. produced by combining two innocuous natural products. Furthermore. In pharmaceuticals manufacture quantitative separation of the catalyst is also important in order to avoid contamination of the product. in which an enantioselective isomerisation and an enantioselective hydrogenation are the key steps. supercritical CO2. Obviously. 1273–1283 | 1279 . The best solvent is no solvent and if a solvent (diluent) is needed then water has much to offer: it is non-toxic. the organic chemist’s penchant for using different solvents for the various steps in multi-step syntheses makes recycling difficult owing to cross contamination. performing the reaction in an aqueous biphasic system. distil and recover four solvents (methylene chloride. The problem with solvents is not so much their use but the seemingly inherent inefficiencies associated with their containment. especially in the fine chemicals industry.. both solvents are subject to the same restrictions as discussed above for monophasic systems. in some cases. it is adapted to continuous operation. irreproducible activities and selectivities and degradation of the support. generally speaking. respectively (Fig. which we have discussed in detail elsewhere. esters and.45 We also note that the use of water and supercritical carbon dioxide as reaction media is consistent with the current trend towards the use of renewable. fluorous biphasic. ethers. recovery and re-use.46 whereby the catalyst resides in the water phase and the product is dissolved in the organic phase. is currently being touted as an environmentally attractive solvent for chemical reactions. 11).Fig. whereby the catalyst is dissolved in one phase and the reactants and product(s) in the second liquid phase. which are ultimately derived from carbon dioxide and water. A homogeneous catalyst. Preferably. and ionic liquids and multiphase homogeneous catalysis has become an important area of research. 9. 2007. Several different combinations have been intensely studied in recent years. The catalyst is recovered and recycled by simple phase separation. placing it more in This journal is ß The Royal Society of Chemistry 2007 the lower end of fine chemicals rather than with typical pharmaceutical manufacturing processes. An insoluble solid. These issues surrounding a wide range of volatile and nonvolatile. So many of the solvents that are favoured by organic chemists. it has been estimated by GSK workers42 that ca. including water (aqueous biphasic). The benchmarking exercise performed by the GCI Pharmaceutical Round Table (see above) revealed that solvents were a major contributor to the E Factors of pharmaceutical manufacturing processes. 10. such as leaching of the metal. allows for Green Chem. that solvents would be recycled by distillation and that this would involve a 10% loss. This can be achieved by employing liquid–liquid biphasic catalysis.
. therefore.. 0. An example of a large scale application of this concept is the Ruhrchemie/Rhone Poulenc process for the ˆ hydroformylation of propylene to n-butanal. Furthermore.g. in principle. In contrast. 8. enabling their facile separation. for which Codexis received a 2006 Presidential Green Chemistry Challenge Award. in fermentation processes.6 kg Me3SiCl. a key raw material for semi-synthetic penicillin and cephalosporin antibiotics. i. Biocatalysis Biocatalysis has many attractive features in the context of green chemistry: mild reaction conditions (physiological pH and temperature). It involved the use of environmentally unattractive reagents. by hydrolysis of penicillin G. 13). a chlorinated hydrocarbon solvent (CH2Cl2) and a reaction temperature of 240 uC. which employs a water-soluble rhodium(I) complex of trisulfonated triphenylphosphine (tppts) as the catalyst and has an E Factor of 0.57 Up until the mid-1980s a chemical procedure was used for this hydrolysis (Fig.2 kg PCl5.e. In the case of dead cells. 12). enzymatic cleavage of penicillin G (Fig.4 l of n-BuOH and 8. to manipulate enzymes such that they exhibit the desired substrate specificity. The time is ripe for the widespread application of biocatalysis in industrial organic synthesis. generate less waste and are. the development of effective immobilisation techniques has paved the way for optimising the performance and recovery and recycling of enzymes.. 1. Advances in recombinant DNA techniques have made it. production of chemicals This journal is ß The Royal Society of Chemistry 2007 . an environmentally compatible.52 have also been extensively studied.42 e. be used as a source of energy for the process.56 An illustrative example of the benefits to be gained by replacing conventional organic chemistry by biocatalysis is provided by the manufacture of 6-aminopenicillanic acid (6-APA). etc.50 and ionic liquids.e. using techniques such as site directed mutagenesis and in vitro evolution.. to adjust the pH. as well as biphasic mixtures of these alternative media. and other alternative reaction media. The enzymatic process currently accounts for the majority of the several thousand tons of 6-APA produced annually on a world-wide basis. subsequent enzymatic coupling of the side-chain to the 6-APA nucleus or the related 7-amino desacetoxycephalosporanic acid (7-ADCA) has replaced chemical coupling in the synthesis of certain semi-synthetic penicillins and cephalosporins. In a recent variation on this theme. we have reported examples of aqueous biphasic carbonylations and oxidations. Thus..58 In contrast.6–0. This affords processes which are shorter.59 12. regio.57 An example of what can be achieved by applying modern biotechnology to biocatalysis is provided by the process developed by Codexis for the production of an intermediate for Pfizer’s blockbuster drug Atorvastatin (Lipitor).6 kg PhNMe2.. To our knowledge there are no reported E Factors for fermentation processes. that the waste biomass is generally easy to dispose of. The process. involved three enzymatic steps (Fig. pH profile. We note.2 kg NH3.53 the so-called ‘miscibility switch’ was used to perform a catalytic reaction smoothly in a monophasic ionic liquid– scCO2 mixture. however. Biocatalytic processes can be performed with isolated enzymes or as whole cell biotransformations.and stereoselectivities in reactions of multifunctional molecules.recovery and recycling of the catalyst by simple phase separation. activity. Isolated enzymes have the advantage of not being contaminated with other enzymes present in the cell while the use of whole cells is less expensive as it avoids separation and purification of the enzyme. when growing microbial cells are used.54 Fig. 2007.1 compared with 0. 1273–1283 possible to produce virtually any enzyme for a commercially acceptable price and protein engineering has made it possible.49 supercritical carbon dioxide. both environmentally and economically more attractive than conventional routes. such as fluorous biphasic systems. biodegradable catalyst (an enzyme) and solvent (water) combined with high activities and chemo-. the use of enzymes generally circumvents the need for functional group activation and avoids the protection and deprotection steps required in traditional organic syntheses. This would seem to be a hiatus which needs to be filled. whereby a switch from a low-polarity form to a high-polarity form is achieved upon treatment with carbon dioxide at atmospheric pressure. all of which were optimised by in vitro evolution of the individual enzymes using gene shuffling.51.55 Furthermore.g. substantial amounts of biomass can be generated as waste but little attention has been paid to this aspect. in principle. i. 0. an ionic liquid with scCO2.4 l of CH2Cl2 were required to produce 1 kg of 6-APA. as animal feed. Subsequent lowering of the pressure afforded a biphasic system whereby the catalyst was contained in the ionic liquid phase and the product in the scCO2 phase.47 Similarly.48 An aqueous biphasic system is not the answer in all cases. 9. or can. 12) is performed in water at 37 uC and the only reagent used is NH3 (0. Similarly. 1280 | Green Chem. Chemicals from renewable raw materials: biomass utilisation Another important goal of green chemistry is the utilisation of renewable raw materials. 1. however. e. stability. the E Factors of the two methods are essentially the same: the waste cell debris is separated before or after the biotransformation. 11. 12 Enzymatic versus chemical deacylation of penicillin G. Another approach worthy of mention is the use of amidine/alcohol or guanidine/alcohol mixtures as ‘‘switchable solvents’’.09 kg per kg of 6-APA).9 for conventional monophasic hydroformylation processes.
The E Factor provided a very simple means of measuring one’s performance and has been adopted by the chemical industry world-wide for this purpose.g. Chem. that is low E Factors.65 These processes will also have to be efficient in raw material utilisation and generate minimum waste. as its measuring staff. corn stover. which are depolymerised to fermentable sugars. dehydration and/or hydrogenation. i. 903–906.. 1471–1477. Trost. from biomass rather than fossil resources such as oil.. In the short term maize is being used as a renewable raw material to produce bioethanol and chemicals such as lactic acid and 1. 1991. in turn. This will be necessary to avoid the food versus fuel dilemma. in Ullmann’s Encyclopedia of Industrial Chemistry. 347. 4 C. Science. By publishing the table of E Factors we challenged the fine chemical and pharmaceutical industries to make the paradigm shift from a concept of process efficiency which was exclusively focused on chemical yield to one that is motivated by elimination of waste and maximisation of raw materials utilisation. Looking to the future. Fig. Different value chains will be formed.e. Caruana. Progr. 2007. Eng. The fact that the absolute amounts of waste generated in these sectors are lower than those in the bulk chemicals industry should not be used as an excuse not to address this issue. the processes used for the conversion of renewable feedstocks—mainly carbohydrates but also triglycerides and terpenes—should produce minimal waste. i. is the key to sustainability.64 Whichever approach is used. p.g. There is a clear need for a meaningful metric for comparing different methodologies for biomass conversion. H. 9. respectively. the lignocellulose is hydrolysed to liberate the lignin.3-propane diol and acrylic acid.3-propanediol but it is clear that lignocellulosic materials. 1273–1283 | 1281 . Conversion of lignocellulosic biomass in biorefineries could involve thermochemical and/or biotechnological processes. 1991. pyrolysis or gasification of lignocellulose affords pyrolysis oil or syn gas.. a recent publication from members of the ACS GCI Pharmaceutical Round Table identified a list of key areas where further improvement is most needed. 1983. Sheldon. coal and natural gas. 254. based on coal gasification. Chemicals from Synthesis Gas. here again optimum biomass utilisation and minimisation/elimination of waste. and polysaccharides. Miki and Y. or dedicated energy crops will be the feedstocks for second generation biofuels and biobased commodity chemicals.61 In the former.e. the displacement of archaic ‘‘stoichiometric’’ technologies by greener catalytic alternatives and the replacement of toxic and/or hazardous solvents and reagents with cleaner alternatives will continue to be important drivers.62 Metabolic pathway engineering63 is used to optimise the production of the required product based on the amount of substrate (glucose) consumed. or its direct equivalent. which can be used as an energy source. Here again.3 In the biotechnological approach. A. two other more recent trends will gain in importance. This is currently the focus of considerable attention and is perceived as the key to developing a sustainable source of liquid fuels and chemicals. Fine chemical and pharmaceutical companies always knew that their manufacturing processes were generating substantial quantities of waste but putting a number to it via the conception of the E factor really brought the message home. 87(12). Dordrecht. 13. e. flavours and fragrances and industrial monomers will be produced in biorefineries.. form the raw material for other bulk chemicals such as 1. A19. can be used to convert the syn gas to liquid fuels or chemicals. 2 See T. p. 1992. specialty chemicals such as vitamins. vol. Ind. the monosaccharides can be converted to valuable chemicals by chemical catalysis. M. available as agricultural waste. In addition. a direct consequence of the recent enormous increase in biodiesel production is that the coproduct. glycerol. Chem.and 1. Reidel. Green Chem. Conclusions and future outlook As Lord Kelvin said: ‘‘To measure is to know’’. In the case of syn gas. and second the development of new products that are biocompatible and biodegradable and are also produced from renewable resources by green catalytic processes with low E Factors. A so-called biobased economy is envisaged in which commodity chemicals (including biofuels). The pharmaceutical industry in particular has made substantial progress in the last few years and has adopted the E Factor.2. 1991. A.. For example. 11–13. (London). Iwata. 13 Codexis process for atorvastatin intermediate. Sheldon. the atom efficiency. the change from fossil fuels to renewable resources as feedstocks for existing products. has become a low-priced commodity chemical which could.67 The impact of the E Factor has not been restricted to the fine chemicals industry but has also played a broader role as a ‘‘measure of the efficiency of the chemical industry’’68 and. Alternatively.. 15.chemical and allied industries. M. The (partial) shift from oil to biomass as a raw material will have far reaching consequences for the structure of the This journal is ß The Royal Society of Chemistry 2007 References 1 R.60. Fujita. 5 B. This was underscored by the recent statement: ‘‘Another aspect of process development mentioned by all pharmaceutical company process chemists who spoke with C&EN is the need for determining an E Factor’’. 3 R. will continue to do so as the chemical industry progresses towards being a sustainable enterprise. First.66 Similarly. the technologies developed in the 1970s. they should be preferably catalytic in order to be sustainable. e. hopefully.
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