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Petr Beňovský
ENVIRONMENTAL ASPECTS

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GREEN CHEMISTRY, SUSTAINABLE CHEMISTRY
The design of chemical products and processes that reduce or eliminate the use or generation of
hazardous substancese;
Systematically pursued from the 90s of the 20th century;
1952 – Upjohn – the synthesis of cortisone – just 10 step synthesis of cortisone using
fermentation  for a key hydroxylation reaction at position 11 of progesterone

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GREEN CHEMISTRY METRICS
Atom Economy
Trost, B. Science 254, 1471 (1991)
Characterizes the “greeness“ of a synthetic process by calculating the number of atoms from all of
the reactants that make it into the final product;
Does not address the hazard, reaction yield, stoichiometry, the amount of solvent, …
% Atom Economy = Molecular weight of the product / Molecular        weight of all products x 100

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GREEN CHEMISTRY METRICS
Environmental Factor, E-Factor
The ratio of waste over product
It is usual to calculate E-factor without process water
E-Factor = the amount of waste (kg) / the amount of the product (kg)
Industry Segment
Volume (t/y)
E-Factor
Oil Refining
106 - 108
< 0.1
Bulk Chemicals
104 - 106
< 1 - 5
Fine Chemicals
102 - 104
5 - 50
Pharmaceuticals
10 - 102
25 - 100

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GREEN CHEMISTRY METRICS
Reaction Mass Efficiency (RME)
The idea is to keep the simplicity of the atom economy concept, but avoid the high impact of
solvents which are found in the E-factor;
RME takes into account reaction yield, stoichiometry and the use of catalysts or other reagents;
% Reaction Mass Efficiency = Mass of desired product / Mass of all reactants x 100

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GREEN CHEMISTRY METRICS
Process Mass Intensity (PMI)
PMI measures the mass of materials used to make 1 kg of the API
% Process Mass Intensity = Mass of all material used to make the product (kg) / Mass of product
(kg) x100
Allows companies to benchmark and quantify improvements to the efficiency and sustainability of
their production
Reasonable target of a single synthetic step is any value between 10 and 40

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GREEN CHEMISTRY METRICS
Process Mass Intensity (PMI)

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IBUPROFEN EXAMPLE
Originator – Boots Group (1960s)
Original name – Brufen (Aspro, Panadol, Nurofen)
Generic names – Motrin, Advil, Nuprin, Ibalgin
Sold as the racemate despite the fact that (S)-(+)-Ibuprofen is the active form;
Fast epimerization in vivo

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IBUPROFEN EXAMPLE
Original synthesis – overall yield 40%
Annual production in Great Britain 3000 tones

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IBUPROFEN EXAMPLE
New synthesis – BHC company (1990)
Overall yield 77%
Presidential Green Chemistry Challenge Greener Synthetic Pathways Award v roce 1997

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BIOCATALYSIS
Myths of biocatalysis:
•Expensive
•Unstable
•Not readily available
•Sensitive to reaction conditions
•Not good enough or wrong selectivity
•Give poor volumetric productivity
•Difficult work-up
Nowadays, all of them are mostly wrong

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BIOCATALYSIS
2018 – Nobel Prize for directed evolution of enzymes (Frances H. Arnold, George P. Smith)
Iterative change of amino acids in the enzyme until the desired property (acitivity, stability,
selectivity) is achieved;
Directed evolution mimics the processes of Darwinian evolution in a test tube

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BIOCATALYSIS
Bornscheuer, U.T. et al Angew.Chem.Int.Ed. 43, 6032 (2004)

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BIOCATALYSIS
https://www.youtube.com/watch?v=up5QUdTLsBU&feature=youtu.be
CODEXIS

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BIOCATALYSIS
CODEXIS

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BIOCATALYSIS
CODEXIS
Atorvastatin (Lipitor®)
2006 – Presidential Green Chemistry Challenge Award
Substantial waste reduction
Overall yield > 90%
Purity > 98%
ee > 99.9%
Low loading of enzymes
Solvent recycling
E-Factor is 5.8 (without used water)
E-Factor is 18 (with used water)

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GREEN CHEMISTRY, SUSTAINABLE CHEMISTRY
Ryoji Noyori
“Green chemistry is not just a mere catch phrase;
it is the key to the survival of mankind“