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: valavanidis@chem.uoa.gr, thvlach@chem.uoa.gr, cfiot@chem.uoa.gr

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.

Introduction Organic Synthesis of chemical compounds, include prevention of waste, atom economy and use of less hazardous chemicals in synthetic methods, the use of safer, environmentally benign solvents, renewable raw materials, energy efficiency, catalysis, design for degradation of chemical products after use and pollution prevention for sustainable development. Green Chemistry promotes changes to attitudes among research chemists and managers of chemical industry to approach chemical processes in a more constructive way, involving economical synthesis, less waste, protection of the health of workers and prevention of pollution [1]. In recent years, environmentally benign chemical techniques are growing in importance in academic and industrial research laboratories. Also, 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 [2,3]. The chemical industry has made great improvements in the efficiency of its processes, but finite natural resources will inevitable limit the ability to manufacture in wasteful ways. 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]. The reactions involved in the synthesis of chemical products must minimize environmental impact and waste. The old catalysts were traditionally metals which are toxic and scarce, so non-metallic catalysts must be developed (organocatalysts or enzymes) which perform useful catalytic functions, designed to maximize efficiency and reduce waste. Although every new chemical process is very difficult to satisfy all principles of Green Chemistry, it must comply with some of them to be greener compared to older ones. Energy efficiency is another filed that that new methodologies must take into account. Many solvents that are used at present in the chemical industry and in research laboratories are very flammable and toxic. Large quantities are used in isolation, separation and purification of materials. If reactions could be optimised to prevent the formation of by-products, then purification processes would be eliminated. Finding also environmentally benign solvents is another important problem for chemistry experiments[5-7]. ld 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. A very well known group of drugs are analgesics, such as aspirin, acetaminophen and ibuprofen. Ibuprofen is also a member of non-steroidal antiinflammatory drugs. The traditional industrial synthesis of Ibuprofen (Boots Co, England, 1960s, branded products: Aspro, Panadol, Nurofen) was a six-step process, resulting in large quantities of chemical byproducts which had to be disposed causing an acute problem of chemical waste and pollution. In general the old organic synthesis of Ibuprofen had very poor atom economy, a terminology used as one of the principles of Green Chemistry that must be improved. In the 1990s the BHC Co developed a new greener industrial synthesis of Ibuprofen that had only three synthetic steps. In this process, most of the toms of the reactants are incorporated in to the product, resulting in only small amounts of unwanted byproducts. The process has very good atom economy, reducing the waste which has to be disposed [8,9]. The old method starts from the compound 2-mehtylpropylbenzene that can be made from chemicals separated from crude oil. One of the problem with the old synthetic method is that is a multi-step synthesis and produces overall a low yield. If each step has a yield of 90% then the second step will be 90X90 = 81%. 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

product. Finally, the overall figure is 40%, which means that more than half the materials are wasted, especially if we consider that 3,000 tones are made per year (only in the United Kingdom). The green synthesis of Ibuprofen (after the patent ran out in the mid-1980s) was able to be developed by alternative synthetic methodology. The new method was with the same starting material but in three steps, with higher atom economy (77% yield) and less waste (using catalysts, such as Raney Nickel, CO/Pd). But the most important was that reagents and products are the same in each step and only the catalyst differs. In the old method the AlCl3 is not a true catalyst and has to be disposed in landfill sites, and every step has to start with fresh materials. The catalysts used in the green synthesis can be recovered and reused so that it generates no waste.

Figure 1. 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 2,000 million kilograms because it is used for the production of Nylon 6,6 and catechol which is used as a building block for pharmaceuticals and pesticides. In the past industrial synthesis of adipic acid used benzene as a starting material (non-renewable, carcinogenic chemical), which was the product of petroleum refining, Later, the industrial process of manufacturing Adipic acid involved oxidation of cyclohexanone or a cyclohexanone/cyclohexanol mixture with nitric acid, which inevitable produces NOx (nitrous oxide, which contributes to global warming and ozone depletion) as a by-product. In the last few years, efforts have been 3

accomplished in a greener, clean, synthesis of adipic acid that is less damaging to the environment with the use of catalysts [10]. 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, under organic solvent- and halide-free conditions and the use of novel catalysts, such as Tungsten catalysts (Na2WO4 / KHSO4/ Aliquat 336 [11,12]

Figure 2. 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, cyclohexanol, cyclohexanone and 1,2-cyclohexanediol with yields in the range of 45-86% [13]. Also, scientists developed new biocatalytic synthesis of adipic acid from D-glucose which uses genetically engineered Klebsiella pneumoniae (a non-virulent strain of E.coli). The scientist who developed this biocatalytic synthesis won the Presidential Green Chemistry Challenge Awards Program. 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 method is simple and can be applied to a teaching laboratory of organic synthesis [17]. Adipic acid (AA) synthesis A. In a dry 25 mL screw-capped round bottom flask add a special magnetic bar. B. i) Add in the following order: 0.25 g of sodium Tungstate dehydrate, ii) 0.25 of Aliquat 336 (phase transfer catalyst) which is a viscous liquid, and can be added with a small Pasteur pipette, iii) 6.0 g (5.5 mL) of 30% H2O2 (carefully, causes burns in contact with skin), iv) 0.19 of potassium hydrogen sulfate (KHSO4), v) mix the components by swirling the vial for 10 sec and add 1.0 g of Cyclohexene. C. Connect an air condenser, place in the flask on the Al block and start stirring the reaction mixture. Slowly in the beginning for one minute and then more vigorously. After 45 minutes remove the flask and cool it for 3 minutes. The mixture is a milky white colour. Heat the mixture gently. With a pipette transfer 4

the cloudy mixture to a smaller beaker, trying to avoid the Aliquat 336 catalyst (liquid layer on the top of the aqueous mixture, some stuck to the flask and stir bar) Cool the beaker on ice for 10 minutes. Precipitation as white crystal, scratch the inside of the beaker with a glass rod. Cool again. Isolate the crude AA by filtration on a Bchner funnel, rinse the beaker with 2 mL ice-cold water. Leave the sample on the funnel for 5 min. E. Recrystallization. The recrystallization with deionized water (1 mL for every 2.3 g of crude product). Stir and heat the mixture at 80-100 oC. Add more water if acid do not dissolve, heat again. Allow to cool 5-10 min. AA starts to precipitate, place the beaker on ice, Isolate the crystalline product by filtration on a Bchner funnel. Rinse with cold water. Transfer on a clean watch glass, dry it in an oven (at 115 oC) for 10-15 min. Cool and determine its weight and melting point. The synthesis of Adipic acid with the traditional and the new route can be considered also for atom (or mass) efficiency. A. Traditional Route from mixture of cyclohexano0ne/cyclohexanone with oxidation by nitric acid (in the presence of metals Cu (0.1-05% and V (0.02-0.1%) C6H12O + 2 HNO3 + H2O C6H10O4 + NOx (NO, NO2, N2O, N2) In this method, nitric oxide is hazardous, and the released N2O contributes to global warming and ozone depletion. The yield of the reaction is 92-96%. 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 = 55.7% B. New greener route from cyclohexene with hydrogen peroxide and the catalyst Na2WO4.2H2O (1%) and [CH3(n-C8H17)3N] HSO4 (1%) (Sato, et al. A green route to adipic acid., Science, 281: 1646-1647, 1998 ) C6H10 + 4 H2O2 catalysts C6H10O4 + 4 H2O The new route does not produce hazardous chemicals yield of adipic acid is 90%. 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. Maleic Anhydrite synthesis under Green Chemistry principles Another very useful example of organic synthesis for teaching student on the advantages of green chemistry principles, especially from the environmental and economic point of view, is the synthesis of Maleic Anhydride (MA) (cis-butenediol acid, C4H4O4). Maleic 5

Anhydride is widely used in the manufacture of polyester resins and paints, and is a valuable intermediate in the manufacture of 1,4-butanediol (used in polyurethane industrial process and in the preparation of butyrolactone (a solvent and paint remover). 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. All three routes of manufacture involved the feedstock of benzene, butene or butane with air (oxidizing medium) passing over a Vanadium pentoxide catalyst at 3-5 bar pressure and temperature 350-450 oC. But then in the 1970s the oil crisis brought changes to the manufacture of MA. The butane process was adopted. In the 1990s with the environmental concerns growing and with the emphasis on waste minimization, the process change again. Two chemical manufacturers , UCB Chemicals and BASF, started to generate MA as a by-product of the oxidation of naphthalene to phthalic acid and phthalic anhydride. This process is greener and more attractive. The industrial process got rid of toxic benzene and the atom efficiency of the synthesis was much better with minimum waste. In terms of carbon efficiency the old route with 33% of the starting material and the formation of CO2 (global warming), whereas the butane process produces only water as a by-product. Overall, the butane feedstock provides the most green synthetic route [18]. Maleic Anhydrite Synthesis: Old and greener synthesis A. Old process: Benzene feedstock , V2O5 and MoO3 catalysts, 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) = 44.4% B. New process: Butane feedstock, (VO)2P2O5 catalyst , fixed bed reactor C4H10 + 3.5 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) 3.5(2)(16) (10)(1) = 170 Mass efficiency = 98/170 (X100) = 57.6%. 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, without the use of solvent was applied as a patent by the Standard Oil Company (Indiana) [19]. Also, E.I du Pont de Nemours and Co (Wilmigton, Delaware, USA), after ten years of research a new process was developed for n-butane oxidation to MA using a 6

circulating fluidized bed reactor [20]. From the Institute of Macromolecular Chemistry (Iasi, Romania) scientists developed an alternative clean method for the synthesis of MA copolymers. The process uses microwave irradiation to assist the free radical polymerization of monomers (MA and vinyl monomers) yielding high molecular mass polymers [21]. 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. Microwaveassisted reactions need much shorter times, have better selectivities and produce higher yields [22]. The use of a synthetic method which is clean, efficient and economical without solvents and easier work-up for the products is inevitably environmentally benign procedure. The scientific literature is full of novel organic syntheses of various chemicals by microwave-assisted reactions. Teaching laboratory exercises in Universities can be set up by using a commercial microwave oven. There are numerous examples of microwave-assisted organic reactions from a variety of scientific papers on the subject. Some examples: (i) (ii) 2-alkylated hydroquinones under microwave irradiation using cyclohexadione and aldehydes catalysed by KF-Al2O3 in dry media [23] 1,4-

(ii) Fused polynuclear tetrahydro arenas with microwave irradiation. A fast, simple, high yielding and regioselective procedure by an intramolecular Friedel-Crafts alkylation in dry media of the corresponding 1-bromo-4arylbutanes immobilized in silica [24]. (iii) An interesting microwave-assisted Diels-Alders reaction of anthracene with fumaric acid [25]. (iv) Various organic synthesis and the methodology of microwave-assisted irradiation can be found in numerous reviews [26-28].

(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. 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. Sonication enables the rapid dispersion of solids, decomposition of organic chemicals. Sonochemistry corresponds to the green chemistry objectives: provides energy savings, high yields and selectivity in reactions, and also can use aqueous media for non-classical reagents, no waste and high efficiency [29]. Examples of ultrasound-assisted organic synthesis can be found in reviews [30,31]. An interesting example is the combined microwave and ultrasound assisted Williamson ether synthesis, 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].

Chlorinated aromatic waste in laboratories: disposal and decomposition Chlorinated hydrocarbons, 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. Chlorinated solvents are toxic substances, because of their persistence and bioaccumulation in aquatic organisms. In the last decades, 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. Scientists are becoming aware of the importance of waste-minimisation schemes and methods for their safe decomposition to environmentally benign substances [33-35]. Various techniques have been deployed for their disposal or treatment to become less hazardous to the environment. Incineration is a widely employed technique for their destruction at high temperatures, but the method has also many disadvantages, it is expensive and produces toxic residue ash. In the 1980s around 90-100.000 tones of chlorinated wastes (2/3 from Germany) were incinerated each year by an incinerator in the North Sea (Dutch sector) [34]. The various methods used for the treatment or destruction of chlorinate solvent waste are [34]: Chemical dechlorination by various reagents (alkali metal polyethylene glycolate, APEG) is an alternative method. Bioremediation is another method which uses the metabolism of microorganism to break down chemicals as a source of food and energy, especially in sites of contamination. In principle is an enzymatic biodegradation process. Bioremediation can be made commercially viable by accelerating the work of natural bacteria residing at the site of contamination. The use of activated sludge process to remove polychlorinated substances from waste is another well established method. The degradation of highly chlorinated solvents is achieved by a combination of anaerobic and aerobic treatments. Supercritical waster oxidation (SCWO) is another method which uses the water at high temperatures and pressures above its critical point. In the presence of oxygen or air, destruction efficiencies exceeding 99.5% at 625oC in seconds. 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. The Advanced Oxidation Processes (AOP) by a combination of ultraviolet light (UV) and either oxidants (e.g. Fe/H2O2, H2O2, O3 ) or oxidants and a catalyst (e.g. TiO2 photocatalysis). AOP methods are associated with the generation of hydroxyl radicals which a short-lived but potent oxidizing agent. Sonochemical degradation of chlorinated wastes in aerated solutions is another method. Hydroxyl radicals are produced from water which give rise to advanced oxidative phenomena. The technique has been effectively applied to a range of chlorinated hydrocarbons. 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. Also, the same method can be applied efficiently to a wide range of chlorinated organic compounds. Sonochemical degradation is fast and the products are less hazardous to the aquatic environment [36]. Experimental procedure. A solution of chlorobenzene in water 1 mmol in 1L of distilled water was used. 100 mL of the solution was placed in a 150 mL conical flask. The solution was bubbled for 2-3 mins with air and then closed. The flask was placed in a ultrasound bath operated at 2000 kHz with an input power of 200 W. for 60 minutes. The temperature was 25 oC. The progress of the sonolysis can be monitored by HPLC every 10 minutes. The detection wavelength was 254 nm. The mobile phase was acetonitrile: water mixture (50:50), with a flow rate of 0.3 mL/min and an injection volume of 10 L [37]. 8

Figure 3. Degradation reaction products of chlorobenzene after sonication and possible reaction mechanisms.

Results and Discussion Chemical laboratories for the teaching or Organic Synthesis in university and higher education establishments must introduce more efficient, new, and greener synthesis of organic compounds in order to teach new chemists the advantages but also the principles of Green Chemistry. The replacement of toxic and noxious solvents by more environmentally-benign ones is an important area for the teaching the principles of Green Chemistry. Already, benzene, carbon tetrachloride and chloroform has been phased out by industry and gradually from academic research laboratories. 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, atom economy and protection of the environment. Examples of the synthesis of AA and MA can be used in the laboratory exercises. Atom economy for various reactions can be calculated to give a picture of the efficiency of greener routes to organic synthesis. The use of microwave oven and ultrasound baths is another area that must be explored in chemical teaching laboratories. There are numerous examples to choose and many products can be prepared at short time and in clean form. Finally, the degradation of chlorobenzene and other chlorinated solvents can be an interesting example for the recycling of dangerous to the environment chemicals. 9

Refereneces 1. Anastas PT, Warner JC. Green Chemistry: Theory and Practice. Oxford University Press, New York, 1998. 2. Warren D. Green Chemistry. A Teaching Resource. Royal Society of Chemistry, Cambridge, 2001. 3. Clark J, Macquarrie D. Handbook of Green Chemistry and Technology. Blackwell Publishing, Abingdon, Oxfordshire, 2002. 4. Poliakoff M, Licence P. Green Chemistry. Nature 450: 810-812, 2007. 5. Tundo P, Anastas P, Eds. Green Chemistry: Challenging Perspectives. Oxford University Press, Oxford, UK, 2000. 6. Sheldon RA, Arends I. Green Chemistry and Catalysis. WileyVCH, Indianopolis, USA, 2006. 7. Sheldon RA. Atom efficiency and catalysis in organic synthesis. Pure Appl. Chem. 72(7): 1233-1246, 2000. 8. Ibuprofen- a case study in green chemistry. Royal Society of Chemistry, Cambridge,UK (http://www.rsc.org/education/teachers/learnnet/ibuprofen/ibuprofen.pdf) 9. The BHC Company Synthesis of Ibuprofen. From Cann MC, Connelly ME. Real World Cases in Green Chemistry. American Chemical Society, Washington, DC, 2000. (http://alpha.chem.umb.edu/chemistry/orgchem/greensynthiboprufencasestudy. pdf ) 10. Anastas PT, Kirchhoff MM, Williamson TC. Catalysis as a foundational pillar of green chemistry. Appl Catal A: General, 221: 3-13, 2001. 11. Sato K, Aoki M, Noyori R. A green route to adipic acid: direct oxidation of cyclohexene with 30 percent hydrogen peroxide. Science 281:1646-1647, 1998. 12. Usui Y, Sato K. A green method of adipic acid synthesis: organic solvent- and halide-free oxidation of cyclohexanones with 30% hydrogen peroxide. Green Chem 5, 373-375, 2003. 13. Li H, Zhu W, He X, Pan J, Shu H, Guo J, et al. Green syntheis of adipic acid with hydrogen peroxide catalyzed by oxpoeroxo tungsten complexes. The 10th Annual Green Chemistry and Engineering Conference, June 26-30, 2006. 14. Draths KM, Frost JW. In: Anastas PT, Williamson TC (Editors). Green Chemistry: Frontiers in Benign Chemical Syntheses and Processes. Oxford University Press, New York, 1998, Chapter 9, p. 150. 15. Draths KM, Frost JW. The Presidential Green Chemistry Challenge Awards Program. Summer of 1998 Award. EPA 744-R-98-001. US Environmental Protection Agency, Office of Pollution Prevention and Toxics, Washington DC, 1998, p. 3. 16. 1998 Academic Award. Green Chemistry. Dr. K. M. Draths and Prof. J.W. Frost (Michigan State University) (http://www.epa.gov/greenchemistry/pubs/pgcc/winners/aa98b.html) 17. Reed SM, Hutchison JE. Green Chemistry in the organic teaching laboratory: an environmentally benign synthesis of adipic acid. J Chem Educ 77:1627-1628, 2000. 18. Maleic Anhydride Synthesis [http://www.webelements. com/nexus/node/152] 10

19. Patent No. 4515904, 30.9.1983 (Robert C. Edwards, Standard Oil Company, Indiana, USA). Catalysts for the production of maleic anhydride by the oxidation of butane. 20. Contractor RM, Gemett DI, Horowitz HS, Bergna HE, Patience GS, Schwartz JT, Sisler GM. A new commercial scale process for n-butane oxidation to Maleic Anhydride using a circulating fluidized bed reactor. Studies Surf Sci Catalysis 82:233-242, 1994. 21. Popescu I, Chitanu GC. Synthesis of Maleic Anhydride copolymers by conventional and non-conventional methods. 2nd International IUPAC Conference on Green Chemistry, 14-19 September, 2008, Moscow, Russia. 22. Lidstrom P, Tierney J, Wathey B, Microwave assisted organic synthesis: a review. Tetrahedron 57:9225-9283, 2001. 23. Kumar HMS, Reddy BVS, Reddy EJ, Yadav JS. Microwave-assisted eco-friendly synthesis of 2-alkylated hydroquinones in dry media. Green Chem June:141-142, 1999. 24. Kurteva VB, Santos AG, Afonso CAM. Microwave accelerated facile synthesis of fused polynuclear hydrocarbons in dry media by intramolecular Friedel-Crafts alkylation. Org. Biomol. Chem 2:514-523, 2004. 25. Giguere RJ, Bray TL, Duncan SM, Majestich E. Application of commercial microwave ovens to organic synthesis. Tetrahedron Lett 27:4945-4948, 1986. 26. Roberts BA, Strauss CR. Toward rapid green predictable microwave-assisted synthesis. Review. Acc. Chem. Res. 38:653-661, 2005. 27. Nuchter M, Ondruschka B, Bonrath W, Gum A. Microwave assisted synthesis- a critical technology overview. Green Chem. 6:128-141, 2004. 28. Blackwell HE. Out of the oil bath and into the oven-microwave-assisted combinatorial chemistry heats up. Org. Biomol. Chem. 1:1251-1255, 2003. 29. Cintas P, Luche J-L. Green Chemistry: The sonochemical approach. Green Chem 1:115-125, 1999. 30. Mason TJ. Ultrasound in synthetic organic chemistry. Review. Chem Soc. Rev. 26:443-451, 1997. 31. Cravotto G, Cintas P. Power ultrasound in organic synthesis: moving cavitational chemistry from academia to innovative and large-scale applications. Chem. Soc. Rev. 35:180-196, 2006. 32. Peng Y, Song G. Combined microwave and ultrasound assisted Williamson ether synthesis in the absence of phase-transfer catalysts. Green Chem. 4:349-351, 2002. 33. Clark RB. Halogenated Hydrocarbons in Marine Pollution. Oxford Science Publications, Oxford , 2nd ed., 1989. 34. Hitchman ML, Spackman RA, Ross NC, Agra C. Disposal methods for chlorinated aromatic waste. Chem. Soc. Rev. 24: 423-430, 1995. 35. Valavanidis A. Health and Safety in the Chemical Laboratory: Reduction or replacement of toxic and dangerous solvents in organic synthesis. Green Chemistry and Sustainable Development, 2nd International Symposium, University of Patras, March 2007, proceedings. 11

36. Chamarro E, Marco A, Esplugas S. Use of Fenton reagent to improve organic chemical biodegradability. Water Res. 35:1047-1051, 2001. 37. Stavarache C, Yim B, Vinatoru M, Maeda Y. Sonolysis of chlorobenzene in Fenton type aqueous systems. Ultrasonics Sonochemistry 9:291-296, 2002. 38. Kappe CO. Microwaves in Organic and Medicinal Chemistry. Wiley-VCH, Weinheim, Germany, 2005. 39. Mikami K. Green Reaction Media in Organic Synthesis. Blackwell Publishing, Oxford, UK, 2005.

12