The E factor at 21

Roger A. Sheldon Delft University of Technology

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Outline

The E factor at 21

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1. Origins of the E factor 2. Green chemistry, catalysis & sustainability 3. Suspect solvents 4. Biocatalysis 5. The bio-based economy 6. The metrics of sustainability 7. Conclusions & prospects

Phloroglucinol Synthesis anno 1980

Ca. 40kg of solid waste per kg phloroglucinol

Atom Utilisation = 126/2282 = ca. 5 %

E Factor = ca. 40

MW = 126

HO OH

O H

product

O2N NO2

CH3

NO2

K2Cr2O7

H2SO4 / SO3

O2N NO2

COOH

NO2

Fe/HCl

- CO2

H2N NH2

NH2

aq.HCl

ΔT

TNT phloroglucinol

HO OH

O H

“ To measure is to know ” Lord Kelvin

byproducts

+ Cr2 (SO4)3 + 2KHSO4 + 9FeCl2 + 3NH4Cl + CO2 + 8H2O

392 272 1143 160 44 144

> 90 % yield Selective? Efficient?

TNT

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Reaction Stoichiometry and Atom Economy

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Conclusion?

From the traditional one of chemical yield to one that assigns value to waste elimination and avoiding toxic/hazardous materials An environmental factor was missing

A new paradigm was needed for efficiency in organic synthesis

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Green chemistry efficiently utilises

(preferably renewable) raw materials,

eliminates waste and avoids the use

of toxic and/or hazardous solvents

and reagents in the manufacture and

application of chemical products.

Green (Clean) Chemistry

Sheldon, Arends and Hanefeld , Green Chemistry

and Catalysis, Wiley, New York, 2007

Anastas & Warner, Green Chemistry : Theory

& Practice ,Oxford Univ. Press,New York,1998

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Green (Clean) Chemistry

Green chemistry is pollution prevention not end-of-pipe remediation

“Environmental pollution is an incurable disease. It can only be prevented”.

Barry Commoner “The Closing Circle” , 1971

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Meeting the needs of the present generation

without compromising the needs of future

generations to meet their own needs

What is Sustainability?

Brundtland Report, ‘Our Common Future’, 1987

Profit

People

Planet

Making every decision with the future in mind

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Sustainable

Economic (Profit)

Environment (Planet)

Social (People)

Viable

Equitable

Bearable

The Sustainability Venn Diagram

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Green Chemistry

• Waste minimization

• Environmentally acceptable solvents, reagents and end-products

• Renewable feedstocks

• Products & processes

The Bio-Based Economy

- Biomass as feedstock - Biodegradable products - (Bio)catalytic conversions

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Tonnage E Factor

Oil Refining 106-108 <0.1

Bulk Chemicals 104-106 <1 - 5

Fine chemical Industry 102-104 5 - >50

Pharmaceutical Industry 10-103 25 - >100

R.A.Sheldon, Chem & Ind, 1992, 903 ; 1997, 12

E Factor = kg waste/kg product

[i]

“Another aspect of process development mentioned by all pharmaceutical process chemists who spoke with C&EN is the need for determining an E Factor”. A. N. Thayer, C&EN, August 6, 2007, pp. 11-19

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The E factor

• Is the actual amount of all waste formed in the process, including solvent losses and waste from energy production (c.f. atom utilisation is a theoretical nr.) • E = [kgs raw materials- kgs product]/[kgs product] • A good way to quickly show (e.g. to students) the enormity of the waste problem

(E)verything but the Product

What about the process water? Only if it needs to be treated

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E = Total mass of waste Mass of final product

AE (%) = m.w of product x 100 Σ m.w. of reactants

Reaction mass efficiency (RME)

Mass of product C x 100 Mass of A + Mass of B

E factor Atom efficiency (AE)

RME(%) =

Mass intensity (MI)

MI = Total mass in process Mass of product

CE(%) =

Carbon efficiency (CE)

Carbon in product x 100 Total carbon in reactants

Effective mass yield (EMY)

EMY(%) = Mass of product x 100 Mass of hazardous reagents

Mass Productivity (MP)

Mass of product Total mass in process

MP =

Metrics of Green Chemistry

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E-factor M&M model Industry segment

0.1 Oil refining

1 Bulk Chemicals &

Polymers 10

100 Fine Chemicals

250 Pharmaceuticals &

Electronics

The Goal Is Zero

E-factor as a green chemistry metric

Irvin J. Levy Professor of Chemistry Gordon College, Wenham, MA 01984

http://www.cs.gordon.edu/~ijl/visualizingWaste/

E-factor = mass of waste ÷ mass of product

E-factor = (mass of inputs - mass of outputs) ÷ mass of product

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On the Way Towards Greener Processes, as Quantified by E Factors

B. H. Lipshutz, N. A. Isley, J. C. Fennewald, E. D. Slack 15

The Environmental Impact EQ

EQ = E(kg waste) × Q

Q = Unfriendliness Multiplier

e.g. NaCl : Q = 1 ( arbitrary)

Cr salts : Q = 1000?

R.A.Sheldon, Chem & Ind, 1992, 903 ; 1997, 12

There are many shades of green!

Quantification of Q

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http://www.metzger.chemie.uni-oldenburg.de/eatos/eatosmanual.pdf

Environmental Assessment Tool for Organic Syntheses

EATOS

- Mass and Energy Flow - Environment, Health and Safety - Persistence, bioaccumulation and toxicity (PBT) - Costs

Combines raw material efficiency with LCA and economic indicators

J. O. Metzger and M. Eissen, Chem. Eur. J. 8, 3580-3585 (2002)

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http://www.metzger.chemie.uni-oldenburg.de/eatos/eatosmanual.pdf

Environmental Assessment Tool for Organic Syntheses

EATOS

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Major Sources of Waste

• Stoichiometric Reagents

- Acids & Bases

- Oxidants & reductants

- Na2Cr2O7, KMnO4, MnO2

- LiAlH4, NaBH4, Zn, Fe/HCl

• Solvent losses ( 85% of non-aqueous mass)

The Solution : Atom & step economic catalytic processes

in alternative reaction media

(the best solvent is no solvent) 19

J. J. Berzelius 1779-1848

Organic Chemistry (1807) Catalysis (1835)

Urea synthesis 1828 ( Wöhler ) First synthetic dye 1856 Aniline purple (Perkin)

Dyestuffs Industry (based on coal-tar)

Fine Chemicals

Catalysis in Organic Synthesis

ca. 1900 Catalysis definition (Ostwald) Catalytic Hydrogenation (Sabatier) ca. 1920 Petrochemicals

1936 Catalytic cracking 1949 Catalytic reforming 1955 Ziegler-Natta catalysis

Bulk Chemicals & Polymers

Bridging the Gap

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The Ideal Synthesis 100% Yield

One Step

Simple & Safe

Economical in Time & Waste

Environmentally Acceptable

- atom economy

- step economy

- human economy

Urea Taxol Apoptolidine 1828 1990’s 2005 #Steps 1 37 98

Shorten the synthesis or change the target

1. Ni cat.

2. H2 / cat.

+ N

O

13 steps

Wilstatter

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"The ideal chemical process is that which a one-armed operator can perform by pouring the reactants into a bath tub and collecting pure product from the drain hole"

Sir John Cornforth (Nobel Prize 1975)

The Ideal Process

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Catalysis

Biocatalysis

Heterogeneous Homogeneous

Sheldon, Arends and Hanefeld , Green Chemistry And Catalysis, Wiley, New York, 2007

Organocatalysis

Catalysis & Green Chemistry

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The Solvent Problem : Catalysis in Non-conventional Reaction Media

• Toxicity and/or hazards of atmospheric and

ground water pollution by conventional solvents

• Separation/recycling of homogeneous catalysts

“The best solvent is no solvent”

• (Biphasic) catalysis in non-conventional media

- water

- supercritical carbon dioxide

- ionic liquids

Two challenges :

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Solvent Selection Guide

Water scCO2 Acetone Ethanol 2-Propanol 1-Propanol Heptane Ethyl Acetate Isopropyl acetate Methanol MEK 1-Butanol t-Butanol

Cyclohexane Toluene Methylcyclohexane TBME Isooctane Acetonitrile 2-MeTHF THF Xylenes DMSO Acetic Acid Ethylene Glycol

Pentane Hexane(s) Di-isopropyl ether Diethyl ether Dichloromethane Dichloroethane Chloroform NMP DMF Pyridine DMAc Dioxane Dimethoxyethane Benzene Carbon Tetrachloride

P. Dunn et al, Green Chem. 2008, 10, 31-36 25

Biocatalysis is Green & Sustainable • Enzymes are derived from renewable resources and are biodegradable (even edible sometimes) • Avoids use of (and product contamination by)

scarce precious metals • Mild conditions: ambient T & P in water

• High rates & highly specific : substrate, chemo-, regio-, and enantiospecific • Higher quality product • No special equipment needed

Reduced environmental footprint 26

Historically: Adapt Process to fit Catalyst

Available

Catalyst

Dream Process

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Nightmare Process

Catalyst

Compromise process to accommodate catalyst

Adapt catalyst to

optimum process

EVOLVE

Dream Process

Adapted

Catalyst

Future: Adapt Catalyst to fit Ideal Process

Directed Evolution 28

The Challenge

Disadvantages of Enzymes

Low operational stability & shelf life

Cumbersome recovery & re-use

Product contamination

Allergic reactions to proteins

Non viable biocatalytic applications

Costs are too high

Not practical

The Solution: Immobilization 29

Heterogeneous Catalysis with Enzymes

• Available Technologies – Proprietary CLEA (Cross-Linked Enzyme Aggregate)

Technology – On various carriers – Encapsulation – Combinations

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“In an ideal chemical factory there is, strictly speaking, no waste but only products. The better a real factory makes use of its waste, the closer it gets to its ideal, the bigger is the profit.“ A. W. von Hofmann (1884)

Conclusions & Take Home Message

1. There is not one winner. 2. There are many chemo- and bio-catalytic methods 3. There are many shades of green.

Waste Valorisation: The New Frontier

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Remediation

Prevention

Utilisation

Valorisation

Green Chemistry

Sustainable Development

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The Size of the Opportunity

• Lignocellulosic biomass residues: 220 X 109 tonnes /annum • Rice husks: 120 X 106 tonnes / annum

• Sugar cane bagasse: 220 X 106 tonnes / annum

• Waste straw in China: 600 X 106 tonnes / annum

• Orange peel in Brazil: 8 X 106 tonnes / annum

C. O. Tuck, E. Perez, I. T. Horvath, R. A. Sheldon, M Poliakoff, Science, 2012, 337 , 695-699

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Product €/ton

Average Bulk Chemical 1000

Transportation Fuel 200-400

Fermentation Feedstock 100-300

Animal Feed 70-120

Electricity Generation 60-150

Landfill -/- 400

The Valorisation Scale

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Product €/GJ

Epichlorohydrin 30 - 40

Transport fuel 10

Electricity 3

Valorisation of glycerol ( 25.3 GJ/tonne)

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Meaningful Metrics for Biomass Valorisation

• Boundary conditions?

(Cradle-Gate-Gate-Grave-Cradle)

• Land & Water Usage

• Economics

kgs product(s) kgs product(s)+ kgs waste

Meff = energy out energy in

Eeff =

A concise set of metrics for quick evaluation of petrochemical vs bio-based processes

“To measure is to know” Lord Kelvin

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Sustainability metrics of

chemicals from biomass

List of selected metrics:

- material efficiency

- total energy efficiency

- land use

- economic added value

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www.ubiochem.org

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Sustainability metrics of chemicals from biomass

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Lignocellulosic biomass to

sustainable fuels & chemicals

The stone age didn’t end when there were no more stones left

Y.Cao, X. Jiang, R. Zhang & M. Xian, Appl Microbiol Biotechnol (2011) 91:1545

Metabolically engineered E. coli

Production of Phloroglucinol by Fermentation

3.8 g/L in 12 h

Not (yet) commercially viable

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and Sustainable

Thank you, any questions? 41