Science advances on Environment, Toxicology & Ecotoxicology issues www.chem-tox-ecotox.org “Laboratory experiments of organic synthesis and decomposition of hazardous environmental chemicals following green chemistry principles” A. Valavanidis,Th.Vlachogianni and K. Fiotakis Department of Chemistry, University of Athens, University Campus Zografou, 15784 Athens, Greece E-mail: [email protected], [email protected], [email protected] Abstract The basic principles of Green Chemistry cover a wide range of issues for Organic Synthesis of chemical compounds: design of organic synthesis processes to maximize prevention of waste, atom economy, the use of less hazardous chemicals and safer or environmentally benign solvents, renewable raw materials, energy efficiency and catalysis. Also, Green Chemistry is interested for the best form of waste disposal and design for degradation of chemical products after use, complying with pollution prevention measures and sustainable development. In the present paper we offer some important examples of Organic Synthesis with innovative “greener” techniques which can be used for teaching or/and applying in a chemical laboratory of a university. The “greener” organic synthesis of IBUPROFEN (active ingredient of many painkillers) is a typical example. The original synthetic route involved six consecutive steps and an overall atom efficiency of only 40%, while 60% of the mass of atoms ended up in waste products. The organic synthesis of Adipic acid (AA), a feedstock used to make nylon, using better oxidizing agents, a reaction without organic solvents and much less waste than the conventional route. The synthesis of Maleic Anhydride (MA), widely used in the manufacture of polyester resins and paints, is an example of replacement of dangerous starting chemical, the best selectivity and the “greener” synthetic route. Microwaveassisted organic reactions is another example that can apply to teaching laboratories, as well as ultrasound-assisted organic synthesis. Organic chlorinated chemical solvents are by far the most dangerous environmental pollutants because of the low biodegradability and their accumulation potential in soil, water and biological tissues. Chlorinated liquid wastes from organic is an important environmental issue. Various green methods have been used to decompose chlorinated solvent waste, using ultrasound to cleanup waste waters containing chlorinated organic compounds. This method has practical applications and can be used efficiently in the management of chemical liquid waste. These examples can be presented in laboratory classes for undergraduates and post graduates with the aim to promote and enhance the perception of Green Chemistry principles to students and scientists working in Organic Synthesis. In the 1990s the BHC Co developed a new greener industrial synthesis of Ibuprofen that had only three synthetic steps. The process has very good atom economy. Ibuprofen is also a member of non-steroidal antiinflammatory drugs. If reactions could be optimised to prevent the formation of by-products. designed to maximize efficiency and reduce waste. The old method starts from the compound 2-mehtylpropylbenzene that can be made from chemicals separated from crude oil. then purification processes would be eliminated. atom economy and use of less hazardous chemicals in synthetic methods. a terminology used as one of the principles of Green Chemistry that must be improved. England. One of the problem with the old synthetic method is that is a multi-step synthesis and produces overall a low yield. The traditional industrial synthesis of Ibuprofen (Boots Co. Nurofen) was a six-step process. Large quantities are used in isolation. reducing the waste which has to be disposed [8. Also. Green Chemistry promotes changes to attitudes among research chemists and managers of chemical industry to approach chemical processes in a more constructive way. such as aspirin. recent developments in green synthesis of organic compounds give the opportunity to introduce the new “thinking” in university teaching laboratories and laboratories in the chemical industry [2. In terms of atom economy the method is wasteful because in every step many of the atoms of the reactants used do not appear in the final 2 . The chemical industry has made great improvements in the efficiency of its processes. 1960s. separation and purification of materials.9]. In recent years. Finding also environmentally benign solvents is another important problem for chemistry experiments[5-7]. involving economical synthesis. Although every new chemical process is very difficult to satisfy all principles of Green Chemistry. catalysis. resulting in only small amounts of unwanted byproducts. Energy efficiency is another filed that that new methodologies must take into account. but finite natural resources will inevitable limit the ability to manufacture in wasteful ways. In this process.Introduction Organic Synthesis of chemical compounds. Panadol. Οld and new “greener” synthesis of anti-inflammatory drug Ibuprofen Pharmaceutical drugs has become a booming business and their sales have more than quadruplet since 1985. protection of the health of workers and prevention of pollution [1]. most of the toms of the reactants are incorporated in to the product. The old catalysts were traditionally metals which are toxic and scarce. The reactions involved in the synthesis of chemical products must minimize environmental impact and waste. acetaminophen and ibuprofen. energy efficiency.3]. branded products: Aspro. it must comply with some of them to be greener compared to older ones. renewable raw materials. If each step has a yield of 90% then the second step will be 90X90 = 81%. less waste. Many solvents that are used at present in the chemical industry and in research laboratories are very flammable and toxic. resulting in large quantities of chemical byproducts which had to be disposed causing an acute problem of chemical waste and pollution. A very well known group of drugs are analgesics. environmentally benign chemical techniques are growing in importance in academic and industrial research laboratories. environmentally benign solvents. The challenge for both academic and industrial laboratories is to devise sustainable strategies that meet the demand of chemical products from an ever.increasing population [4]. design for degradation of chemical products after use and pollution prevention for sustainable development. In general the old organic synthesis of Ibuprofen had very poor atom economy. so non-metallic catalysts must be developed (organocatalysts or enzymes) which perform useful catalytic functions. include prevention of waste. the use of safer. the overall figure is 40%. carcinogenic chemical). The green synthesis of Ibuprofen (after the patent ran out in the mid-1980s) was able to be developed by alternative synthetic methodology. and every step has to start with fresh materials.000 tones are made per year (only in the United Kingdom). In the past industrial synthesis of adipic acid used benzene as a starting material (non-renewable. efforts have been 3 . Later.000 million kilograms because it is used for the production of Nylon 6. the industrial process of manufacturing Adipic acid involved oxidation of cyclohexanone or a cyclohexanone/cyclohexanol mixture with nitric acid. CO/Pd). with higher atom economy (77% yield) and less waste (using catalysts. which inevitable produces NOx (nitrous oxide. especially if we consider that 3. The new method was with the same starting material but in three steps. In the last few years. But the most important was that reagents and products are the same in each step and only the catalyst differs. Figure 1. which was the product of petroleum refining.6 and catechol which is used as a building block for pharmaceuticals and pesticides.product. which means that more than half the materials are wasted. such as Raney Nickel. Old and new “greener” synthetic route for Iboprufen Experimental section Synthesis of Adipic Acid with an environmentally benign method Adipic acid is produced annually in excess of 2. which contributes to global warming and ozone depletion) as a by-product. Finally. In the old method the AlCl3 is not a “true” catalyst and has to be disposed in landfill sites. The catalysts used in the green synthesis can be recovered and reused so that it generates no waste. accomplished in a greener. Summer of 1998 Awards in the US [14-16]. The case of Adipic acid has become in recent years the typical green chemistry synthesis in the organic teaching laboratory. The mixture is a milky white colour. cyclohexanone and 1. iv) 0. Also. iii) 6.19 of potassium hydrogen sulfate (KHSO4).25 of Aliquat 336 (phase transfer catalyst) which is a viscous liquid.5 mL) of 30% H2O2 (carefully. After 45 minutes remove the flask and cool it for 3 minutes. Connect an air condenser. ii) 0.0 g of Cyclohexene.coli). clean. i) Add in the following order: 0. causes burns in contact with skin). The scientist who developed this biocatalytic synthesis won the Presidential Green Chemistry Challenge Awards Program. C.0 g (5. such as Tungsten catalysts (Na2WO4 / KHSO4/ Aliquat 336 [11. v) mix the components by swirling the vial for 10 sec and add 1. Traditional route and “greener” synthetic route of Adipic acid New greener methods for the synthesis of adipic acid by oxidation with hydrogen peroxide have been developed ever since by various researchers. using oxpoero tungsten and molybdenum complexes for the oxidation of cyclohexene. Slowly in the beginning for one minute and then more vigorously. scientists developed new biocatalytic synthesis of adipic acid from D-glucose which uses genetically engineered Klebsiella pneumoniae (a non-virulent strain of E.12] Figure 2. and can be added with a small Pasteur pipette. synthesis of adipic acid that is less damaging to the environment with the use of catalysts [10]. Heat the mixture gently.and halide-free conditions and the use of novel catalysts. The method is simple and can be applied to a teaching laboratory of organic synthesis [17]. place in the flask on the Al block and start stirring the reaction mixture.25 g of sodium Tungstate dehydrate. Adipic acid (AA) synthesis A. In a dry 25 mL screw-capped round bottom flask add a special magnetic bar. under organic solvent. B. With a pipette transfer 4 . The first alternative method was the use of cyclohexene or cyclohexanone that can be oxidized directly to colourless crystalline adipic acid with aqueous 30% H2O2. cyclohexanol.2-cyclohexanediol with yields in the range of 45-86% [13]. ”.7% B. Product mass = (6C)(12) (10H)(1) (4O)(!6) = 146 g Reactant mass = (6C)(12) (18H)(1) (9O)(16) (2N)(14) = 262 g Mass efficiency = 146/262 X 100 = 55. Transfer on a clean watch glass.3 g of crude product). and the released N2O contributes to global warming and ozone depletion. place the beaker on ice. rinse the beaker with 2 mL ice-cold water. Maleic 5 .the cloudy mixture to a smaller beaker. Product mass = (6C)(12) (10H)(1) (4 O)(16) (2N)(14) = 146 g Reactant mass = (6C)(12) (18H)(1) (8 O)(16) = 218 g Mass efficiency = 146/218 X 100 = 67% It is realized that mass efficiency is 11% higher than the traditional route. et al. Stir and heat the mixture at 80-100 oC. Maleic Anhydrite synthesis under Green Chemistry principles Another very useful example of organic synthesis for teaching student on the advantages of green chemistry principles. 281: 1646-1647. nitric oxide is hazardous. Allow to cool 5-10 min.1%) C6H12O + 2 HNO3 + H2O → C6H10O4 + NOx (NO. AA starts to precipitate. Leave the sample on the funnel for 5 min. especially from the environmental and economic point of view. N2) In this method. Isolate the crystalline product by filtration on a Büchner funnel. heat again. 1998 ) C6H10 + 4 H2O2 →catalysts→ C6H10O4 + 4 H2O The new route does not produce hazardous chemicals yield of adipic acid is 90%. dry it in an oven (at 115 oC) for 10-15 min. A “green” route to adipic acid….1-05% and V (0. some stuck to the flask and stir bar) Cool the beaker on ice for 10 minutes. Recrystallization. is the synthesis of Maleic Anhydride (MA) (cis-butenediol acid. Science. Cool and determine its weight and melting point. Isolate the crude AA by filtration on a Büchner funnel. trying to avoid the Aliquat 336 catalyst (liquid layer on the top of the aqueous mixture. New greener route from cyclohexene with hydrogen peroxide and the catalyst Na2WO4. Cool again.2H2O (1%) and [CH3(n-C8H17)3N] HSO4 (1%) (Sato. N2O. The recrystallization with deionized water (1 mL for every 2. Precipitation as white crystal. Traditional Route from mixture of cyclohexano0ne/cyclohexanone with oxidation by nitric acid (in the presence of metals Cu (0. The yield of the reaction is 92-96%. E.02-0. C4H4O4). Add more water if acid do not dissolve. scratch the inside of the beaker with a glass rod. Rinse with cold water. A. NO2. The synthesis of Adipic acid with the traditional and the new route can be considered also for atom (or mass) efficiency. I du Pont de Nemours and Co (Wilmigton. fixed bed reactor C4H10 + 3. New process: Butane feedstock. Delaware.4-butanediol (used in polyurethane industrial process and in the preparation of butyrolactone (a solvent and paint remover). fixed bed reactor 2 C6H6 + 9O2 (air) → catalysts → 2 C4H2O3 + H2O + 4 CO2 The reactions has 95% yield Product mass: 2(4)(12) 2(3)(16) 2(2)(1) = 196 Reactant mass: 2(6)(12) 9(2)(16) 2(6)(1) = 444 Mass efficiency = 196/344 (X 100) = 196/444 (X100) = 44. In terms of carbon efficiency the old route with 33% of the starting material and the formation of CO2 (global warming). But then in the 1970s the oil crisis brought changes to the manufacture of MA.6%. Overall. started to generate MA as a by-product of the oxidation of naphthalene to phthalic acid and phthalic anhydride. after ten years of research a new process was developed for n-butane oxidation to MA using a 6 . (VO)2P2O5 catalyst . The industrial process got rid of toxic benzene and the atom efficiency of the synthesis was much better with minimum waste. UCB Chemicals and BASF. and is a valuable intermediate in the manufacture of 1. butene or butane with air (oxidizing medium) passing over a Vanadium pentoxide catalyst at 3-5 bar pressure and temperature 350-450 oC.4% B. In the 1990s with the environmental concerns growing and with the emphasis on waste minimization. Maleic Anhydrite Synthesis: Old and greener synthesis A. Also. the butane feedstock provides the most “green” synthetic route [18].5(2)(16) (10)(1) = 170 Mass efficiency = 98/170 (X100) = 57. E.Anhydride is widely used in the manufacture of polyester resins and paints. V2O5 and MoO3 catalysts. without the use of solvent was applied as a patent by the Standard Oil Company (Indiana) [19]. whereas the butane process produces only water as a by-product.5 O2 (air) →catalyst →C4H2O + 4H2O The reaction has a yield of 60% Product mass: (4)(12) (3)(16) (2)(1) = 98 Reactant mass: (4)(12) 3. The butane process was adopted. the process change again. USA). Total world production of MA is in the range of one million tones annually Before the 1960s MA was a highly valuable chemical product with limited markets and little manufacturing competition. Two chemical manufacturers . All three routes of manufacture involved the feedstock of benzene. Manufacture process for the production of MA with the use of various catalysts (phosphorus-vanadium and phosphorus-vanadium-co-metal catalyst) at temperatures 0200 oC. Old process: Benzene feedstock . This process is greener and more attractive. Romania) scientists developed an alternative clean method for the synthesis of MA copolymers. (iii) (iv) Ultrasound-assisted organic synthesis: is Green Chemistry synthesis? The application of ultrasound as a method for organic synthesis has been recognized by organic synthetic chemists in the last decade. 7 . Microwaveassisted reactions need much shorter times. From the Institute of Macromolecular Chemistry (Iasi. simple.4- (ii) Fused polynuclear tetrahydro arenas with microwave irradiation. have better selectivities and produce higher yields [22]. high yielding and regioselective procedure by an intramolecular Friedel-Crafts alkylation in dry media of the corresponding 1-bromo-4arylbutanes immobilized in silica [24]. (iv) Various organic synthesis and the methodology of microwave-assisted irradiation can be found in numerous reviews [26-28]. Some examples: (i) (ii) 2-alkylated hydroquinones under microwave irradiation using cyclohexadione and aldehydes catalysed by KF-Al2O3 in dry media [23] 1. Sonochemistry corresponds to the “green’ chemistry objectives: provides energy savings. efficient and economical without solvents and easier work-up for the products is inevitably environmentally benign procedure. Sonication enables the rapid dispersion of solids. The use of a synthetic method which is clean. decomposition of organic chemicals. The process uses microwave irradiation to assist the free radical polymerization of monomers (MA and vinyl monomers) yielding high molecular mass polymers [21]. Teaching laboratory exercises in Universities can be set up by using a commercial microwave oven. (iii) An interesting microwave-assisted Diels-Alders reaction of anthracene with fumaric acid [25]. A fast. There are numerous examples of microwave-assisted organic reactions from a variety of scientific papers on the subject. high yields and selectivity in reactions. no waste and high efficiency [29].31].circulating fluidized bed reactor [20]. and also can use aqueous media for non-classical reagents. Microwave-assisted eco-friendly organic synthesis Organic reactions performed under microwave irradiation (MWT) have some significant advantages in comparison with conventional reactions at high temperatures. The scientific literature is full of novel organic syntheses of various chemicals by microwave-assisted reactions. Examples of ultrasound-assisted organic synthesis can be found in reviews [30. An interesting example is the combined microwave and ultrasound assisted Williamson ether synthesis. The chemical and physical effects of ultrasound arise from the cavitational collapse which produces extreme conditions locally and thus induce the reaction of chemical reactants which aRe not easily attained by conventional conditions. which proves to be an efficient and ecologically valuable route for preparing ethers in the absence of organic auxiliary substances (such as phase-transfer catalysts) [32]. The Advanced Oxidation Processes (AOP) by a combination of ultraviolet light (UV) and either oxidants (e. The flask was placed in a ultrasound bath operated at 2000 kHz with an input power of 200 W.000 tones of chlorinated wastes (2/3 from Germany) were incinerated each year by an incinerator in the North Sea (Dutch sector) [34]. Sonochemical degradation of chlorinated wastes in aerated solutions is another method. Also. Fe/H2O2. The detection wavelength was 254 nm. Various techniques have been deployed for their disposal or treatment to become less hazardous to the environment. Sonochemical degradation is fast and the products are less hazardous to the aquatic environment [36]. 8 . Electrochemical treatment has been proposed for the treatment of polychlorinated solvent waste because of several advantages Photochemical processes which are used for decomposition of chlorinated waste. Bioremediation is another method which uses the metabolism of microorganism to break down chemicals as a source of food and energy. A solution of chlorobenzene in water 1 mmol in 1L of distilled water was used. The various methods used for the treatment or destruction of chlorinate solvent waste are [34]: Chemical dechlorination by various reagents (alkali metal polyethylene glycolate. In the presence of oxygen or air. APEG) is an alternative method.g. with a flow rate of 0. Chlorinated solvents are toxic substances.5% at 625oC in seconds. are used as solvents in many university laboratories for organic synthesis and inevitably there are large quantities of chlorinated solvents in any organic laboratory waste. Experimental procedure. but the method has also many disadvantages. the same method can be applied efficiently to a wide range of chlorinated organic compounds. The solution was bubbled for 2-3 mins with air and then closed. because of their persistence and bioaccumulation in aquatic organisms. destruction efficiencies exceeding 99. The degradation of highly chlorinated solvents is achieved by a combination of anaerobic and aerobic treatments. An example of waste treatment of chlorinated waste in a chemical laboratory is the sonolysis of chlorobenzene in a Fenton (Fe2+ /H2O2) type aqueous system.g. In principle is an enzymatic biodegradation process. legislation is being provided for controlling the release of such pollutants in the environment and methods for their disposal are being developed which are very costly. O3 ) or oxidants and a catalyst (e. The use of activated sludge process to remove polychlorinated substances from waste is another well established method. Bioremediation can be made commercially viable by accelerating the work of natural bacteria residing at the site of contamination. The mobile phase was acetonitrile: water mixture (50:50). Scientists are becoming aware of the importance of waste-minimisation schemes and methods for their safe decomposition to environmentally benign substances [33-35]. it is expensive and produces toxic residue ash. The technique has been effectively applied to a range of chlorinated hydrocarbons. Supercritical waster oxidation (SCWO) is another method which uses the water at high temperatures and pressures above its critical point.3 mL/min and an injection volume of 10 μL [37]. AOP methods are associated with the generation of hydroxyl radicals which a short-lived but potent oxidizing agent. The temperature was 25 oC. TiO2 photocatalysis). H2O2. Hydroxyl radicals are produced from water which give rise to advanced oxidative phenomena. In the 1980s around 90-100. In the last decades. The progress of the sonolysis can be monitored by HPLC every 10 minutes. for 60 minutes. especially in sites of contamination. 100 mL of the solution was placed in a 150 mL conical flask.Chlorinated aromatic waste in laboratories: disposal and decomposition Chlorinated hydrocarbons. Incineration is a widely employed technique for their destruction at high temperatures. Atom economy for various reactions can be calculated to give a picture of the efficiency of “greener” routes to organic synthesis. benzene. Already. The replacement of toxic and noxious solvents by more environmentally-benign ones is an important area for the teaching the principles of Green Chemistry.Figure 3. Finally. new. 9 . the degradation of chlorobenzene and other chlorinated solvents can be an interesting example for the recycling of dangerous to the environment chemicals. Results and Discussion Chemical laboratories for the teaching or Organic Synthesis in university and higher education establishments must introduce more efficient. carbon tetrachloride and chloroform has been phased out by industry and gradually from academic research laboratories. The use of microwave oven and ultrasound baths is another area that must be explored in chemical teaching laboratories. Degradation reaction products of chlorobenzene after sonication and possible reaction mechanisms. and “greener” synthesis of organic compounds in order to teach new chemists the advantages but also the principles of Green Chemistry. atom economy and protection of the environment. There are numerous examples to choose and many products can be prepared at short time and in clean form. The examples of Ibuprofen. Adipic acid and Maleic anhydride are very important to show the big changes happening in the last decades for the manufacture of basic chemical in industry and the benefits in terms of waste. energy. Examples of the synthesis of AA and MA can be used in the laboratory exercises. Connelly ME. UK. Hutchison JE. J. Tundo P.a case study in green chemistry.gov/greenchemistry/pubs/pgcc/winners/aa98b.pdf) 9. 15. Sheldon RA. 2001. 11. Catalysis as a foundational pillar of green chemistry.UK (http://www. Cambridge. Green Chemistry: Challenging Perspectives. DC. Aoki M. Arends I. 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