Homogen catalysis

Homogen catalysis
1

Homogen catalysis
vs
heterogeneous catalysis
2
Homogene catalysis:
Production of compounds in multi-tons scale to gram scale –
from simple to highly advanced compounds.
Increased value ($/kg)
Heterogenous catalysis:
Production of compounds in multi-tons scale –
mainly simple compounds
Low value ($/kg)

Homogen catalysis vs
heterogeneous catalysis –
from a practical point of view
3
Homogene catalysis:
All constituents in one phase – liquid phase
E.g. transition metal/organic catalyst – discrete catalyst
Heterogenous catalysis:
One or more of the constituents are in different phases
Reaction takes place at the phase interface - the catalyst surface

Advantages - disadvantages
Homogene catalysis:
Advantages: From small to large molecules
One active site – control of selectivity
Low catalyst loadings – high turnover
4
Disadvantages: Seperation
Lower stability
Sometimes – high catalyst loadings
Complex mechanisms
Heterogenous catalysis:
Advantages: Seperation of reaction products from catalyst
High stability
Catalyst regeneration
Low catalyst loadings – high turnover
Disadvantages: Small molecules
Several active sites - less control of side reactions
”No” selectivity

Heterogeneous catalysis -
small molecules with impact
5
N 2 + 3 H 2
Catalyst
2NH 3
3-5% of the worlds
energy production!

Small molecules with impact
6
H
H
H
H
+ O 2
Ag110
H
H
O
H
H
H
H
O
H
H
a large number of organic compounds
- fundamental for the world
H 3 C
H 2
C CH2
CH 3
V 2 O 5
O
O
O
14-electron oxidation!!!
O
O
O
+ O 2
a large number of organic compounds
- fundamental for the world

7
Advantages for
homogeneous catalysis
(a) Selectivity
(b) Activity
(c) Ease of modification
(d) Easy of study
(e) Efficiency

The physical chemistry behind catalysis
8

Activation of organic compounds
by transition metals
9
Bonding ability - transition metal d-orbitals
x
z
y
d yz (d xy, d xz )
d z 2 (d x 2 -y 2)
Bonding ability - organic compounds
LUMO - π*
HOMO - π

Bonding interactions
10
HOMO
LUMO
LUMO
HOMO
M
Cl
Cl
Pd
Cl
Electron-rich - HOMO(M)-LUMO(alkene)
Wacker process
Cl
Cl
Ti
Cl
Electron-poor - LUMO(M)-HOMO(alkene)
Ziegler-Natta process

Wacker process
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Cl
Cl
Pd
Cl
Electron-rich - HOMO(M)-LUMO(alkene)
Wacker process
H 2 O
PdCl 2
O
Several millions tons/year
Catalyst: [PdCl 2 ] n =
Pd
Cl
Pd
Cl
Cl
Cl
Pd
Cl
Cl
Pd
Cl
Cl
Pd
Commercially available
insoluble oligomer
rust brown

Looks simple – but no!
12
H 2 O
O
PdCl 2

R
Ziegler-Natta
TiCl 4 /
AlCl 3
R
H 2
C C
H 2
n
Polymerization
13

Reduction of alkenes
14
R
H 2
H
R
H
L 3 RhCl

Asymmetric catalysis
15

Asymmetric catalysis
16

Pasteurs crystals
17
EtOOC
OH
HO
COOEt
EtOOC
OH
HO
COOEt
Chiral molecules

Chiral molecules
18

Is the heart always to the left?
19

Why are the stairs always turning the same
way?
20

21
Carvone
Mint
Caraway

Chiral molecules - receptor interaction
23

When it goes wrong
24
Goya: Mother showing her derformed child to two women
Louvre, Paris

Nature gives us only one choice!
26

Narwhale
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Chemical reaction
31

Control of chirality with catalysis
32
Energy
Left
Right
E ‡ S
E ‡cat R
E ‡ R
Reactants
Product S
Product R
ee = (R-S)/(R+S)x100

Nobel prize – chemistry –
2001
33
Dr. William S. Knowles, Monsanto Company, St. Louis, USA
Professor Ryoji Noyori, Nagoya University, Japan
”their work on chirally catalyzed hydrogenation reactions”
Professor K. Barry Sharpless, The Scripps Research Institute, USA
”his work on chirally catalyzed oxidation reactions”
”This years Nobel Prize in Chemistry concerns the development of
transition metal catalysts for stereoselective hydrogenation and oxidations –
two important classes of synthetic reactions. Through the Laureates’ work
a myriad of useful chiral compounds have become accessible”

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Catalytic asymmetric hydrogenation
H
H
H H
R
R
Kat.
H H
R
H
H

35
Monsanto synthesis of L-DOPA - 1974
MeO
COOH
H
H
MeO
COOH
AcO
NHAc
Rh-komplex
AcO
H NHAc
100% udbytte
95% ee
OMe
H 3 O
P
P
HO
COOH
OMe
HO
H NHAc

Noyori hydrognation of alkenes
36
Ph Ph O
P
Ru
P
Ph Ph O
O
O
(S)-BINAP-Ru-komplex
CH 2
MeO
COOH
H H
Ru-komplex
CH 3
MeO
(S)-Naproxen
92% udbytte
95% ee
COOH
H

38
Warfarin
- from rat poison to heart
medicin
OH
O
O
O
Warfarin

Warfarin
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• One of the world’s most widely used anticoagulants
• Prevents blood clotting and atrial fibrillation
• Estimated 2 mill. users (USA) ~22 mill. presciptions/year (USA)
• Sales ~500-1000 million $ a year (USA)
• Different activity and metabolism of the enantiomers
• Only marketed as a racemate for more than 40 years
• Originally used as a rat poison
OH
O
O
O

Clinical pharmacology of warfarin
40
• 5-8 times higher anticoagulant activity of (S)-warfarin compared
to (R)-warfarin
• Half-lives of 21-43 h for (S)-warfarin and 37-89 h for (R)-warfarin
• Different metabolic pathways of (S) and (R) enantiomers
• Many problems with drug-drug interactions for racemic warfarin
due to the metabolism of the (S)-enantiomer
• A stable concentration is critical, but very difficult, to maintain
OH
O
O
O

41
S-warfarin metabolized by cytochrome P450
X-ray crystal structure of S-warfarin in cytochrome P450 2C9

Warfarin – clinical pharmacology
42
H
N
O
H
N
O
Glutamic acid residue
in glycoprotein
CO 2 H
CO 2 H
CO 2 H
CO 2 γ-carboxy
O glutamic acid
2
clotting factor
OH
OH
Vit K - hydroquinone
Me
R
O
O
Me
O
R
Vit K - epoxide
Vit K reductase
O
Me
Vit K reductase
Warfarin
O
R
Vit K - quinone
Warfarin

Asymmetrisk synthesis of
warfarin
43
OH
O
O
+
Ph
O
Me
Chiral catalysts
OH Ph O
O
O
Me
Catalysts
N
H
N
Me
CO 2 H
H
N
N
H
(R) or(S)-warfarin
>20 analogues
CO 2 H
Up to 85% yield
70% ee
Up to 96% yield
82 % ee (99.9% ee after recrystallization)

How did it all start?
45

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Questions - discussion
• Discuss the origin of chirality
• Discuss the activation of alkenes by early and late transition metal complexes
• Try to understand the role of d-electron occupation
• Discuss the reaction mechanism for Wacker process
• Discuss the reaction mechanism for Ziegler-Natta procecss
• Discuss the reaction mechanism for hydrogenation of alkenes
• Calculate the increase in reaction rate by a reduction of the activation energy
by 10 kcal/mol