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Afscheidsrede prof.dr. R.A. Sheldon hoogleraar Biokatalyse en Organische Chemie December 7, 2007 ‘E Factors, Green Chemistry and Catalysis: Records of the Travelling Chemist’. 7 december 2007. R. A. Sheldon, Rec. Trav. Chem. 2007, 1, 1. Green Chemistry.

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slide1

Afscheidsrede prof.dr. R.A. Sheldonhoogleraar Biokatalyse en Organische ChemieDecember 7, 2007‘E Factors, Green Chemistry and Catalysis:Records of the Travelling Chemist’

7 december 2007

R. A. Sheldon, Rec. Trav. Chem. 2007, 1, 1

slide2

Green Chemistry

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.

Anastas and Warner, Eds, Green Chemistry.

Theory & Practice, Oxford U. Press, 1998

slide3

Sustainability

Meeting the needs of the present generation without compromising the needs of future generations to meet their own needs

is the goal

“What we need is more imagination not more knowledge”

Albert Einstein

slide4

Do politicians understand the issues?

It’s not pollution that is the problem it’s the impurities

in our air and water.

Dan Quayle

slide5

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

392 272 1143 160 44 144

byproducts

Phloroglucinol Synthesis

CH3

COOH

O2N

NO2

O2N

NO2

H2N

NH2

HO

OH

K2Cr2O7

Fe/HCl

aq.HCl

D

-

CO2

T

H2SO4 / SO3

NO2

NO2

NH2

O

H

TNT

phloroglucinol

Ca. 40kg of solid waste per kg phloroglucinol

HO

OH

O

H

MW = 126

Atom Utilisation = 126/2282 = ca. 5%

E Factor = ca. 40

product

“ To measure is to know ” Lord Kelvin

slide6

Oxygen utilisation (1990)

Syn gas utilisation (1983)

Oxidant % Active O Byproduct

H2O2 47 H2O

t-BuOOH 18 t-BuOH

CH3COOOH 22 CH3COOH

NaOCl 22 NaCl

KIO4 KIO3

2 CO + 3 H2 HOCH2CH2OH

100%

2 CO + 4 H2 H2C=CH2 + 2H2O

44%

CH3 HC=CH2 + Cl2 + H2O CH3CH(OH)CH2Cl + HCl

O

Ca(OH)2

25% atom utilisation

+ CaCl2 + H2O

CH3HC

CH2

2. PO : Catalytic Oxidation

O

CH3HC=CH2 + H2O2

76% atom utilisation

+ H2O

CH3HC

CH2

“Atom for Atom”

Atom utilisation (1991)

1. PO : Chlorohydrin process

See Chem. Eng. Progr. 1991, 87(12), 11

See also Trost, Science, 1991, 254, 1471

slide7

E Factors

E Factor = kg waste/kg product

Tonnage E Factor

Bulk Chemicals 104-106 <1 - 5

Fine chemical Industry 102-104 5 - >50

Pharmaceutical Industry 10-103 25 - >10

[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.

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

slide8

I Factor = 4.19

R. A. Sheldon, Green Chem, 2007, 9, 1273-1283

the e factor
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 = [raw materials-product]/[product]
  • A good way to quickly show (e.g. to students) the
  • enormity of the waste problem
  • Undergraduate Course : “Green Chemistry &
  • Sustainable Technology”
slide10

Major Sources of Waste

  • STOICHIOMETRIC ACIDS & BASES
  • STOICHIOMETRIC OXIDANTS & REDUCTANTS
  • - Na2Cr2O7, KMnO4, MnO2
  • - LiAlH4, NaBH4, Zn, Fe/HCl
  • SOLVENT LOSSES
  • - Air emissions & aqueous effluent
slide11

The Solution is Catalytic

  • Substitution of conventional Bronsted & Lewis acids
  • by recyclable,non-corrosive solid acids e.g zeolites
  • Atom efficient catalytic processes:
  • -hydration (H2O)reduction (H2),oxidation (O2 ,H2O2)
  • -carbonylation (CO),hydroformylation (CO/H2)
  • -amination (NH3), reductive amination (NH3 /H2)
  • with olefins and (alkyl)aromatics as raw materials
  • Alternative reaction media / biphasic catalysis
  • Biocatalysis, naturally
slide12

Novel Media

O2 H2O2

CO H2 H2O

Enzymes

Renewables

Cascades

Chirotechnology

Research Themes

Catalysis

&

Green Chemistry

Sheldon, Arends and Hanefeld , Green Chemistry

And Catalysis, Wiley, New York, 2007

slide14

Peroxometal mechanism 1973

Shell SMPO process 1973

O

H

O

H

M

O

M

O

+

O

T

i

(

I

V

)

/

S

i

O2

O

O

+

R

O

H

+

R

O

O

H

R

R

Sheldon, Rec.Trav.Chim.Pays-Bas, 92, 253, 1973

Sheldon and van Doorn, J.Catal. 31, 427, 1973

Mimoun, Sharpless

Pd/Pt (4nm)

H2

+

O2

H2O2

TS-1

O

H2O2

+

+

H2O

MeOH

TS-1

O

H2O2

+

+

H2O

MeOH

Enichem 1985

Headwaters/Evonik 2006

Ti-beta, Ti-MCM41, Ti-ITQ, etc

van Bekkum, Corma

Dakka, Sato, LeBars

Redox Molecular Sieves (Zeozymes)

Metal

Catalyzed

Epoxidation

slide15

A

m

m

o

x

i

m

a

t

i

o

n

B

e

c

k

m

a

n

n

r

e

a

r

r

a

n

g

e

m

e

n

t

Green Caprolactam Process : Sumitomo

v

a

p

o

u

r

O

NOH

H2O2 / NH3

NH

p

h

a

s

e

O

T

S

-

1

H

i

g

h

S

i

MFI

C6H10O + H2O2 + NH3 C6H11NO + 2H2O

Atom efficiency = 75% ; E = 0.32 (<0.1)

O

NOH

(NH3OH)2SO4

NH

H2SO4

O

Atom efficiency =29% ; E = 4.5

Ichihashi and Kitamura,Catal.Today, 73, 23, 2002

redox molecular sieves philosophers stones or trojan horses
Redox Molecular Sieves :Philosophers’ Stones or Trojan horses ?

Filtration Test for

Heterogeneity:

60

50

40

30

conversion (%)

20

hot

cold

10

0

0

30

60

90

120

150

180

Time (min)

Lempers (1998)

Chen (1995), Elings (1997), Plyuto, Schuchardt

Sheldon, Wallau, Arends and Schuchardt,

Acc. Chem. Res., 31 (1998) 485-493.

slide18

Catalysis in Non-conventional Reaction Media

Two challenges :

  • Toxicity and/or hazards of atmospheric and
  • ground water pollution by conventional solvents
  • Separation/recycling of homogeneous catalysts
  • (Biphasic) catalysis in non-conventional media
  • - water
  • - supercritical carbon dioxide (Martyn Poliakoff)
  • - ionic liquids (Ken Seddon)
  • - fluorous biphasic (Istvan Horvath)

“The best solvent is no solvent”

slide19

OH

Pd / tppts /H+

CO

COOH

Ibuprofen

Aqueous Biphasic Cataysis

2. Aerobic Oxidation

1. Carbonylation

R2

H

+

0

.

5

O2

R1

O

H

Pd2+/

L

air

OH

O

R

R

2

R

Pd2+ L

water

+

H2O

O

1

R

NaO3S

S

O3

N

a

P

NaO3S

S

O3Na

tppts

S

O3Na

N

N

Papadogianakis, Verspui (2001)

Moiseev

ten Brink (2001)

ten Brink, Arends, Sheldon, Science 287 (2000) 1636

slide20

Catalysis in Ionic Liquids

  • Negligible vapour pressure
  • Designer solvents
  • Catalytic hydroformylation,
  • carbonylation, hydrogenation
  • and biocatalysis

R2

OH

+

+

+

+

N

N

OH

N

N

N

OH

R3

R

R1

R

N

+

R4

OH

R

Anions :

B

F4

,

P

F6

,

R

C

O

,

H2

P

O4

,

N

O3

,

H

O

C

H2

C

O2

2

O

O

O

OH

O

OH

+

+

OH

NH2

O

O

CaLB in [bmim][BF4] and [bmim][PF6]

O

Madeira Lau (2003) Seddon

RCOOOH

RCOOH

Product recovery?

H2O2

H2O

Madeira Lau, van Rantwijk, Seddon, Sheldon, Org.Lett. 2, 4189, 2000 Sheldon, Chem. Comm. 2001, 2399-2407

slide21

OAc

In situ product removal with scCO2

scCO2 phase

OH

OAc

lipase

IL phase

scCO2 as mobile phase in batch or continuous operation

Reetz et al,Chem.Comm.,2002, 992

Lozano et al,Chem.Comm.,2002, 692

slide22

The Miscibility Switch

Reactant

Carbon dioxide

CO2

+

Product

IL

+

Catalyst

+

Reactant

+

CO2

P 

P 

P 

CO2

CO2

IL

+

Catalyst

+

Product

+

IL

IL

Ionic liquid + catalyst

Product

High pCO2

one phase

Low pCO2

two phases

Reaction

Separation

Peters & Witkamp

slide24

O.

O.

  • No solvent
  • No Br-
  • NaOCl
  • Recyclable
  • Cheap raw
  • material
  • Chimassorb 944

N

N

N

R1

.

R1

OH

O

+ “O”

N

N

N

O

+ H2O

(CH2)6

H

CH2Cl2/ H2O

R2

R2

N

N

5

“O” = NaOCl, m-CPBA, oxone (+ Br -)

NH(tert-octyl)

PIPO

van Bekkum et al , Synthesis, 1996, 1153

Cu(II) / PIPO / O2

Dijksman (2001)

N

.

O

TEMPO

Laccase : a multicopper oxidase

O

TEMPO (5m%)

OH

H

l

a

c

c

a

s

e

O

RCH2OH

+

0

.

5

O

2

2

N

.

Cu(II) / bipy (5m%)

Base / MeCN / H2O

O

+

RCHO

H

O

N

l

a

c

c

a

s

e

2

o

x

Gamez

O

Li (2004), Matijosyte

de Vries/Hagen

Organocatalytic Oxidations

slide25

subtilisin

phytase

CaLB

CPO

laccase

HNlase

Biocatalysis

Inventing New Enzymes & Enzymatic Reactions

why biocatalysis
Why Biocatalysis?
  • Mild conditions: ambient temperature &
  • pressure in water
  • Enzymes are derived from renewable sources
  • and are biodegradable
  • High rates & highly specific : substrate,
  • chemo-, regio-, and enantiospecific
  • Higher quality product
  • Green Chemistry (environmental footprint)
slide27

BASF Process

NH2

NH2

Lipase

O

O

O

ee > 99% (S)

+

O

NH2

O

NH

NaOH

glycol-water

(2:1), 150oC

ee > 99% (S)

ee > 99% (R)

> 3000 tpa

Enzymatic Ammoniolysis

R

O

O

R

Nu

NuH

Ser

O

Nu = OH, OR, NH2 , RNH, OOH, etc

O

O

NH3/t-BuOH

R

R

OEt

NH2

lipase, 40oC

  • Green amide synthesis
  • Enantioselective with
  • amino acid esters

Steverink(1995), Hacking (1999)

Wegman(2001)

If you want to find something new

you have to DO something new Edward De Bono

slide28

O

O

100

NH2

90

H

N

O

80

70

60

% yield (amide)

CaLB, 50oC, 96h

50

40

Kinetic resolution

30

Nano Pd

20

Dynamic kinetic

NH2

10

resolution

- 88 % yield (4 days)

- ee product 98 % .

0

0

20

40

60

80

100

120

time (h)

H.Ismail(2007)

Easy-on-easy-off resolution

NHCOCH2Ar

NH2

H2O

NH2

P

h

ArCH2COX

P

h

p

e

n

a

c

y

l

a

s

e

+

P

h

p

H

7

e

e

>

9

9

%

p

e

n

a

c

y

l

a

s

e

NH2

p

H

1

0

-

1

1

e

e

>

9

9

%

P

h

V.Svedas

L.van Langen(2001), R.Madeira Lau(2003), H.Ismail(2007)

Dynamic Kinetic Resolution

Pd –catalyzed racemization of 1-phenethylamine :

Murahashi (1983) ; Reetz , DKR (1996).

slide29

O

A

sp

O

H

H

N

N

H

A

r

g

O

2

A

r

g

H

N

N

O

H

H

N

65% ee

V

N

H

O

O

H

i

s

N

N

H

2

H

N

L

y

s

H

i

s

van de Velde

Aksu-Kanbak

Correia

vanadate phytase

H2O

X

H2O2

O

Linker

S

e

O

O

O

H

O

X

X

Se

Se

OH

OOH

X

=

N

O

,

C

F

2

3

X

=

N

O

,

C

F

Ser

2

3

O

O

subtilisin

van der Toorn

R2

R1

R2

R1

O

ten Brink (2001)

O

C

P

O

ArSCH3

H2O2

H2O

+

S

+

A

r

C

H3

N

N

99% yield

>99% ee

FeIII

N

N

S

C

y

s

van Deurzen (1996)

van de Velde (2000)

Heme

Low stability

Inventing New Enzymes : Chemomimetic Biocatalysis

historically adapt process to fit catalyst
Historically: Adapt Process to fit Catalyst

Available

Catalyst

Dream Process

slide31

Future: Adapt Catalyst to fit Ideal Process

EVOLVE

Catalyst

Adapted

Catalyst

Dream Process

Nightmare Process

Compromise process to

accommodate catalyst

Adapt catalyst to

optimum process

Directed Evolution

BOC HTS (directed evolution lab.) L.Otten

dna shuffling evolution in the fast lane

gene A

Genes

From Nature

gene B

gene C

gene D

DNA ShufflingTM

Library of

Novel Genes

Repeat

HTP Screening

DNA Shuffling : Evolution in the Fast Lane

Novel Genes

Stemmer,Nature,370, 389-391, 1994; Huisman et al (Codexis)

See also Reetz, Advan. Catal. 2006, 1-69.

slide33

O

O

OH

O

KRED

Cl

Cl

OEt

OEt

9

9

%

ee

>

NADP+

NADPH

g

l

u

c

o

n

a

t

e

g

l

u

c

o

s

e

GDH

OH

O

OH

O

a

q

.

NaCN

,

pH 7

Cl

NC

OEt

OEt

HHDH

(>99.9% ee)

Green Synthesis of Lipitor Intermediate (Codexis)

Presidential Green Chemistry Challenge Award 2006

KRED = keto reductase ; GDH = glucose dehydrogenase

HHDH = halohydrin dehalogenase (non-natural nucleophile)

Nature Biotechnol. 2007, 25, 338-334

Huisman, Grate, Lalonde et al (Codexis)

slide34

1. KRED + GDH

Parameter

Process Design

Initial Performance

Final Performance

Substrate loading

160 g/L

80 g/L

180 g/L

Reaction time

<16 hrs

24 hrs

8 hrs

Enzyme loading

<1 g/L

10 g/L

0.7 g/L

Isolated yield

>90%

~80%

97%

Phase separation time

>1 hr

~1 min.

Volumetric Productivity

>240 g/L.day

80 g/L.day

540 g/L.day

2. HHDH

Parameter

Process Design

Initial Performance

Final Performance

Substrate loading

120 g/L

20 g/L

140 g/L

Reaction time

<16 hrs

72 hrs

5 hrs

Enzyme loading

<1.2 g/L

130 g/L

1.2 g/L

Isolated yield

>90%

~60%

92%

Volumetric Productivity

>180 g/L.day

7 g/L.day

670 g/L.day

Improving Performance by Directed Evolution:

test tube to commercial process with gene shuffling

slide35

Disadvantages of Enzymes

  • Low operational stability & shelf-life
  • Cumbersome recovery & re-use
  • (batch vs continuous operation)
  • Product contamination

Solution : Immobilization

slide36

Cross-Linked Enzyme Aggregates (CLEAs)

X-linker

precipitant

aggregate

CLEA

-

Enzyme in solution

glutaraldehyde or dextran polyaldehyde as X-linker

  • Enables recycling via filtration
  • Higher productivity
  • No need for highly pure enzyme
  • Simple procedure / widely applicable
  • Stability towards denaturation
  • CLEAS active in:
  • scCO2 (M. Poliakoff)
  • ILs (Sheldon)

Sorgedrager (2006), Janssen (2006 )

(CLEA Technologies B.V.)

slide37

Examples of Successful CLEAtion

  • Hydrolases
  • Pen. acylases (2)
  • Lipases (7)
  • Esterases (3)
  • Proteases (3)
  • Nitrilases (2)
  • Aminoacylase
  • Phytase
  • Galactosidase
  • Oxidoreductases
  • ADH
  • FDH
  • Glucose oxidase
  • Galactose oxidase
  • Laccase
  • Catalase
  • Chloroperoxidase
  • Lyases
  • R- & S- HnLases
  • PDC
  • DERA
  • Nitrile hydratase

Cao, Lopez-Serrano, Mateo, Perez, van Langen, Sorgedrager

Janssen, Bode, van Pelt, Chmura, Matijosyte, Aksu-Kanbak,

Evolution vs Cleationism

slide38

5

a

t

m

H2

amidase

OCH3

OCH3

OH

O

N

O

N

H

N

0

,

4

%

cat.

2

H

H

O

O

O

Catalyst :

Rh(monophos) on TUD-1

99% yield / 95% ee

97% yield / > 99% ee

Simons (2007)

PS- I

H

O

RCO2OH

H

2

2

O

H

lipase

H

O

O

RCOOH

PS- I(O2CR)2

2

Kotlewska

Catalytic Cascade Processes

slide39

Trienzymatic Cascade with a

Triple-Decker combi CLEA

OH

CONH2

OH

H2O

CN

O

Pen G amidase

HCN /(S)-HnL

NLase

OH

COOH

Conv. 96% / ee >99%

Chmura, Stolz

slide40

Renewables & Green Chemistry :

the Biorefinery

Fuels

CO2

+

H2O

photo-

Biomass

Polymers

synthesis

Bulk & Fine

Chemicals

Greener products

Emons (1992), Arts(1996), Papadogianakis

Metrics for renewables ?

slide41

Carboxystarch : Safe & Natural Absorbing Polymer (SNAP)

OH

H

H

COOH

Laccase CLEA

TEMPO/O2

H

[

H

[

O

O

O

O

H

HO

H

HO

H

H

OH

OH

H

O

H

O

]

]

n

n

starch

c

a

r

b

o

x

y

s

t

a

r

c

h

  • Non- toxic & biodegradable
  • Green (bio) catalytic process
  • Green raw materials

Boumans (TNO)

The plan is nothing, the planning is everything

Mao Zedong

slide42

Enantio-

selectivity

Environment

Elegance

Economy

E

The E Factor

Think Green

It’s better to travel one mile than to read a thousand books

Confucius

collaboration funding
Collaboration & Funding

EU

IOP Katalyse

IOP Koolhydraten

Hoechst Celanese

slide45

behind every

successful man there is

an astonished woman