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
1
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.
2
Anastas and Warner, Eds, Green Chemistry.
Theory & Practice, Oxford U. Press, 1998
Sustainability
Meeting the needs of the present generation
without compromising the needs of future
generations to meet their own needs
is the goal
3
“What we need is more imagination not more knowledge”
Albert Einstein
Do politicians understand the issues?
It’s not pollution that is the
problem it’s the impurities
in our air and water.
Dan Quayle
4
Phloroglucinol Synthesis
CH3
O2N
COOH
NO2
K2Cr2O7
O2N
NO2
HO
NH2
Ca. 40kg of solid waste per kg phloroglucinol
HO
OH
aq.HCl
DT
- CO2
NO2
TNT
NH2
Fe/HCl
H2SO4 / SO3
NO2
H2N
OH
phloroglucinol
OH
+ Cr2 (SO4)3 + 2KHSO4 + 9FeCl2 + 3NH4Cl + CO2 + 8H2O
392
272
1143
160
44
144
OH
MW = 126
product
byproducts
Atom Utilisation = 126/2282 = ca. 5%
E Factor = ca. 40
5
“ To measure is to know ” Lord Kelvin
Syn gas utilisation (1983)“Atom
2 CO + 3 H2
for Atom”Oxygen
Oxidant
HOCH2CH2OH
2 CO + 4 H2
H2C=CH2 + 2H2O
44%
47
18
22
22
Byproduct
H2O
t-BuOH
CH3COOH
NaCl
KIO3
Atom utilisation (1991)
1. PO : Chlorohydrin process
CH3 HC=CH2 + Cl2 + H2O
Ca(OH)2
% Active O
H2O2
t-BuOOH
CH3COOOH
NaOCl
KIO4
100%
utilisation (1990)
CH3CH(OH)CH2Cl + HCl
O
CH3HC
CH2
+ CaCl2 + H2O
2. PO : Catalytic Oxidation
CH3HC=CH2 + H2O2
25% atom utilisation
O
CH3HC
CH2
+ H 2O
76% atom utilisation
6
See Chem. Eng. Progr. 1991, 87(12), 11
See also Trost, Science, 1991, 254, 1471
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
“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.
7
R.A.Sheldon, Chem &Ind, 1992, 903 ; 1997, 12
I Factor = 4.19
8
R. A. Sheldon, Green Chem, 2007, 9, 1273-1283
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”
9
Major Sources of Waste
• STOICHIOMETRIC ACIDS & BASES
• STOICHIOMETRIC OXIDANTS & REDUCTANTS
- Na2Cr2O7, KMnO4, MnO2
- LiAlH4, NaBH4, Zn, Fe/HCl
• SOLVENT LOSSES
- Air emissions & aqueous effluent
10
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
11
Research Themes
O2 H2O2
CO H2 H2O
Novel Media
Enzymes
Catalysis
&
Green Chemistry
Renewables
Cascades
Chirotechnology
12
Sheldon, Arends and Hanefeld , Green Chemistry
And Catalysis, Wiley, New York, 2007
Heterogeneous Catalysis
13
Peroxometal mechanism 1973
Shell SMPO process 1973
O
M
Ti (IV)/SiO2
O
+ ROH
+ ROOH
O
H
OH
O
M
R
O
O +
R
Sheldon, Rec.Trav.Chim.Pays-Bas, 92, 253, 1973
Sheldon and van Doorn, J.Catal. 31, 427, 1973
H2 + O2
Pd/Pt (4nm)
MeOH
Headwaters/Evonik 2006
Mimoun, Sharpless
TS-1
H2O2
TS-1
H2O2 +
Metal
Catalyzed
Epoxidation
H2O2 +
O
+ H2O
MeOH
O
+ H2O
Enichem 1985
Ti-beta, Ti-MCM41, Ti-ITQ, etc
van Bekkum, Corma
Dakka, Sato, LeBars
14
Redox Molecular Sieves (Zeozymes)
Green Caprolactam Process : Sumitomo
O
H2O2 / NH3
NOH
TS-1
Ammoximation
vapour
phase
NH
O
High Si MFI
Beckmann rearrangement
C6H10O + H2O2 + NH3
C6H11NO + 2H2O
Atom efficiency = 75% ; E = 0.32 (<0.1)
O
(NH3OH)2SO4
NOH
H2SO4
NH
O
Atom efficiency =29% ; E = 4.5
15
Ichihashi and Kitamura,Catal.Today, 73, 23, 2002
Redox Molecular Sieves :
Philosophers’ Stones or Trojan horses ?
Filtration Test for
Heterogeneity:
60
conversion (%)
50
40
30
20
hot
cold
10
0
0
30
60
90
120 150 180
Time (min)
Chen (1995), Elings (1997), Plyuto, Schuchardt
Lempers (1998)
16
Sheldon, Wallau, Arends and Schuchardt,
Acc. Chem. Res., 31 (1998) 485-493.
Homogeneous Catalysis
17
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)
18
“The best solvent is no solvent”
Aqueous Biphasic Cataysis
2. Aerobic Oxidation
1. Carbonylation
OH
R2
H
R1
OH
CO Pd / tppts /H+
+ 0.5 O2
Pd2+/L
air
OH
2
COOH
R
1
Ibuprofen
R
R
O
NaO3S
NaO3S
tppts
P
R
Pd2+ L
+ H2O
O
water
SO3Na
SO3Na
SO3Na
Papadogianakis, Verspui (2001)
N
Moiseev
N
ten Brink (2001)
19
ten Brink, Arends, Sheldon, Science 287 (2000) 1636
Catalysis in Ionic Liquids
R2
N
+
N
R
R1
+N
N
OH
+
+
N
R3
OH
N
+
OH
R
R4
OH
R
Anions : BF4 , PF6 , RCO2 , H2PO4 , NO3 , HOCH2CO2
O
• Negligible vapour pressure
• Designer solvents
• Catalytic hydroformylation,
carbonylation, hydrogenation
and biocatalysis
O
O
OH
+
O
+
OH
NH2
OH
O
O
CaLB in [bmim][BF4] and [bmim][PF6]
O
RCOOOH
H2O
RCOOH
H2O2
Madeira Lau (2003) Seddon
Product recovery?
20
Madeira Lau, van Rantwijk, Seddon, Sheldon, Org.Lett. 2, 4189, 2000
Sheldon, Chem. Comm. 2001, 2399-2407
In situ product removal with scCO2
scCO2 phase
OH
OAc
OAc
lipase
IL phase
scCO2 as mobile phase in batch or continuous operation
21
Reetz et al,Chem.Comm.,2002, 992
Lozano et al,Chem.Comm.,2002, 692
The Miscibility Switch
Reactant
IL
+
Catalyst
+
Reactant
+
CO2
High pCO2
one phase
CO2
+
Product
IL
+
Catalyst
+
Product
Low pCO2
two phases
P
CO
2+
IL
Carbon dioxide
P
P
CO2
IL
Ionic liquid + catalyst
Reaction
Product
Separation
22
Peters & Witkamp
Organocatalysis
23
O.
N
R1
OH
H
N
O.
+ “O”
•
•
•
•
•
No solvent
No BrNaOCl
Recyclable
Cheap raw
material
Chimassorb 944
R1
O
CH2Cl2 / H2O
R2
O.
N
N
+ H2O
R2
N
“O” = NaOCl, m-CPBA, oxone (+ Br -)
N
(CH2)6
N
N
5
NH(tert-octyl)
PIPO
van Bekkum et al , Synthesis, 1996, 1153
Dijksman (2001)
Cu(II) / PIPO / O2
N
O
.
TEMPO
Laccase : a multicopper oxidase
O
O2
H2 O
laccase
N
.
O
laccase ox
Li (2004), Matijosyte
+
N
O
RCH2OH
OH
TEMPO (5m%)
H
+ 0.5 O2
Cu(II) / bipy (5m%)
Base / MeCN / H2O
RCHO
Gamez
de Vries/Hagen
24
Organocatalytic Oxidations
subtilisin
CaLB
CPO
phytase
Biocatalysis
laccase
HNlase
25
Inventing New Enzymes & Enzymatic Reactions
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)
26
Enzymatic Ammoniolysis
R
BASF Process
O
O
R
NuH
Ser
NH2
Nu
NH2
Lipase
O
O
O
O
ee > 99% (S)
Nu = OH, OR, NH2 , RNH, OOH, etc
O
R
OEt
lipase,
40oC
O
O
NH3/t-BuOH
R
• Green amide synthesis
• Enantioselective with
amino acid esters
Steverink(1995), Hacking (1999)
Wegman(2001)
+
NH2
O
NaOH
NH2
NH
glycol-water
(2:1), 150oC
ee > 99% (S)
ee > 99% (R)
> 3000 tpa
27
If you want to find something new
you have to DO something new
Edward De Bono
Easy-on-easy-off resolution
NHCOCH2Ar
NH2
Ph
ArCH2COX
pen acylase
pH 10-11
NH2
Ph
V.Svedas
pen acylase P h
pH 7
ee > 99%
+
Ph
NH2
H2O
ee > 99%
L.van Langen(2001), R.Madeira Lau(2003), H.Ismail(2007)
Dynamic Kinetic Resolution
100
90
80
70
60
50
40
30
20
10
0
% yield (amide)
NH2
0
20
40
60
80
time (h)
100
O
HN
CaLB, 50oC, 96h
Kinetic resolution
Dynamic kinetic
resolution
O
O
Nano Pd
NH2
120
- 88 % yield (4 days)
- ee product 98 % .
H.Ismail(2007)
28
Pd –catalyzed racemization of 1-phenethylamine :
Murahashi (1983) ; Reetz , DKR (1996).
ArSCH3 +H2O2
N
N
FeIII
N
S
CPO
Ar
N
S
O
O
CH3
+ H2O
99% yield
>99% ee
Cys
van Deurzen (1996)
van de Velde (2000)
Heme
Low stability
HN
Arg
O
HN
Linker
Se
OH
O
X
O
Se OH
X = NO2 , CF3
van der Toorn
Arg
O
O
O
Se
OOH
X
O
R1
ee
H 2O
H2O2
O
subtilisin
OH
NH2
N
H H
N NH O V
65%
O
O
His
N
NH2
HN
Lys
His
van de Velde
vanadate phytase Aksu-Kanbak
Correia
X
Ser
Asp
R2
R1
X = NO , CF
2
3
R2
ten Brink (2001)
29
Inventing New Enzymes : Chemomimetic Biocatalysis
Historically: Adapt Process to fit Catalyst
Available
Catalyst
Dream Process
30
Future: Adapt Catalyst to fit Ideal Process
EVOLVE
Adapted
Catalyst
Catalyst
Dream Process
Nightmare Process
Compromise process to
accommodate catalyst
Adapt catalyst to
optimum process
Directed Evolution
31
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
Novel Genes
32
Stemmer,Nature,370, 389-391, 1994; Huisman et al (Codexis)
See also Reetz, Advan. Catal. 2006, 1-69.
Green Synthesis of Lipitor Intermediate (Codexis)
Presidential Green Chemistry Challenge Award 2006
O
O
Cl
OH
KRED
O
Cl
OEt
> 99% ee
NADP+
NADPH
OEt
gluc o nate
g luc o se
GDH
OH
Cl
O
aq. NaCN, pH 7
OEt
HHDH
OH
NC
O
OEt
(>99.9% ee)
KRED = keto reductase ; GDH = glucose dehydrogenase
HHDH = halohydrin dehalogenase (non-natural nucleophile)
33
Nature Biotechnol. 2007, 25, 338-334
Huisman, Grate, Lalonde et al (Codexis)
Improving Performance by Directed Evolution:
test tube to commercial process with gene shuffling
1. KRED + GDH
2. HHDH
Parameter
Substrate loading
Parameter
Reaction time
Substrate loading
Enzyme loading
Reaction time
Isolated yield
Enzyme loading
Phase separation time
Isolated yield
Volumetric Productivity
Volumetric Productivity
Process Design Initial Performance Final Performance
160 g/L
80 g/L
180 g/L
Process Design Initial Performance Final Performance
<16 hrs
24 hrs
8 hrs
120 g/L
20 g/L
140 g/L
<1 g/L
10 g/L
0.7 g/L
<16 hrs
72 hrs
5 hrs
>90%
~80%
97%
<1.2 g/L
130 g/L
1.2 g/L
>1 hr
~1 min.
>90%
~60%
92%
>240 g/L.day
80 g/L.day
540 g/L.day
>180 g/L.day
7 g/L.day
670 g/L.day
34
Disadvantages of Enzymes
• Low operational stability & shelf-life
• Cumbersome recovery & re-use
(batch vs continuous operation)
• Product contamination
Solution : Immobilization
35
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
CLEAS active in:
- scCO2 (M. Poliakoff)
- ILs
(Sheldon)
• Stability towards denaturation
36
Sorgedrager (2006), Janssen (2006 )
(CLEA Technologies B.V.)
Examples of Successful CLEAtion
Hydrolases
Oxidoreductases
Lyases
• Pen. acylases (2)
• ADH
•R- & S- HnLases
• Lipases (7)
• FDH
• PDC
• Esterases (3)
• Glucose oxidase
• DERA
• Proteases (3)
• Galactose oxidase
• Nitrilases (2)
• Nitrile hydratase
• Laccase
• Aminoacylase
• Catalase
• Phytase
• Chloroperoxidase
• Galactosidase
Cao, Lopez-Serrano, Mateo, Perez, van Langen, Sorgedrager
Janssen, Bode, van Pelt, Chmura, Matijosyte, Aksu-Kanbak,
37
Evolution vs Cleationism
Catalytic Cascade Processes
5 atm H2
O
OCH3
N
H
0,4 % cat. O
O
OCH3
N
H
amidase
OH
H2N
O
Catalyst :
Rh(monophos) on TUD-1
H2O2
RCO2OH
99% yield / 95% ee
O
97% yield / > 99% ee
Simons (2007)
PS- I
H
OH
lipase
H2O
RCOOH
PS- I(O2CR)2
O
Kotlewska
38
Trienzymatic Cascade with a
Triple-Decker combi CLEA
OH
CONH2
OH
CN
O
HCN /(S)-HnL
H2O
NLase
Pen G amidase
OH
COOH
Chmura, Stolz
Conv. 96% / ee >99%
39
Renewables & Green Chemistry :
the Biorefinery
CO2
photo+ synthesis Biomass
H2O
Greener products
Fuels
Polymers
Bulk & Fine
Chemicals
Emons (1992), Arts(1996), Papadogianakis
40
Metrics for renewables ?
Carboxystarch : Safe & Natural Absorbing Polymer (SNAP)
H OH
H
H O
O
HO
H
H
OH
O
H
Laccase CLEA
TEMPO/O2
]
n
starch
COOH
H O
O
HO
H
H
OH
O
H
]
n
carboxy starch
• Non- toxic & biodegradable
• Green (bio) catalytic process
Boumans (TNO)
• Green raw materials
41
The plan is nothing, the planning is everything
Mao Zedong
Enantioselectivity
Environment
E
The
Think
E Green
Factor
Elegance
Economy
42
It’s better to travel one mile than to read a thousand books
Confucius
43
So it goes…………
Collaboration & Funding
EU
IOP Katalyse
IOP Koolhydraten
Hoechst Celanese
44
behind every
successful man there is
an astonished woman
45
46
47