Green Chemistry (Full Course).pptx

Green chemistry: principles and metrics Prepared and Organized by: Dr Hesham Safwan BSc. Clinical Pharmacy – Cairo University MSc. Biomedical Sciences – Chemical Biology and Drug Design – Zewail City for Science and Technology...

Green chemistry: principles and metrics Prepared and Organized by: Dr Hesham Safwan BSc. Clinical Pharmacy – Cairo University MSc. Biomedical Sciences – Chemical Biology and Drug Design – Zewail City for Science and Technology 1 Introduction 2  Green Chemistry Green chemistry is the design of chemical products and processes that reduce or eliminate the use and generation of hazardous substances. Green chemistry looks at pollution prevention on the molecular scale. 3  Green Chemistry “Reducing”: the heart of Green Chemistry Cost Material s Risk & Energy Hazard Waste Non- renewabl es 4  The 12 Principles of Green Chemistry Anastas, P. T.; Warner, J. C.; Green Chemistry: Theory and Practice, Oxford University 5 Press: New York, 1998, p.30.  The 12 Principles of Green Chemistry Prevention Atom Economy Less Hazardous of waste Chemical Synthesis Safer chemistry for Design safer accident prevention chemicals Real time analysis for Use safer solvents pollution prevention Design for Energy Design for Efficiency degradation Use Renewable feedstocks Use safe Reduce Derivatives catalyst 6 s  The 12 Principles of Green Chemistry 1. Prevention of waste: It is better to prevent waste than to treat or clean up waste after it has been created. Organic waste is primarily produced at certain stages of synthesis, so-called. "Dirty reactions" during which toxic reactants and solvents are used, and a large number of toxic byproducts are formed. These are the most common basic reactions of organic synthesis (halogenation, oxidation, alkylation, nitration and sulfonation) that are applied in different industrial branches. 7  The 12 Principles of Green Chemistry Major Sources of Waste Stoichiometric Reagents: Solvent losses ‒ Acids & (85% of non- Bases (e.g aqueous mass) H2SO4 and NaOH). Multistep ‒ Oxidants & syntheses reductants (e.g. K2Cr2O7 & Fe/HCl). 8 Pollution Prevention Hierarchy Increase greeness Prevention & Reduction Recycling & Reuse Treatment Disposal 9  The 12 Principles of Green Chemistry 1. Prevention of waste: Case study: ethylene oxide Conventional ethylene oxide synthesis included: A 2-step synthesis with a chlorohydrin intermediate. For each kilogram of product, 5 Kg of waste were disposed. 1 0  The 12 Principles of Green Chemistry 1. Prevention of waste: Case study: ethylene oxide Alternative production of ethylene oxide: Use of molecular oxygen removes the need for chlorine. New process generates more than 16 times less waste than the original one, and eliminates the formation of waste water. 1 1  The 12 Principles of Green Chemistry 2. Atom Economy Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product. The principle of Atom Economy is logically linked to the principle of waste prevention, since it requires all raw materials used in production to maximize utilization or inclusion in the final product to ultimately reduce the amount of waste. The principle of increasing atomic usability was defined in 1991 by Barry Trost of Stanford University. 1 2  The 12 Principles of Green Chemistry 2. Atom Economy Ideally all atoms from the reagents are incorporated into a final product. High atom economy ↔ less waste production There are no co-products or byproducts in the reaction. The molecular waste is therefore reduced. 1 3  The 12 Principles of Green Chemistry 2. Atom Economy 1 4  The 12 Principles of Green Chemistry 2. Atom Economy Assume 100% yield. Case study: Epoxidation of styrene 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. 1 5  The 12 Principles of Green Chemistry 2. Atom Economy Styrenes are precursors to polystyrene. Polystyrene is one of the most widely used plastics. Conventional method of styrene production: Use of benzene, a known carcinogen, as a starting material. High temperature (800-950 °C). 1 6  The 12 Principles of Green Chemistry 2. Atom Economy Case study: styrene Alternative method of styrene production from butadiene using Diels-Alder reaction: Diels-Alder reaction = 100% atom economy. Use of non-toxic starting material. Cu-Zeolite - H2 + Diels-Alder Styrene 1 7  The 12 Principles of Green Chemistry 3. Less Hazardous Chemical Syntheses Wherever practicable, synthetic methods should be designed to use and generate substances that possess little or no toxicity to human health and the environment. Case study: Synthesis of dimethyl carbonate. 1 8  The 12 Principles of Green Chemistry 3. Less Hazardous Chemical Syntheses 1 9  The 12 Principles of Green Chemistry 4. Design safer chemicals Chemical products should be designed to preserve efficacy of the function while reducing toxicity. The goal of producing safe chemicals (non- carcinogenic, mutagenic, neurotoxic) is the balance between optimal performance and chemical product function, ensuring that toxicity and risk are reduced to the lowest possible level. Example: the use of molecular modelling and ADMET calculations in pharmaceutical chemistry to select the possible biologically active compounds. 2 0  The 12 Principles of Green Chemistry 4. Design safer chemicals Hazard types to avoid: Toxicological/Eco- Physical toxicological Explosivit Carcinogenicity. y Reproductive. Flammabil Developmental. ity Neurological. Corrosivit Ozone depleting y potential. Bioaccumulation. Persistence in the 2 1  The 12 Principles of Green Chemistry 4. Design safer chemicals Case study: Pesticides Conventional use of agricultural pesticide and a malarial control agent Dichlorodiphenyltrichloroethane (DDT). Carcinogenic. The threat to wildlife - especially birds – has almost led to the extinction of a bald eagle population. 2 2  The 12 Principles of Green Chemistry 4. Design safer chemicals Case study: Pesticides Alternative (and natural) use of Spinosad for insect control: Produced by bacteria Saccharopolyspora spinosa. Isolated from Caribbean soil samples. Toxicity scorecard It selectively targets nervous system Rat: LD50>5000 mg/kg of insects. Duck: LD50>5000 mg/kg Fish: LC50-96h=30.0 mg/L Demonstrates high selectivity, low Bee: LD50=0.0025 mg/bee mammalian toxicity, and a good environmental profile. 2 3  The 12 Principles of Green Chemistry 4. Design safer chemicals Case study: Ranitidine (Zantac) It was banned in 2019 due to detection of low levels of the nitrosamine impurity (N- nitrosodimethylamine) (NDMA) which is a carcinogenic compound. Case study: Thalidoamide It was banned in 1960 due to teratogenic effect of (S) isomer. 2 4  The 12 Principles of Green Chemistry 5. Safer Solvents and Auxiliaries The use of auxiliary substances (solvents, separation agents, etc.) should be made unnecessary whenever possible and when used, they should be harmless. Chromatographic separations, where large quantities of solvents are used, are problematic due to environmental pollution. Most conventional organic solvents are toxic, flammable and corrosive. Their recycling requires energy efficient distillation with considerable losses and therefore the development of environmentally-friendly solvents is necessary. 2 5  The 12 Principles of Green Chemistry 5. Safer Solvents and Auxiliaries 2 6  The 12 Principles of Green Chemistry 6. Design for Energy Efficiency Energy requirements should be recognized for their environmental and economic impacts and should be minimized. Most energy is used for heating, cooling, separations and pumping. Synthetic methods should be conducted at ‘ambient’ conditions – room temperature and atmospheric pressure – in order to minimize energy usage. It is necessary to choose the reactions and catalysts that require lower temperatures. 2 7  The 12 Principles of Green Chemistry 7. Use of Renewable Feedstocks A raw material or feedstock should be renewable rather than depleting whenever technically and economically practical. Because of this, the making of biodegradable plastic materials is a current trend. Biodegradable packaging has a future in the food industry. The principle also implies the use of renewable energy technologies that include solar energy, wind power, hydropower, biomass energy and biofuels. 2 8  The 12 Principles of Green Chemistry 7. Use of Renewable Feedstocks For example, Brazil with its sugar cane production and bioethanol production ensures energy independence and employment. Renewable resources can be made increasingly viable technologically and economically through green chemistry. e.g: Carbon dioxide. Chitin. Waste utilization. 2 9  The 12 Principles of Green Chemistry 8. Reduce Derivatives Unnecessary derivatization should be avoided whenever possible (eg. blocking group, protection/deprotection) 3 0  The 12 Principles of Green Chemistry 8. Reduce Derivatives Case study: 6-aminopenicillanic acid 3 1  The 12 Principles of Green Chemistry 8. Reduce Derivatives Case study: Lactic acid 3 2  The 12 Principles of Green Chemistry 9. Catalysis Catalytic reagents (as selective as possible) are superior to stoichiometric reagents. In order to protect the environment, the catalysis principle promotes the use of biodegradable catalysts, which implies less energy use, avoiding the use of organochlorine compounds. 3 3  The 12 Principles of Green Chemistry 9. Catalysis Catalysts can facilitate complex reactions by: ‒ Lowering the activation energy of the reaction. ‒ Reducing temperature necessary to achieve a reaction. ‒ Controlling the site of the reaction (selectivity enhancement). 3 4  The 12 Principles of Green Chemistry 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 non- harmful degradation products. 3 5  The 12 Principles of Green Chemistry 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. Real time analysis for a chemist is the process of “checking the progress of chemical reactions as it happens”. 3 6  The 12 Principles of Green Chemistry 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. 3 7  The Ideal Green Synthesis To be called "green," each reaction should have three green components: Solvent. Reagent / catalyst. Energy consumption. 3 8  The Green Chemistry Metrics 3 9  The Green Chemistry Metrics The yield % Metrics definition Ideal value yield% yield%= [moles of product / moles of limiting 100 reagent] × 100 % What is missing? What byproducts are produced? How much waste is generated? Is the waste benign or harmful waste? How much energy is required? Are purification steps needed? What solvents are used? (are they benign and/or reusable?) Is the “catalyst” truly a catalyst? (stoichiometric vs. catalytic) 4 What is the cost of the reaction? 0 The Green Chemistry Metrics The yield % 4 1 The Green Chemistry Metrics 4 2  The Green Chemistry Metrics The Atom economy The atom economy determines how many reactant atoms end up in the desired product of a chemical synthesis and how many contribute to the formation of waste products. Metrics Definition Ideal value Atom 𝑇h𝑒𝑚𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟 𝑤𝑒𝑖𝑔h𝑡 𝑜𝑓 𝑡h𝑒 𝑝𝑟𝑜𝑑𝑢𝑐𝑡 100 × 100 economy 𝑇h𝑒 𝑠𝑢𝑚 𝑜𝑓 𝑀𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟 𝑤𝑒𝑖𝑔h𝑡𝑠 𝑜𝑓 % (AE%) 𝑠𝑡𝑜𝑖𝑐h𝑖𝑜𝑚𝑒𝑡𝑟𝑖𝑐 𝑟𝑒𝑎𝑐𝑡𝑎𝑛𝑡𝑠 Atom economy does not account for solvents, reagents, reaction yield, and reactant molar excess. 4 3 The Green Chemistry Metrics The Atom economy 4 4 4 5  The Green Chemistry Metrics Calculate molecular formula and molecular weight C6H10O C19H17P C7H12 C18H15PO 98 g/mol 276 g/mol 96 g/mol 278 g/mol AE%= [96 / (98+276)]× 100 = 25.66% Elimination reaction 4 6  The Green Chemistry Metrics Calculate molecular formula and molecular weight C6H10 Br2 C6H10Br2 82 g/mol 160 g/mol 242 g/mol AE%= [242 / (82+160)]*100 = 100% Addition reaction 4 7  The Green Chemistry Metrics Calculate molecular formula and molecular weight C5H12O2 CH5N C4H9NO C2H6O 102 g/mol 31 g/mol 87 g/mol 46 g/mol AE%= [87 / (102+31)]*100 = 65.4% Substitution reaction 4 8  The Green Chemistry Metrics Calculate molecular formula and molecular weight C4H9Br C2H5ONa C4H8 C2H6O 137 g/mol 68 g/mol 56 g/mol 46 g/mol AE%= [56 / (137+68)]*100 = 27.3% Elimination reaction 4 9  The Green Chemistry Metrics The E-factor Metrics Definition Idea l Valu e Environmen The E-factor measures total waste tal factor relative to product including the (E-factor) losses of𝑇h𝑒𝑚𝑎𝑠𝑠 𝑜𝑓 𝑤𝑎𝑠𝑡𝑒 𝑖𝑛 𝐾𝑔 solvents, acids and 𝑇h𝑒𝑚𝑎𝑠𝑠 𝑜𝑓 𝑝𝑟𝑜𝑑𝑢𝑐𝑡 𝑖𝑛 𝐾𝑔 bases used in the work Zero 5 0  The Green Chemistry Metrics The E-factor High E factor indicates more waste generation and negative environmental impact However, E-Factor does not give any data about the quality of waste. Waste includes products that do not have any further use and also reagents and solvents used during production and are either not recycled or recycled. The "good" E factor in industry is usually around 0.1, meaning that 10 kg of the desired product is only 1 kg of waste and by- products. In pharmaceutical production which requires highly pure products, the E-factor can be 100, which means that every kg of product produces 100 kg of waste. 5 1  The Green Chemistry Metrics Elimination reaction 0.01 mole used Calculate molecular formula and molecular weight C6H10O C19H17P C7H12 C18H15PO 98 g/mol 276 g/mol 96 g/mol 278 g/mol Calculate the mass of product (moles*M. Wt) (yield 86%) 0.83 g 2.39 E-factor = [(2.39/ 0.83] = 2.88 g 5 2  The Green Chemistry Metrics Addition reaction 94% 0.01 mole used Calculate molecular formula and molecular weight C6H10 Br2 C6H10Br2 82 g/mol 160 g/mol 242 g/mol Calculate the mass of each reagent and product (moles*M. Wt) 0.82 g 1.6 g 2.27 g E-factor = [(0.82+1.6)-(2.27) / 2.27] = 0.066 5 3 The Green Chemistry Metrics The Reaction mass efficiency (RME %) Metrics definition Idea l valu 𝑇h𝑒𝑚𝑎𝑠𝑠 𝑜𝑓 𝑡h𝑒𝑝𝑟𝑜𝑑𝑢𝑐𝑡 ×100 e 𝑇h𝑒𝑚𝑎𝑠𝑠 𝑜𝑓 𝑠𝑡𝑜𝑖𝑐h𝑖𝑜𝑚𝑒𝑡𝑟𝑖𝑐 𝑟𝑒𝑎𝑐𝑡𝑎𝑛𝑡𝑠 Reaction 100 mass % The reaction mass efficiency accounts for all reactant mass efficiency (i.e., (RME stoichiometric %) quantities used) and includes yield, and atom economy. The RME is probably the most helpful metric for chemists to determine the greenness of the reaction. 5 4  The Green Chemistry Metrics The mass intensity and mass productivity Metrics definition Ideal valu 𝑇h𝑒𝑡𝑜𝑡𝑎𝑙 𝑚𝑎𝑠𝑠 𝑜𝑓 𝑠𝑡𝑜𝑖𝑐h𝑖𝑜𝑚𝑒𝑡𝑟𝑖𝑐 𝑟𝑒𝑎𝑐𝑡𝑎𝑛𝑡𝑠 e Mass 𝑖𝑛𝑐𝑙𝑢𝑑𝑖𝑛𝑔 𝑡h𝑒 𝑠𝑜𝑙𝑣𝑒𝑛𝑡𝑠𝑎𝑛𝑑 𝑤𝑜𝑟𝑘𝑢𝑝 𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛𝑠 1 g/g intensity 𝑇h𝑒𝑡𝑜𝑡𝑎𝑙 𝑚𝑎𝑠𝑠 𝑜𝑓 𝑠𝑡𝑜𝑖𝑐h𝑖𝑜𝑚𝑒𝑡𝑟𝑖𝑐 𝑝𝑟𝑜𝑑𝑢𝑐𝑡𝑠 (MI) 1 Mass ×100 100% 𝑀𝑎𝑠𝑠 𝐼𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦 𝑀𝐼 productivity Mass productivity may be a useful metric for businesses since it highlights resource utilization. 5 5  The Green Chemistry Metrics Reaction Mass efficiency = [40/ (37+30)] *100 = 59.70% Mass Intensity = [(37+60+250+100+25+25+5) / 40]= 12.55 g/g Mass productivity = (1/12.55)*100= 7.96% 5 6  The Green Chemistry Metrics Benzyl alcohol (10.81g, 0.10 mol, FW 108.1) is reacted with p- toluenesulfonyl chloride (21.9 g, 0.115 mol, FW 190.65) in toluene (500 g) and triethylamine (15 g) to give the sulfonate ester (FW 262.29) isolated in 90% yield (0.09 mol, 23.6 g). Calculate the AE, E-Factor, RME, MI and mass productivity 262.29 Atom economy = ( 108.1+190.65 ) ×100=87.8% E-factor = (10.81+21.9) - 23.6/23.6 = 0.38 Reaction mass efficiency = Mass intensity = ( 10.81+21.9+ 500+ 15 ) =23.2 𝑔 / 𝑔=23.2 𝑘 𝑔 /𝑘 𝑔 23.6 Mass productivity = 1 1 ×100= ×100=4.3% 𝑀𝑎𝑠𝑠 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦 23.2 5 7 Green Solvents & Solventless Reactions 5 8 Effect of solvent in the chemical reactions: Solvent affects the reactants’ solubility, stability, and reaction rates. Choosing the proper solvent allows for thermodynamic and kinetic control of the chemical reaction. The proper selection of solvent became a major focus of green synthesis. Common Solvents hazards: The large-scale use of the common solvents (about 28 million tons annually), that are classified as VOCs (volatile organic compounds) leads to several hazards such as; 5 9 1. Toxicity: Most of the VOCs have toxic hazards, for example: a. Diethyl ether (because of its flammability and tendency to form peroxides). b. Di-iso-propyl ether (peroxide formation). c. Hexane (neurotoxicity). d. Nitromethane (explosion hazards). e. Ethylene glycol and dimethyl ether (teratogenicity). 2. Pollution: During the period 2008–2018, European emissions inventories report 2–3 million tons of VOCs emitted per year. 6 0  I. Green solvents  Environmentally friendly chemical solvents used as substitutes to common organic petrochemical solvents, obtained from the distillation & purification of agricultural products or any sustainable methods. Their common characteristics are low toxicity, ease of recycling, and ease of biodegradation. The interest in the use of green solvents has arisen recently since the United Nations pronounced its sustainable development goals (SDGs), leading to a wide relevance for using green solvents for a more sustainable future. 6 1 Criteria, based on those of Gu and Jérôme (2013), used to select green solvents: 1. Availability on the required. 2. Technical performance (including solvency) is no worse than the equivalent conventional solvent. 3. Stability during use and storage. 4. Non-flammable or low flammability. 5. Competitively priced. 6. Ability to be recycled. 7. Purity appropriate to use. 8. Resource and energy-efficient production. 9. Produced from renewable intermediates and feedstocks. 10. Established acceptable toxicity and ecotoxicity profiles sufficient for regulatory purposes. 11. Fully biodegradable to completely harmless products. 6 12. Meets standards and regulations for transportation. 2  Water One of the most important solvents in green synthesis is water, protic polar solvent. Non-flammable, nontoxic, not expensive, and available. High polarity of water also has a lot of advantages regarding reactivity and selectivity, like in organometallic catalysis. The possibility to recycle the catalyst in an aqueous biphasic system via phase extraction whereas the product stays dissolved in the organic phase. Disadvantages of water: Not a good solvent for many organic compounds. Very high heat of vaporization (not volatile). 6 3 Applications of water as a green solvent: 6 4 Example 1: Oxidation of alcohols to aldehydes, ketones, and carboxylic acids using water-soluble palladium (II) bathophenanthroline complex as a stable recyclable catalyst for the selective aerobic oxidation of a wide range of alcohols in a biphasic water-alcohol system. 6 5 Example 2: Direct carbonylation of alcohols using Pd (tppts)3 complex as a catalyst in aqueous biphasic medium. Tppts : Triphenylphosphine-3,3′,3′′- trisulfonic acid trisodium salt 6 6 Supercritical Water (SCW) Water exists at pressures above 221 bar and temperatures above 374°C. It acts as a dense gas with a dissolving power equivalent to that of organic solvents of low polarity due to the loss of the ability to form hydrogen bonding. SCW is used as a reaction medium, especially in oxidation processes for the destruction of toxic substances such as those found in industrial aqueous effluents. Supercritical Carbon Dioxide (scCO2) Carbon dioxide, at room temperature, exists as a gas. Above its critical temperature and pressure (31°C and 73.8 bar), CO2 is in the supercritical state, thereby featuring gas-like viscosities and liquid-like densities. 6 7 Advantages of scCO2 scCO2 is renewable, nontoxic, nonflammable, readily evaporating and chemically inert towards many substances. Uses of scCO2 One main use of scCO2 in the food and nutrition industry, for examples, used as an extraction medium for decaffeination processes for coffee beans and tea, thus instead of chlorinated organic solvents. Due to its high miscibility with gases, scCO2 is especially useful in reactions such as hydrogenation with H2, oxidation with O2 and hydroformylation with syngas (CO/H2). Example: Hydrogenation of anthracene with scCO2 6 8  Ionic liquids  Ionic liquids are molten organic salts that are general fluid at room temperature, and stable over a wide range of temperature.  They are typically composed of large asymmetric organic cations and inorganic, or organic anions. Cationic liquids Anionic liquids They are composed of a bulky Halides, tetrafluoroborate, organic cation such as hexafluorophosphate, and imidazolium, pyridinium, nitrate, often include a smaller, ammonium and phosphonium, less bulky cation such as a and a relatively small inorganic proton (H⁺) or lithium ion (Li⁺). anion (like chloride or sulfate) or small organic anion (like acetate or tetrafluoroborate). 6 9 7 0 Advantages & characters of ILs: Liquid at range of 300°C (-96 to +200°C). Anti-microbial properties. Thermally-stable. Excellent solvents for organic, inorganic, and polymeric materials. Nonflammable. Easily prepared. Catalysts as well as solvents. No measurable vapor pressure at room temperature. Employed in nanobiotechnology and nanomedicine. Several drugs are sparingly soluble in aqueous media, and it does not help to achieve their pharmacological effects. To overcome the solubility limitations, ILs have been investigated as solubilizing media. 7 1 7 2  ILs could be used in biphasic systems due to the immiscibility with some organic solvents. After extraction with an organic solvent, the catalyst remains in the IL and can easily be re- used. Applications of ILs: 1. Friedel-Crafts reactions. 8. Sulfonation. 2. Heck and Suzuki coupling. 9. Nitration. 3. Oxidation (with air and/or 10. Halogenation. dioxygen). 11. Diazotization. 4. Reduction. 12. Diels-Alder reaction. 5. Chiral hydrogenation. 13. N-Alkylation and O- 6. Oligomerization. alkylation. 7. Polymerization. 14. Aldol condensation. 7 3 Example 1: Use of the ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquid [bmim][NTf2] in Mannich reaction. [bmim][NTf2] Example 2: The reactions between toluene and nitric acid in (a) a halide-based IL, (b) a triflate-based IL. The choice of IL can control the outcome of a reaction. 7 4  Organic carbonates  Esters of carbonic acid. Characters of Organic Carbonates: Easily available in large amounts, inexpensive, possess low (eco) toxicity, and completely biodegradable. May be open chain or cyclic organic carbonates, the latter have a wider temperature range in the liquid state. Cyclic carbonates fulfill the requirements of green solvents: Low flammability, volatility and low toxicity. 7 5 Examples for Organic Carbonates: Propylene carbonate (PC): is an aprotic, highly dipolar solvent with low viscosity and a very large liquid state range (mp. -49 °C, bp. 243 °C). PC has a high molecular dipole moment (4.9 D) so it is susceptible to microwave irradiation and could be used as solvent for microwave-assisted organic synthesis. Example:  Rhodium-catalyzed asymmetric hydrogenation of olefins in propylene carbonate (PC). 7 6  Biosolvents  Biosolvents, have been developed as alternatives to VOCs.  Biosolvents, are esters of naturally occurring acids and fatty acids, bioethanol, terpenic compounds, isosorbide, glycerol, and glycerol derivatives. Characters of biosolvents: Produced from renewable sources such as vegetable, animal or mineral raw materials by chemical and physical processes without the consumption of fossil resources. Optimal technical specifications (dissolution capability and volatility). Environmental safety. Eco-compatible production. Production from renewable raw materials. 7 7 Examples for biosolvents: 7 8  Biosolvents have been successfully employed in multicomponent reactions. Example 1: Three-component condensation of dimedone, formaldehyde, and styrene in glycerol. Example 2: Biginelli reaction in glycerol. 7 9  II. Solventless Reactions (neat reactions) SLR  Role of the solvent in the reaction; facilitate mass and heat transfer, and to isolate and purify desired products from reaction mixtures.  “No reaction occurs in the absence of solvent” Aristotle said. Which was proved to be not true  Solventless Reactions; chemical reactions that could be done in absence of solvent, could be called dry media reaction or solid-state reaction. Advantages of Solventless reactions: More efficient & more selective compared to traditional reactions. More economic & especially important industry due to high yields of products with minimal energy consumption. Reduces pollution & prevents formation of waste/by-products. Shorter reaction time. Easy extraction process. 8 0 Types of Solventless reactions: a) Neat reactions: mixing & grinding the reactants (gases/solids, solids/liquids, liquids/liquids, and solids/solids. b) Reactions between reactants using solid mineral supports such as silica, alumina and clays (high surface area, catalytic activity, and ability to provide a solid support for reactions). Acid-Base Catalysis: Certain clays, possess intrinsic acid-base properties that make them effective as catalysts in various reactions as esterification, transesterification, and other organic transformations by providing acidic or basic sites. c) Reactions carried out under phase-transfer catalysis (PTC): a technique that facilitates reactions between reactants that are in different phases, often liquid-liquid or solid-liquid systems. In PTC, a phase-transfer catalyst such as Quaternary Ammonium Salts, Phosphonium Salts and Crown Ethers helps transfer one reactant from one phase into another where the reaction can occur. This approach is particularly useful for reactions involving immiscible phases. 8 1  Mixing or Grinding Reactions Grinding of the reactants for a chemical reaction can be carried out by using mortar and pestle or by using high-speed vibrating mill. Grinding technique makes the reactants molecules to collide leading to formation of the final products. The time required to complete the reaction is less than that of the traditional heating techniques. The grinding reactions performed out at room temperature. 8 2 Various organic reactions are carried out by using grinding technique such as Grignard reaction, Aldol condensation, Reformatsky reaction, Knoevenagel condensation, Dieckman reaction, Oxidation and reduction reactions, and Rearrangement reactions. Example 1: Knoevenagel condensation of aromatic aldehyde with active methylene compound using calcium oxide based on grinding method. Example 2 Electrophilic aromatic substitution of anisole: on acidic alumina, at room temperature to form 4-methoxy-acetophenone. 8 3  Ball-Milling Reaction techniques Ball milling techniques could be considered as an automated form of mortar and pestle. Electricity is applied as energy source to operate the ball mill. In case of ball mill, reacting materials are placed in reaction vessel attached with grinding balls & vessel is allowed to shake at high speed to carry out the reaction. Types of ball mills:  Wig-L-Bug mill (back and forth motion),  Retsch mixer mill (side-to-side motion),  Planetary ball mill (planetary motion). 8 4 Various organic reactions are carried out adopting ball-milling techniques such as Nucleophilic reactions, Halogenation reactions, Polymerization reaction, Condensation reactions, Diels-Alder reaction, Oxidation-reduction reaction. Example 1 Condensation of 9,10-phenanthrenequinone with o-phenylenediamine by using Ball- mill technique for grinding to yield Dibenzo[a,c]phenazine. Example 2 Condensation of benzaldehyde, malononitrile, and thiourea or urea by ball milling in 40 minutes to produce 2-thioxo or 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivative in excellent yields (up to 98%). 8 5  Microwave-assisted solventless reactions Using microwave irradiation (MWI) as heating source to carry out chemical transformations in minutes. MWs are the electromagnetic radiation with frequencies between 300 MHz and 300 GHz. MWs are non-ionizing form of radiation energy that cannot break chemical bonds but can transfer energy selectively to various substances. Some materials (such as hydrocarbons, glass, and ceramics) are nearly transparent to microwaves, so therefore behave as good insulators in a microwave oven while metals reflect MWs. Molecules with dipole moment (many types of organic compounds) and salts absorb MWs energy directly. Microwaves couple directly with molecules in the reaction mixture producing a rapid rise in temperature. Most of microwave-assisted organic synthesis (MAOS) are performed in open glass containers (test tubes, beakers and round-bottomed flasks) using neat reactants under solvent-free conditions. 8 6 Some of the supported reagents, namely clay-supported iron (III) nitrate (clayfen), and copper (II) nitrate (claycop) a class of phase-transfer catalysts known for their use in facilitating various chemical reactions. They allow for efficient phase-transfer catalysis in reactions involving multiple phases, such as solid-liquid, liquid-liquid, or gas-liquid systems. They could be used in MW assisted reactions. Advantages of microwave-assisted organic synthesis (MAOS): Rapid heating, high temperature, homogeneity, and selective heating. Example 1 Synthesis of Imatinib: It involves fast, high yield, and convenient synthesis of Imatinib on an aldehydic, super acid-sensitive resin, through an efficient, MW- assisted synthetic protocol. 8 7 Example 2 MW solventless synthesis of N-acetylated cephalosporin: The cephalosporic acid is a carboxylic acid which gets adsorbed on the basic alumina and then it is brought in contact with MW radiation only for 2 minutes. 8 8 Alternative Sources of Energy 8 9  The primary goal of synthetic chemists today is to devise sustainable methods for carrying out chemical syntheses. A synthetic reaction has many components which need to be addressed to make a reaction “Green”. One of the important components is the energy source required to drive a reaction to completion. Though a “room temperature” reaction is an ideal “green” reaction, but there are many reactions which can not proceed without the application of external energy, i.e. high-temperature reactions. In these cases, conventional heating possesses many problems such as long reaction time leading to waste of energy and unnecessary by-products. In such cases, the reactions can be made benign by using alternative energy sources like microwave heating, ultrasonic sound and ultraviolet/visible light. 9 0 Advantages of non-conventional energy sources: ‒ Shorter reaction time. ‒ By-product elimination. ‒ Improved yields. ‒ Enhanced selectivity. ‒ Homogeneous heating. ‒ In conventional heating, the heat energy is transferred to the reaction media from the heating source (e.g. oil bath) through the reaction vessel resulting in inhomogeneous heating. ‒ Combining two different types of unconventional energy sources such as microwave-ultrasound or microwave-UV Visible radiation is the latest green-hybrid strategy which promises to create a new discipline of chemistry giving an innovative dimension to sustainable synthesis. 9 1  Microwaves (MWs) The utility of MW in conducting chemical reactions is based on the ability of certain materials to absorb and transform electromagnetic energy into heat. If the material is conducting, MWs are mostly reflected from the surface. e.g. metals, graphite If it is an insulator, MWs penetrate the surface without any absorption, loss, or heat generation. e.g. quartz glass, porcelain, ceramics If the material is dielectric, the dipoles (permanent or induced) undergo reorientation during the passage of MWs, leading to absorption of MWs which causes heat generation due to dielectric heating. e.g. water MWs, being electromagnetic, have two components–electric and magnetic field components. The electric field component is responsible for the dielectric heating. 9 2  MWs interact with molecules via two modes of action: dipolar rotation and ionic conduction. In dipolar rotation, a molecule rotates back and forth constantly, attempting to align its dipole with the ever-oscillating electric field; the friction between each rotating molecule results in heat generation. In ionic conduction, a free ion or ionic species moves translationally through space, attempting to align with the changing electric field. Like in dipolar rotation, the friction between these moving species results in heat generation, and the higher the temperature of the reaction mixture, the more efficient the transfer of energy becomes. In both cases, the more polar and/or ionic species, the more efficient the rate of 9 heat generation. 3  Many organic compounds are available, which are polarizable and whose dipoles can reorient rapidly in response to the changes in electric field. Hence reactions carried out under MW heating can be achieved within a very short time and with high selectivity. 9 4 MW-assisted synthesis of Phenacetin (NSAID): MW-enhanced synthesis of Phenacetin. The reaction is carried out in a MW oven at 30% power for five minutes. High yield (81%) of the desired analgesic drug is obtained. 9 5 MW-assisted synthesis of Rosiglitazone (used in the treatment of type 2 diabetes mellitus): 9 6 9 7  Ultrasonic sound (US) Sonochemistry propagates chemical reactions by cavitation method and so a general requirement is that at least one of the phases of the reaction mixture should be a liquid. Ultrasound is transmitted via a series of compression and rarefaction waves which spreads through the molecules of the medium through which it passes. When the rarefaction cycle overcomes the attractive forces of the molecules of this liquid medium, the formation of “cavitation bubbles” takes place. These bubbles grow in size over a few cycles but are unstable due to interference of other bubbles forming and resonating around them. The result is the expansion of certain bubbles to an unstable size leading to violent collapse. This violent collapse generates the energy for carrying out chemical reactions. 9 8  Many theories have been formulated as the cause of this energy release of which the most accepted one is the “hot spot” approach. Each of the cavitation bubbles is considered to be a microreactor, generating high temperature and pressure within them. 9 9 Synthesis of Vitamin A acetate via dehydration of hydroxenin monoacetate: 10 0 An efficient process for the synthesis of Tryptamines: (serotonin receptor agonists acting at 5-HT1 receptors, some are used to treat migraine disorders) from their nitro precursor under ultrasonic irradiation in water. 10 1  Photochemistry Photochemical reactions catalyzed by ultraviolet light, visible light or infrared radiation adopt a completely different path compared to temperature driven reactions. The photon can be absorbed directly by the reactant or by a photosensitizer which absorbs the photon and transfers the energy to the reactant. When photons interact with a molecule, the energy is transferred to the molecule, thereby changing its electronic structure. Thus, the molecule is excited and this whole process takes as little as 10-15 sec. In an extremely short period of time, large activation energy barriers can be overcome, thereby allowing a reaction which, if carried out using conventional heating would have required very long reaction time. The absorption of a photon not only gives the molecule the necessary activation energy, but also enables an otherwise inaccessible reaction path, by changing the symmetry of the molecule’s electronic configuration. 10 2 10 3 Sonication of photopinacolisation of benzophenone: Photosynthesis of cyclic peptide by photodecarboxylation: 10 4 Photosynthesis of Ibuprofen (NSAID): 10 5 Photosynthesis of Ascaridol (antileishmanial agent): 10 6 Catalysis 10 7  Catalysis is the increase in the rate of a chemical reaction due to the participation of a catalyst. A catalyst allows for the lowering of the activation energy for a reaction to occur. Decreased activation energy results in faster and less energy-intensive reactions and processes. 10 8  Activation energy The Activation Energy, Ea, is the minimum energy necessary to form an activated complex in a reaction. Or…. The minimum energy requirement to overcome a reaction barrier and initiate a reaction. 10 9  Catalysis Reaction Diagram Lowere d activat ion energy ! In general, it’s more effective, safer, and sustainable to use catalysts than not! 11 0 Catalysis Principle #1: It is better to prevent waste than to treat or clean up waste after it is formed. Principle #6: Energy requirements should be minimized. Synthetic methods should be conducted at ambient temperature and pressure. Principle #9: Catalytic reagents are superior to stoichiometric reagents. Using catalysts should reduce Energy required (e.g. heat). The use of stoichiometric reagents. By-products. Waste. 11 1  Types of Catalysts  Homogeneous catalyst A catalytic reaction where the catalyst is in the SAME phase as the reactants. Ideally, the catalyst is soluble in a solution.  Heterogeneous catalyst A catalytic reaction where the catalyst is in a DIFFERENT phase from the reactants. Ideally, the catalyst is immiscible in a solution and is a solid. 11 2 Mechanistic Differences *the catalyst has to be properly separated from the reaction mixture 11 3 Homogenous vs Heterogenous Homogeneous Heterogeneous Difficult separation Easy separation Difficult to regenerate Easy regeneration Expensive Cheap High reaction rates Lower rates Less sensitive More sensitive High selectivity Lower selectivity Known mechanisms Requires more energy Unique mechanisms 11 4 Iron (II) is used as a homogenous catalyst in the reaction between iodide ions and peroxodisulfate ions in iodine synthesis in water (same phase). The positive Fe3+ ion enables the collision between the two negatively charged reactants. 11 5 Ibuprofen synthesis conventional method (Boots synthesis) 6 steps 11 6 Ibuprofen synthesis with the aid of catalysis (Boots- Hoechst-Celanese (BHC) synthesis) 3 steps Catalytic hydrogenation Carbonylation with carbon in the presence of nickel monoxide in the presence of a catalyst 100% atom palladium catalyst. 100% economy atom economy 11 7 The anti-Parkinsonian drug, lazabemide, palladium- catalyzed amidocarbonylation 11 8  Designing a Green Catalyst Not all catalysts are created equal. Chemists need to consider various factors when deciding on the catalyst: Low toxicity. Earth abundance. Efficiency. Rate and energy input. Compatible with green solvent. Longevity and Recyclability. Ease of production. Large volume and consistent in quality. Many metals which are High selectivity for the desired product(s). used as catalysts are depleting 11 9 The Nobel Prize in Chemistry 2010 was awarded jointly to Richard F. Heck, Ei-ichi Negishi and Akira Suzuki for “Palladium- catalyzed cross couplings in organic synthesis”. 12 0 Suzuki coupling The transition metal of palladium was used to catalyze the C-C bond formation from a halide (R1-X) with an organoboron species (R2-BY2). Negishi coupling The transition metal of palladium or nickel in different oxidation states was used to catalyze the C-C bond formation from a halide with an organozinc species. Heck coupling The chemical reaction of an unsaturated halide (or triflate) with an alkene in the presence of a base and a palladium catalyst to form a substituted alkene. 12 1 Metal-based organic catalysis Metal-based catalysts are a widely used catalytic system and have notable contributions towards the synthesis of organic compounds. They can be simple metal salts, metal oxides, or metal complexes exhibiting high catalytic activity. They have diverse applications as catalysts under homogeneous, heterogenous or solid support conditions, from academic to industrial research laboratories. 12 2  Organocatalysis Organocatalysis is the use of small organic molecules predominantly composed of C, H, O, N, S, and P to accelerate chemical reactions. The advantages of organocatalysts include:  Lack of sensitivity to moisture and oxygen  Catalyze asymmetric and enantioselective reactions  Low cost  Low toxicity All of this demonstrates a direct benefit in the production of pharmaceutical intermediates when compared with (transition) metal catalysts. 12 3 Some examples of Organocatalysts (small mole-catalysts): 12 4 Proline-catalyzed asymmetric aldol condensations O O O OH R1 L-proline + H H R2 10 mol%, DMF, 4°C R2 R1 12 5  Alternative Types of Catalysts Metal-Organic Frameworks High surface area Tunable pores allow for a wide range of possibilities to selectively sequester chemical compounds. Zeolites 3-D framework of crystalline hydrated alumino-silicates consisting of TO4 tetrahedra (T = Si or Al). The nature of the Zeolite is determined by the Si/Al ratio and base used in preparation of the catalyst – the catalyst can be fine-tuned for specific purposes. 12 6  Alternative Types of Catalysts Phase Transfer Catalysis These catalysts act by transporting reactants from one liquid phase to another. Often the reactions happen at the interface of the phases. The most common is aqueous/organic layers. Biocatalysis A catalytic reaction where proteins and enzymes perform chemical transformations/reactions. Often in the same solution. Sometimes referred to as enzymatic catalysis. Photocatalysis Utilize the UV energy to carry out chemical reactions. Proven to be effective in reducing harmful waste during processes. 12 7  Biocatalysis-Enzymes Similar to traditional Homogeneous and Heterogeneous catalysts, enzyme lowers the activation energy to expedite chemical reactions. However, enzymes are much more effective and accurate. 12 8  How are Enzymes so Accurate? Mechanism: 12 9 Advantages vs Disadvantages of Enzymes Advantages Disadvantages Reactions run in water w/o Reaction times may be organic solvents. slower compared to Reactions run at room traditional organic temperature. synthesis No toxic metals. Reaction samples are more No carcinogens. dilute Enzymes are more No toxic waste. expensive and difficult to VERY High selectivity. recover No protecting groups Enzymes lose activity needed. quickly Overall minimal energy is Sensitive to elevated required. temperatures Inhibition of the reaction13 0  Enzymatic Reaction Categories Hydrolases: Oxidoreductases: Catalyze the hydrolysis of Catalyze the oxidation of esters, amides, and alcohols to carbonyls and glycosides. dehydration of alkanes to Transferases: alkenes. Typical enzymes are oxidases, peroxidases, Catalyze the transfer of and dehydrogenases. specific functional groups from one molecule to Isomerases: another (ex. Catalyze the transfer of Transmethylases and stereochemistry from cis to transaminases) trans isomers. Lyases: Ligases: Catalyze group removal Catalyze bond-forming such as decarboxylations. reactions, such as 13 condensation reactions. 1 Example Biocatalysis of S-Ibuprofen: A. niger is an epoxide hydrolase responsible for the selective hydrolysis of the R-enantiomer of ibuprofen. Only selective for the S-enantiomer which is the active configuration of ibuprofen. Eliminates the amount of waste produced. 13 2  Photocatalyst Mechanism 1. Photocatalyst absorbs light energy to produce pairs of electrons. 2. Electrons in the valence band are “excited” and move to the conduction band. 3. The “excited” electrons then help to promote organic compounds to react via oxidation and decompose to CO2 and water. 13 3 Applications of Photocatalysts Destruction of hazardous chemicals or pollutants – e.g., Photocatalytic oxidation of Arsenic: Step 1: Absorption of photon energy (h ) with the formation of an electron- hole pair. The electron (e-) moves to the conduction band, leaving an electron vacancy (h+) in the valence band: TiO2 + h e - + h+ Step 2: The hole readily accepts electrons and so is a powerful oxidizing agent capable of oxidizing adsorbed hydroxyl ions and water to hydroxyl radicals: h+ + OH-abs  HO ads h+ + H2Oabs  HO ads + H+ Step 3: The radicals formed then oxidize the arsenite to arsenate in a series of complex reactions involving an As(IV) intermediate: As(III) + HO  As(IV) + OH- As(IV) + HO As(V) + OH- 13 4  Metal Organic Frameworks (MOFs) MOFs are 3-D microporous crystalline materials comprised of inorganic metal nodes and organic linkers. Extraordinary high surface area. Tunable pore sizes depend on the transition metal and organic linker combinations. The tunable pores allow for a wide range of possibilities to selectively sequester chemical compounds. Many shapes and sizes. 13 5  Zeolites Zeolites are microporous, crystalline aluminosilicate materials commonly used as commercial adsorbents. It has positive ions that can be exchanged for others in a contacting electrolyte solution and used as solid acid catalysts. Until recent years have zeolites been used by chemists for catalysts. Like all greener alternative catalysts, zeolites can provide more environmentally friendly materials by increasing selectivity and reducing waste. 13 6 Applications of Zeolites Selective production of p-xylene *Only p-xylene can selectively pass through the ZSM-5 pores due to the location of methyl groups. 13 7  Solid acid and solid base Catalysts Heterogeneous catalysts that are synthesized by embedding acidic or basic functional groups on the surface of a solid matrix. Their application will result in the development of more sustainable processes with a substantial reduction in the inorganic waste produced by the chemical industry. The use of chemically modified expanded corn starches, containing pendant SO3H or NH2 groups, as solid acid or base catalysts, respectively. In addition to being recyclable, these catalysts are biodegradable and derived from renewable raw materials. 13 8 Factors on catalyst viability as a greener alternative: 1. Selectivity: The amount of reactant converted into the final product. A high percentage of consumed reactant is necessary. A greener alternative catalyst will not be beneficial if the amount and rate of by-product is increased. Making it a less atom economical reaction. 2. Turnover Number (TON): The amount of desired product/mole of catalyst The turnover number directly relates to the catalyst lifetime and how many times it can be used before its efficiency is minimal. So, a greener alternative catalyst must have a higher turnover number to make is commercially viable. If not, this can lead to increased costs and waste. 13 9 Factors on catalyst viability as a greener alternative: 3. Turnover Frequency (TOF): The number of moles of product made/active site per second Catalyst active site Low active site density High active site density Low TOF will mean larger quantity of catalyst is required to have effective production yields. This results in higher costs and potentially more waste. 14 0