The Twelve Principles of Green Chemistry 6/18/2018

12 Principles of Green Chemistry 1. Prevention. It is better to prevent waste than to treat or clean up waste after it is formed. 2. Atom Economy. Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product. 3. Less Hazardous Chemical Synthesis. Whenever practicable, synthetic methodologies should be designed to use and generate substances that possess little or no toxicity to human health and the environment. 4. Designing Safer Chemicals. Chemical products should be designed to preserve efficacy of the function while reducing toxicity. 5. Safer Solvents and Auxiliaries. The use of auxiliary substances (solvents, separation agents, etc.) should be made unnecessary whenever possible and, when used, innocuous. 6. Design for Energy Efficiency. Energy requirements should be recognized for their environmental and economic impacts and should be minimized. Synthetic methods should be conducted at ambient temperature and pressure. 7. Use of Renewable Feedstocks. A raw material or feedstock should be renewable rather than depleting whenever technically and economically practical. 8. Reduce Derivatives. Unnecessary derivatization (blocking group, protection/deprotection, temporary modification of physical/chemical processes) should be avoided whenever possible . 9. Catalysis. Catalytic reagents (as selective as possible) are superior to stoichiometric reagents. 10. Design for Degradation. Chemical products should be designed so that at the end of their function they do not persist in the environment and instead break down into innocuous degradation products. 11. Real-time Analysis for Pollution Prevention. Analytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances. 12. Inherently Safer Chemistry for Accident Prevention. Substance and the form of a substance used in a chemical process should be chosen so as to minimize the potential for chemical accidents, including releases, explosions, and fires. Anastas, P. T.; Warner, J.C. Green Chemistry: Theory and Practice, Oxford University Press,1998. 6/18/2018

1. Prevention It is better to prevent waste than to treat or clean up waste after it is formed. 6/18/2018

Environmental Disasters Love Canal in Niagara Falls, NY a chemical and plastics company had used an old canal bed as a chemical dump from 1930s to 1950s. The land was then used for a new school and housing track. The chemicals leaked through a clay cap that sealed the dump. It was contaminated with at least 82 chemicals (benzene, chlorinated hydrocarbons, dioxin). Health effects of the people living there included: high birth defect incidence and siezure-inducing nervous disease among the children. http://ublib.buffalo.edu/libraries/projects/lovecanal/ 6/18/2018

Environmental Disasters Cuyahoga River – Cleveland, Ohio There were many things being dumped in the river such as: gasoline, oil, paint, and metals. The river was called "a rainbow of many different colors". Fires erupted on the river several times before June 22, 1969, when a river fire captured national attention when Time Magazine reported it. 6/18/2018

2. Atom Economy Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product. 6/18/2018

Organic Chemistry & Percent Yield Epoxidation of an alkene using a peroxyacid 100% yield 6/18/2018

Percent yield:   6/18/2018

Balanced Reactions Balanced chemical reaction of the epoxidation of styrene 6/18/2018

Atom Economy:   6/18/2018 Trost, Barry M., The Atom Economy-A Search for Synthetic Efficiency. Science 1991, 254, 1471-1477.

Atom Economy Balanced chemical reaction of the epoxidation of styrene Assume 100% yield. 100% of the desired epoxide product is recovered. 100% formation of the co-product: m-chlorobenzoic acid A.E. of this reaction is 23%. 77% of the products are waste. 6/18/2018

3. Less Hazardous Chemical Synthesis Whenever practicable, synthetic methodologies should be designed to use and generate substances that possess little or no toxicity to human health and the environment. 6/18/2018

Less Hazardous Chemical Synthesis Polycarbonate Synthesis: Phosgene Process Materials: bisphenol A (BPA), Phosgene, CH2Cl2 Disadvantages phosgene is highly toxic, corrosive requires large amount of CH2Cl2 polycarbonate contaminated with Cl impurities chemical found in hard plastics and the coatings of food and drinks cans which can behave in a similar way to estrogen and other hormones in the human body. BPA is used to make many products, including water bottles, baby bottles, dental fillings and sealants, dental devices, medical devices, eyeglass lenses, DVDs and CDs, household electronic and sports equipment. BPA can also be found in epoxy resins which is used as coatings inside food and drinks cans. Polycarbonates (PC) are a group of thermoplastic polymers containing carbonate groups in their chemical structures. Polycarbonates used in engineering are strong, tough materials, and some grades are optically transparent. 6/18/2018

Less Hazardous Chemical Synthesis Polycarbonate Synthesis: Solid-State Process SSP Advantages diphenylcarbonate synthesized without phosgene eliminates use of CH2Cl2 higher-quality polycarbonates Komiya et al., Asahi Chemical Industry Co. 6/18/2018

4. Designing Safer Chemicals Chemical products should be designed to preserve efficacy of the function while reducing toxicity. 6/18/2018

Designing Safer Chemicals Case Study: Antifoulants (Marine Pesticides) http://academic.scranton.edu/faculty/CANNM1/environmentalmodule.html 6/18/2018

Designing Safer Chemicals: Case Study: Antifoulants Antifoulants are generally dispersed in the paint as it is applied to the hull.  Organotin compounds have traditionally been used, particularly tributyltin oxide (TBTO). TBTO works by gradually leaching from the hull killing the fouling organisms in the surrounding area TBTO and other Organotin Antifoulants have long half-lives in the environment (half-life of TBTO in seawater is > 6 months). They also bioconcentrate in marine organisms (the concentration of TBTO in marine organisms to be 104 times greater than in the surrounding water). Organotin compounds are chronically toxic to marine life and can enter food chain. They are bioaccumulative. Bioconcentration is a term that was created for use in the field of aquatic toxicology. Bioconcentration can also be defined as the process by which a chemical concentration in an aquatic organism exceeds that in water as a result of exposure to a waterborne chemical. Bioaccumulation refers to the accumulation of substances, such as pesticides, or other chemicals in an organism. http://academic.scranton.edu/faculty/CANNM1/environmentalmodule.html 6/18/2018

Designing Safer Chemicals: Case Study: Antifoulants Sea-Nine® 211 The active ingredient in Sea-Nine® 211, 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOI),  is a member of the isothiazolone family of antifoulants. http://academic.scranton.edu/faculty/CANNM1/environmentalmodule.html 6/18/2018

Designing Safer Chemicals: Case Study: Antifoulants Sea-Nine® 211 works by maintaining a hostile growing environment for marine organisms. When organisms attach to the hull (treated with DCOI), proteins at the point of attachment with the hull react with the DCOI.  This reaction with the DCOI prevents the use of these proteins for other metabolic processes. The organism thus detaches itself and searches for a more hospitable surface on which to grow. Only organisms attached to hull of ship are exposed to toxic levels of DCOI.(4,5-dichloro-2-n-octyl-4-isothiazolin) Readily biodegrades once leached from ship (half-life is less than one hour in sea water). 6/18/2018

5. Safer Solvents and Auxiliaries The use of auxiliary substances (solvents, separation agents, etc.) should be made unnecessary whenever possible and, when used, innocuous. 6/18/2018

Safer Solvents Solvent Substitution Water as a solvent New solvents Ionic liquids Supercritical fluids 6/18/2018

Solvent Selection Preferred Useable Undesirable Water Cyclohexane Pentane Acetone Heptane Hexane(s) Ethanol Toluene Di-isopropyl ether 2-Propanol Methylcyclohexane Diethyl ether 1-Propanol Methyl t-butyl ether Dichloromethane Ethyl acetate Isooctane Dichloroethane Isopropyl acetate Acetonitrile Chloroform Methanol 2-MethylTHF Dimethyl formamide Methyl ethyl ketone Tetrahydrofuran N-Methylpyrrolidinone 1-Butanol Xylenes Pyridine t-Butanol Dimethyl sulfoxide Dimethyl acetate Acetic acid Dioxane Ethylene glycol Dimethoxyethane Benzene Carbon tetrachloride “Green chemistry tools to influence a medicinal chemistry and research chemistry based organization” Dunn and Perry, et. al., Green Chem., 2008, 10, 31-36 6/18/2018

6/18/2018 Red Solvent Flash point (°C) Reason Pentane -49 Very low flash point, good alternative available. Hexane(s) -23 More toxic than the alternative heptane, classified as a HAP in the US. Di-isopropyl ether -12 Very powerful peroxide former, good alternative ethers available. Diethyl ether -40 Very low flash point, good alternative ethers available. Dichloromethane n/a High volume use, regulated by EU solvent directive, classified as HAP in US. Dichloroethane 15 Carcinogen, classified as a HAP in the US. Chloroform Dimethyl formamide 57 Toxicity, strongly regulated by EU Solvent Directive, classified as HAP in the US. N-Methylpyrrolidinone 86 Toxicity, strongly regulated by EU Solvent Directive. Pyridine 20 Carcinogenic/mutagenic/reprotoxic (CMR) category 3 carcinogen, toxicity, very low threshold limit value (TLV) for worker exposures. Dimethyl acetate 70 Dioxane 12 CMR category 3 carcinogen, classified as HAP in US. Dimethoxyethane CMR category 2 carcinogen, toxicity. Benzene -11 Avoid use: CMR category 1 carcinogen, toxic to humans and environment, very low TLV (0.5 ppm), strongly regulated in EU and the US (HAP). Carbon tetrachloride Avoid use: CMR category 3 carcinogen, toxic, ozone depletor, banned under the Montreal protocol, not available for large-scale use, strongly regulated in the EU and the US (HAP). 6/18/2018

Solvent replacement table Undesirable Solvent Alternative Pentane Heptane Hexane(s) Di-isopropyl ether or diethyl ether 2-MeTHF or tert-butyl methyl ether Dioxane or dimethoxyethane Chloroform, dichloroethane or carbon tetrachloride Dichloromethane Dimethyl formamide, dimethyl acetamide or N-methylpyrrolidinone Acetonitrile Pyridine Et3N (if pyridine is used as a base) Dichloromethane (extractions) EtOAc, MTBE, toluene, 2-MeTHF Dichloromethane (chromatography) EtOAc/heptane Benzene Toluene 6/18/2018

Pfizer’s results Use of Solvent Replacement Guide resulted in: 50% reduction in chlorinated solvent use across the whole of their research division (more than 1600 lab based synthetic organic chemists, and four scale-up facilities) during 2004-2006. Reduction in the use of an undesirable ether by 97% over the same two year period Heptane used over hexane (more toxic) and pentane (much more flammable) “Green chemistry tools to influence a medicinal chemistry and research chemistry based organization” Dunn and Perry, et. al., Green Chem., 2008, 10, 31-36 6/18/2018

Safer solvents: Supercritical fluids A SCF is defined as a substance above its critical temperature (TC) and critical pressure (PC). The critical point represents the highest temperature and pressure at which the substance can exist as a vapor and liquid in equilibrium. http://www.chem.leeds.ac.uk/People/CMR/whatarescf.html 6/18/2018

http://www.uyseg.org/greener_industry/pages/superCO2/3superCO2_coffee.htm 6/18/2018

Activity-02 Study the flow sheet diagram carefully and rewrite the method The method should not exceed 250 words The submission date is 21st Sep 6/18/2018

6. Design for Energy Efficiency Energy requirements should be recognized for their environmental and economic impacts and should be minimized. Synthetic methods should be conducted at ambient temperature and pressure. 6/18/2018

Energy in a chemical process Thermal (electric) Cooling (water condensers, water circulators) Distillation Equipment (lab hood) Photo Microwave Source of energy: Power plant – coal, oil, natural gas 6/18/2018

Alternative energy sources: Photochemical Reactions Two commercial photochemical processes (Caprolactam process & vitamin D3) Caprolactam process Nitrosyl chloride NOCl  NO˙ + Cl˙ (535nm) Vitamin D3: Photochemical electrocyclic ring opening followed by a thermal 1,7-hydride shift no viable thermal alternative 6/18/2018 Chem-442

7. Use of Renewable Feedstocks A raw material or feedstock should be renewable rather than depleting whenever technically and economically practical. 6/18/2018

Polymers from Renewable Resources: Polyhydroxyalkanoates (PHAs) Fermentation of glucose in the presence of bacteria and Propanoic acid (product contains 5-20% polyhydroxyvalerate) Similar to polypropene and polyethene Biodegradable (credit card) 6/18/2018 Chem-442

Polymers from Renewable Resources: Poly(lactic acid) http://www.natureworksllc.com/corporate/nw_pack_home.asp 6/18/2018

Raw Materials from Renewable Resources: The BioFine Process Paper mill sludge Agricultural residues, Waste wood Levulinic acid Green Chemistry Challenge Award 1999 Small Business Award Municipal solid waste and waste paper 6/18/2018

Levulinic acid as a platform chemical butanediol Acrylic acid Succinic acid MTHF (fuel additive) THF Diphenolic acid gamma butyrolactone DALA (-amino levulinic acid) (non-toxic, biodegradable herbicide) 6/18/2018 Chem-442

Activity-02 Gather some ideas for Green Day Google international celebrated days and develop a program. Discuss the programs on 23rd Sep 6/18/2018

8. Reduce Derivatives Unnecessary derivatization (blocking group, protection/deprotection, temporary modification of physical/chemical processes) should be avoided whenever possible. 6/18/2018

In the first industrial synthesis Penicillin G (R=H) is first protected as its silyl ester [R = Si(Me)3] then reacted with phosphorus pentachloride at -40oC to form the chlorimidate 1  Subsequent hydrolysis gives the desired 6-APA from which semi-synthetic penicillins are manufactured. 6/18/2018

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This synthesis occurs in water at just above room temperature. This synthesis has been largely replaced by a newer enzymatic process using pen-acylase. This synthesis occurs in water at just above room temperature. The new synthesis has many advantages from a green perspective one of which is that the Silyl protecting group is not required. 6/18/2018

Silyl ether Silyl ethers are a group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl group.  Silyl ethers are usually used as protecting groups for alcohols in organic synthesis. 6/18/2018

More than 10,000 metric tons of 6-APA is made every year and much of it by the greener enzymatic process so this is a fantastic example of Green Chemistry making a real difference. 6/18/2018

9. Catalysis Catalytic reagents (as selective as possible) are superior to stoichiometric reagents. 6/18/2018

Biocatalysis Enzymes or whole-cell microorganisms Benefits Fast rxns due to correct orientations Orientation of site gives high stereospecificity Substrate specificity Water soluble Naturally occurring Moderate conditions Possibility for tandem rxns (one-pot) 6/18/2018

A hexokinase is an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate of hexokinases, and glucose-6-phosphate is the most important product 6/18/2018

Biocatalysis has many attractive features in the context of green chemistry, and its impact will become continue to grow. As biofuels companies look for more profitable ways to exploit their technology I expect bio-based routes to certain large volume specialty chemicals to be commercialized in the near future. Examples include 1,4-butanediol, succinic acid, glucaric acid, terpenes, and even isobutene. 6/18/2018

10. Design for Degradation Chemical products should be designed so that at the end of their function they do not persist in the environment and instead break down into innocuous degradation products. 6/18/2018

Persistence Early examples: Sulfonated detergents Alkylbenzene sulfonates – 1950’s & 60’s Foam in sewage plants, rivers and streams Persistence was due to long alkyl chain Introduction of alkene group into the chain increased degradation Chlorofluorocarbons (CFCs) Do not break down, persist in atmosphere and contribute to destruction of ozone layer DDT Bioaccumulate and cause thinning of egg shells 6/18/2018

Degradation of Polymers: Polylactic Acid Manufactured from renewable resources Corn or wheat; agricultural waste in future Uses 20-50% fewer fossil fuels than conventional plastics PLA products can be recycled or composted Cargill Dow 6/18/2018

11. Real-time Analysis for Pollution Prevention Analytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances. 6/18/2018

Real time analysis for a chemist is the process of “checking the progress of chemical reactions as it happens.” Knowing when your product is “done” can save a lot of waste, time and energy! 6/18/2018

Analyzing a Reaction What do you need to know, how do you get this information and how long does it take to get it? 6/18/2018

12. Inherently Safer Chemistry for Accident Prevention Substance and the form of a substance used in a chemical process should be chosen so as to minimize the potential for chemical accidents, including releases, explosions, and fires. 6/18/2018

12. Inherently Safer Chemistry for Accident Prevention Tragedy in Bhopal, India - 1984 In arguably the worst industrial accident in history, 40 tons of methyl isocyanate were accidentally released when a holding tank overheated at a Union Carbide pesticide plant, located in the heart of the city of Bhopal. 15,000 people died and hundreds of thousands more were injured. Chemists try to avoid things that explode, light on fire, are air-sensitive, etc. In the “real world” when these things happen, lives are lost. 6/18/2018

Bhopal, India December 3, 1984 – poison gas leaked from a Union Carbide factory, killing thousands instantly and injuring many more (many of who died later of exposure). Up to 20,000 people have died as a result of exposure (3-8,000 instantly). More than 120,000 still suffer from ailments caused by exposure What happened? Methyl isocyanate – used to make pesticides was being stored in large quantities on-site at the plant Methyl isocyanate is highly reactive, exothermic molecule Most safety systems either failed or were inoperative Water was released into the tank holding the methyl isocyanate The reaction occurred and the methyl isocyanate rapidly boiled producing large quantities of toxic gas. 6/18/2018

Chemical Industry Accidents U.S. Public Interest Research Group Reports (April 2004) find that chemical industry has had more than 25,000 chemical accidents since 1990 More than 1,800 accidents a year or 5 a day Top 3: BP, Dow, DuPont (1/3 of the accidents) http://uspirg.org/uspirgnewsroom.asp?id2=12864&id3=USPIRGnewsroom& 6/18/2018