A.ChakravarthyA.ChakravarthyM.Pharmacy-Pharmaceutical ChemistryM.Pharmacy-Pharmaceutical ChemistryKVSR Siddhartha College of Pharmaceutical KVSR Siddhartha College of Pharmaceutical SciencesSciences

Green chemistryGreen chemistry, also called sustainable , also called sustainable chemistry, is a philosophy of chemical research chemistry, is a philosophy of chemical research and engineering that encourages the design of and engineering that encourages the design of products and processes that minimize the use products and processes that minimize the use and generation of hazardous substances*.and generation of hazardous substances*.The utilization of a set of principles that The utilization of a set of principles that reduces or eliminates the use or generation of reduces or eliminates the use or generation of hazardous substances in the design, hazardous substances in the design, manufacture and application of chemical manufacture and application of chemical products**.products**.

*As defined by United States Environmental Protection Agency*As defined by United States Environmental Protection Agency**** Anastas, P. T.; Warner, J.C. Green Chemistry: Theory and Practice, Oxford University Anastas, P. T.; Warner, J.C. Green Chemistry: Theory and Practice, Oxford University Press,1998Press,1998

ReducinReducingg

HazardHazard

WasteWaste

RiskRisk

Energy Energy

CostCost

ImprovinImprovinggRenewabilityRenewability

ReusabilityReusability

AtomAtomutilizationutilization

EnergyEnergyefficiencyefficiency

1.PREVENTION1.PREVENTION

It is better to prevent waste than to treat or clean It is better to prevent waste than to treat or clean up waste after it is formed.up waste after it is formed.

Industry Tonnage Ratio (kg of byproduct/kg of

product)

Oil refining 106 - 108 <0.1

Bulk chemicals 104 - 106 1-5

Fine chemicals 102 - 104 5-50

Pharmaceuticals 10 - 103 25-100+

Pharmaceuticals and chemical industries though have a lesser waste production compared to other industries like oil refining, have an opportunity of reducing the waste further since the amount of waste per kg of product is relatively higher

2. Atom Economy2. Atom Economy

Synthetic methods should be designed to Synthetic methods should be designed to maximise the incorporation of all materials maximise the incorporation of all materials used in the process into the final product.used in the process into the final product.

Atom economyAtom economy ( (atom efficiencyatom efficiency) describes ) describes the conversion efficiency of a chemical process in the conversion efficiency of a chemical process in terms of all atoms involved (desired products terms of all atoms involved (desired products produced). produced). In an ideal chemical process, the amount of In an ideal chemical process, the amount of starting materials or reactants equals the amount starting materials or reactants equals the amount of all products generated and no atom is wasted.of all products generated and no atom is wasted.

% atom economy= (MW of desired product/MW of all reactants) % atom economy= (MW of desired product/MW of all reactants) *100*100

3. Less Hazardous Chemical 3. Less Hazardous Chemical SynthesisSynthesis

Whenever practicable, synthetic methodologies Whenever practicable, synthetic methodologies should be designed to use and generate should be designed to use and generate

substances that possess little or no toxicity to substances that possess little or no toxicity to human health and the environment.human health and the environment.

Polycarbonate Synthesis using PhosgenePolycarbonate Synthesis using Phosgene

DisadvantagesDisadvantages Phosgene is highly toxic and corrosivePhosgene is highly toxic and corrosive Requires large amount of CHRequires large amount of CH22clcl22

Polycarbonate gets contaminated with chlorine impuritiesPolycarbonate gets contaminated with chlorine impurities

OH OHCl Cl

O

+NaOH

O O *

O

* n

Polycarbonate Synthesis using solid state processPolycarbonate Synthesis using solid state process

AdvantagesAdvantages diphenylcarbonate synthesized without phosgenediphenylcarbonate synthesized without phosgene Eliminates use of CHEliminates use of CH22ClCl22

Higher-quality polycarbonates without chlorine impurities.Higher-quality polycarbonates without chlorine impurities.Komiya Komiya et al., et al., Asahi Chemical Industry Co.Asahi Chemical Industry Co.

OH OH

+ O O *

O

* n

O O

O

4. Designing Safer Chemicals4. Designing Safer Chemicals

Chemical products should be designed to preserve Chemical products should be designed to preserve efficacy of the function while reducing toxicity.efficacy of the function while reducing toxicity.

Tributyltin oxide is usually used mixed with Tributyltin oxide is usually used mixed with paints as an antifoulants for ships. This paints as an antifoulants for ships. This chemical is usually toxic to marine organisms chemical is usually toxic to marine organisms and also bio-accumulate.and also bio-accumulate.Sea-Nine® 211, 4,5-dichloro-2-Sea-Nine® 211, 4,5-dichloro-2-nn-octyl-4--octyl-4-isothiazolin-3-one (DCOI), is now used which is isothiazolin-3-one (DCOI), is now used which is relatively less toxic.relatively less toxic.

http://academic.scranton.edu/faculty/CANNM1/environmentalmodule.html

5. Safer Solvents and Auxiliaries5. Safer Solvents and Auxiliaries

The use of auxiliary substances (solvents, The use of auxiliary substances (solvents, separation agents, etc.) should be made separation agents, etc.) should be made

unnecessary whenever possible and, when unnecessary whenever possible and, when used, innocuous.used, innocuous.

PreferredPreferredWaterWaterAcetoneAcetoneEthanolEthanol2-Propanol2-Propanol1-Propanol1-PropanolEthyl acetateEthyl acetateIsopropyl acetateIsopropyl acetateMethanolMethanolMethyl ethyl Methyl ethyl ketoneketone1-Butanol1-Butanoltt-Butanol-Butanol

Useable CyclohexaneHeptaneTolueneMethylcyclohexaneMethyl t-butyl etherIsooctaneAcetonitrile2-MethylTHFTetrahydrofuranXylenesDimethyl sulfoxideAcetic acidEthylene glycol

UndesirablePentaneHexane(s)Di-isopropyl etherDiethyl etherDichloromethaneDichloroethaneChloroformDimethyl formamideN-MethylpyrrolidinonePyridineDimethyl acetateDioxaneDimethoxyethaneBenzeneCarbon tetrachloride

Green Chemistry Symposium-ll, Sacramento, CA

Pfizer solvent replacement tablePfizer solvent replacement tableRed solvents Green solvents

Pentane Heptane

Hexane(s) Heptane

Di-isopropyl ether or diethyl ether 2-MeTHF or tert-butyl methyl ether

Dioxane or dimethoxyethane 2-MeTHF or tert-butyl methyl ether

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

Green Chemistry Symposium-ll, Sacramento, CA

Ionic solvents:Ionic solvents:Room temperature ionic liquids(RTILs) can be Room temperature ionic liquids(RTILs) can be used as substitutes for aromatic solvents in used as substitutes for aromatic solvents in chemical reactions and separation processes.chemical reactions and separation processes.RTILs are organic salts with melting points RTILs are organic salts with melting points below 100below 1000 0 C, often below room temperature, C, often below room temperature, have no vapour pressure and composed of have no vapour pressure and composed of entirely cations and anions.entirely cations and anions.Exhibit good solvent properties and often Exhibit good solvent properties and often facilitate chemical reactions without being facilitate chemical reactions without being transformed in the process.transformed in the process.Have negligible vapour pressure and miniscule Have negligible vapour pressure and miniscule flammability.flammability.

Exhibit high thermal stability and wide working Exhibit high thermal stability and wide working temperatures.temperatures.Owing to multitude of possible combinations of Owing to multitude of possible combinations of cation and anion, they are susceptible to cation and anion, they are susceptible to numerous permutations that allow various numerous permutations that allow various physical and chemical properties to be adjusted physical and chemical properties to be adjusted at will.at will.Eg: 1-butyl-3-Eg: 1-butyl-3-methylimidazoliumhexafluorophosphate, and methylimidazoliumhexafluorophosphate, and some imidazolium tetrafluoroboratessome imidazolium tetrafluoroborates

Philip E.Rakita, Ozark Fluorine Specialities

6. Design for Energy Efficiency6. Design for Energy Efficiency

Energy requirements should be recognized for their Energy requirements should be recognized for their environmental and economic impacts and should be environmental and economic impacts and should be

minimized. Synthetic methods should be conducted at minimized. Synthetic methods should be conducted at ambient temperature and pressure.ambient temperature and pressure.

Use of alternate, recyclable and more efficient Use of alternate, recyclable and more efficient energy resources.energy resources.Use of light energy as a source for Use of light energy as a source for photochemical reactions.photochemical reactions.Use of microwave chemistry for more efficient Use of microwave chemistry for more efficient energy utilizationenergy utilization

7. Use of Renewable Feedstocks7. Use of Renewable Feedstocks

A raw material or feedstock should be A raw material or feedstock should be renewable rather than depleting renewable rather than depleting

whenever technically and economically whenever technically and economically practical.practical.

Fermentation of glucose in the presence of Fermentation of glucose in the presence of bacteria and propanoic acid gives Polyhydroxy bacteria and propanoic acid gives Polyhydroxy alkanoates (PHAs).alkanoates (PHAs).The PHAs are similar to polypropene and The PHAs are similar to polypropene and polyethene but however are biodegradable.polyethene but however are biodegradable.

PLA (polylactic acid) is another plastic that is PLA (polylactic acid) is another plastic that is being made from renewable feedstocks such as being made from renewable feedstocks such as corn and potato waste.corn and potato waste.

O

HO

OH

OH

OH

OH

Alcaligenes eutrophuspropanoic acid

R

O

O

R = Me, polydroxybutyrateR = Et, polyhydroxyvalerate

n

8. Reduce Derivatives8. Reduce Derivatives

Unnecessary derivatization (blocking group, Unnecessary derivatization (blocking group, protection/deprotection, temporary protection/deprotection, temporary

modification of physical/chemical processes) modification of physical/chemical processes) should be avoided whenever possible.should be avoided whenever possible.

An increase in the number of synthetic steps An increase in the number of synthetic steps would eventually reduce the overall yield and would eventually reduce the overall yield and atom economy.atom economy.Protecting groups are generally used because Protecting groups are generally used because there is no direct way to solve the problem there is no direct way to solve the problem without them.without them.Attempts to reduce the number of steps and Attempts to reduce the number of steps and derivatization is considered important.derivatization is considered important.

9. Catalysis9. Catalysis

Catalytic reagents (as selective as possible) are Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.superior to stoichiometric reagents.

A green catalyst has advantages such as:A green catalyst has advantages such as:Readily separatedReadily separatedReadily regenerated & recycledReadily regenerated & recycledLong service lifeLong service lifeVery high rates of reactionVery high rates of reactionRobust to poisonsRobust to poisonsHigh selectivityHigh selectivityWorks under milder conditionsWorks under milder conditions

Certain chemicals are used as green catalysts Certain chemicals are used as green catalysts which reduce the incidence of toxic chemicals which reduce the incidence of toxic chemicals formed in a reaction by converting them to less formed in a reaction by converting them to less toxic or harmless substances.toxic or harmless substances.Oxidation catalysts, called Fe-TAML® (tetra-Oxidation catalysts, called Fe-TAML® (tetra-amido macrocyclic ligand) activators, are made amido macrocyclic ligand) activators, are made from elements found in nature and work with from elements found in nature and work with hydrogen peroxide to convert harmful hydrogen peroxide to convert harmful pollutants into less toxic or harmless pollutants into less toxic or harmless substances*.substances*.

*Terrence J. Collins;Teresa Heinz Professor of Green Chemistry

Enzymes or whole-cell microorganisms are Enzymes or whole-cell microorganisms are used.used.Benefits include:Benefits include:

Fast reactions due to correct orientationsFast reactions due to correct orientationsOrientation of site gives high stereospecificityOrientation of site gives high stereospecificitySubstrate specificitySubstrate specificityWater solubleWater solubleNaturally occurringNaturally occurringModerate conditionsModerate conditionsPossibility for tandem reactionsPossibility for tandem reactions

Phase Transfer Catalyst:Phase Transfer Catalyst:A phase transfer catalyst is a catalyst which facilitates A phase transfer catalyst is a catalyst which facilitates the migration of a reactant in a heterogeneous system the migration of a reactant in a heterogeneous system from one phase into another phase where reaction from one phase into another phase where reaction can take place.can take place.Ionic reactants are often soluble in an aqueous phase Ionic reactants are often soluble in an aqueous phase but are insoluble in an organic phase unless the phase but are insoluble in an organic phase unless the phase transfer catalyst is present.transfer catalyst is present.Advantages of PTCAdvantages of PTC

Elimination of organic solventsElimination of organic solventsHigh yields and purity of productsHigh yields and purity of productsSimplicity of the procedureSimplicity of the procedureHighly scalableHighly scalableLow energy cosumption and low investment costLow energy cosumption and low investment costMinimization of industrial wasteMinimization of industrial waste

Quarternary ammonium or phosphonium salts Quarternary ammonium or phosphonium salts are most widely used PTCs.are most widely used PTCs.

Eg: methyltrioctyl ammoniumchloride (Eg: methyltrioctyl ammoniumchloride (Aliquat 336 or Aliquat 336 or Adogen 464)Adogen 464), , Tetra-n-butylammonium bromide (TBAB)Tetra-n-butylammonium bromide (TBAB)Triethylbenzylammonium chloride (TEBA)Triethylbenzylammonium chloride (TEBA)Cetyltrimethylammonium bromide (cetrimide)Cetyltrimethylammonium bromide (cetrimide)benzyltrioctyl ammoniumchloride, benzyltrioctyl ammoniumchloride, polyethylene glycoether, polyethylene glycoether, crown etherscrown ethers

Mechanism of phase transfer by PTC:Mechanism of phase transfer by PTC:

Applications of PTCs:Applications of PTCs:In nucleophilic substitution reactionsIn nucleophilic substitution reactionsSynthesis of fine chemicalsSynthesis of fine chemicalsIn perfumery and fragrance industryIn perfumery and fragrance industryIs synthesis of drugs like dicyclonine, Is synthesis of drugs like dicyclonine, phenoperidine, oxaladine, ritaline etc.phenoperidine, oxaladine, ritaline etc.Provides liberty of use of cheaper and easily Provides liberty of use of cheaper and easily available raw materials like potassium available raw materials like potassium carbonate and aqueous sodium hydroxide carbonate and aqueous sodium hydroxide thereby obviating the need of severe thereby obviating the need of severe anhydrous conditions, expensive solvents and anhydrous conditions, expensive solvents and dangerous bases such as metal hydrides and dangerous bases such as metal hydrides and organometallic reagents.organometallic reagents.

Williamsons ether synthesis by PTC:Williamsons ether synthesis by PTC:High-yield etherificationHigh-yield etherificationNo need for excess pre-formed alkoxideNo need for excess pre-formed alkoxideUsually short cycle time and easy workupUsually short cycle time and easy workupNon-dry mild reaction conditionsNon-dry mild reaction conditions

Wittig reaction by PTCWittig reaction by PTCAliquat 336 (N-Methyl-N,N-dioctyloctan-1-Aliquat 336 (N-Methyl-N,N-dioctyloctan-1-ammonium chloride) is used as PTC.ammonium chloride) is used as PTC.

10. Design for Degradation10. Design for Degradation

Chemical products should be designed so that at Chemical products should be designed so that at the end of their function they do not persist in the end of their function they do not persist in the environment and instead break down into the environment and instead break down into

innocuous degradation products.innocuous degradation products.

Plastics, long chain hydrocarbons, CFCs have Plastics, long chain hydrocarbons, CFCs have longer persistence.longer persistence.Chemicals such as DDT bioaccumulate.Chemicals such as DDT bioaccumulate.Drugs such as antibiotics build up in water Drugs such as antibiotics build up in water streams.streams.Design of degradable chemicals is the need of Design of degradable chemicals is the need of the hour.the hour.Polylactic acid:Polylactic acid: Manufactured from renewable resources such as corn or Manufactured from renewable resources such as corn or

wheat; wheat; Uses 20-50% fewer fossil fuels than conventional plasticsUses 20-50% fewer fossil fuels than conventional plastics PLA products can be recycled or compostedPLA products can be recycled or composted

11. Real-time Analysis for 11. Real-time Analysis for Pollution PreventionPollution Prevention

Analytical methodologies need to be further Analytical methodologies need to be further developed to allow for real-time in-process developed to allow for real-time in-process

monitoring and control prior to the formation monitoring and control prior to the formation of hazardous substances.of hazardous substances.

In the process of a chemical reaction, analysing In the process of a chemical reaction, analysing when a reaction is exactly complete can save a when a reaction is exactly complete can save a lot of energy, waste and time.lot of energy, waste and time.Overdoing a reaction may result in energy Overdoing a reaction may result in energy wastage and under-doing the same may result wastage and under-doing the same may result in material wastage.in material wastage.An advanced and sophisticated analytical tool An advanced and sophisticated analytical tool helps reduce this pollutionhelps reduce this pollution

12. Inherently Safer Chemistry for 12. Inherently Safer Chemistry for Accident PreventionAccident Prevention

Substance and the form of a substance used in Substance and the form of a substance used in a chemical process should be chosen so as to a chemical process should be chosen so as to minimize the potential for chemical accidents, minimize the potential for chemical accidents,

including releases, explosions, and fires.including releases, explosions, and fires.

Use of potential toxic, hazardous and highly Use of potential toxic, hazardous and highly inflammable chemicals may result in accidents inflammable chemicals may result in accidents which eventually lead to pollution and danger which eventually lead to pollution and danger to plant and animal life.to plant and animal life.U.S. Public Interest Research Group Reports U.S. Public Interest Research Group Reports (April 2004) find that chemical industry has had (April 2004) find that chemical industry has had more than 25,000 chemical accidents since more than 25,000 chemical accidents since 19901990More than 1,800 accidents a year or 5 a day.More than 1,800 accidents a year or 5 a day.In Bhopal gas tragedy, release of 40 tons of In Bhopal gas tragedy, release of 40 tons of Methyl isocyanate (MIC) took the lives of 15000 Methyl isocyanate (MIC) took the lives of 15000 people leaving hundreds of thousands seriously people leaving hundreds of thousands seriously affected.affected.

THANK YOUTHANK YOU