Hydrogenation in the chemical
industry
Chemo-, stereo-, enantioselectivity
Dr Antal Tungler sci. Adv.
HAS CER, IoI, BME CEPE
2012
Reduction
The reduction can be – Introduction of hydrogen,
– Removal of oxygen
– Introduction of elektron
into or from the material to be reduced.
Methods of Reduction – Chemical reduction
» Organic or inorganic reducing agent
– Catalytic hydrogenation
» Homogeneous or heterogeneous catalyst
– Electrochemical reduction
– Biochemical reduction
Catalytic reduction
It is green, because
– Molecular hydrogen is
» clean
» available;
– Atomselectivity 100% in addition
» Smaller but still high in hydrogenolysis, NO2 reduction;
Chemo-, regio-, diastereo-, and enantioselectivity
– Several functional group can be hydrogenated with high selectivity
– Usually high conversion
– Mild reaction conditions in liquid phase
Milestones of catalytic hydrogenation
1912 Nobel prize in Chemistry – Sabatier
– Catalytic hydrogenations (Ni catalysts) pioneering work
1973 Nobel prize in Chemistry –Wilkinson,
– homogeneous Rh complex for hydrogenations
2001 Nobel prize in Chemistry - W.S. Knowles, R. Noyori, Sharpless
– W.S. Knowles és R. Noyori catalytic asymmetric hydrogenations
– Sharpless catalytic asymmetric oxidations
– Headway of homogeneous catalytic reductions in the last 30 years
In fine chemical synthesis widely applied method
– Roessler: 10-20% of overall reaction steps is cat. hydrogenation
– Mainly heterogeneous catalytic hydrogenations (Ni, Pd, Pt etc.) with supported catalysts
„Catalytic hydrogenation is one of the most useful and versatile tools available to the organic chemist. The scope of the reaction is very broad; most functional groups can be made to undergo reduction, frequently in high yield, to any of several products. Multifunctional molecules can often be reduced selectively at any of several functions. A high degree of stereochemical control is possible with considerable predictability, and products free of contaminating reagents are obtained easily. Scale up of laboratory experiments to industrial processes presents little difficulty.”
Paul Rylander (1979)
Hydrogen production
Steam reforming of hydrocarbons, elimination of CO content
NH3 decomposition, separation of ammonia
NaCl electrolysis (elimination Hg content)
Flue gases of reforming and steam cracking, not for fine chemical purposes
Heterogeneous hydrogenation
Classical hydrogenation catalysts: – Supported precious metals,
– Raney Ni
– supported Ni and Cu
Small particles, high specific surface area
Hydrogenation reactions are exothermic
Most important properties of catalysts: – activity
– stability
– selectivity
Hydrogenation catalysts
homogeneous heterogeneous
Transitional metal
complexes
metals Non-metals
Rh, Pt, Ru, Pd, Co, Precious metals oxides
phosphine, CO, COD
ligands
On supports Cu, Zn, Cr, Mo
Mild conditions Pt, Pd, Rh, Ru sulphides
enantioselectivity Fe group metals Ni, Mo
Separation is difficult: water
soluble complexes
Ni, Fe, Co, skeletal or
supported form
Poison resistant
Cu metal Copper-chromite
Reacting system Reactor type Catalyst form
Gas, vapour fix bed
(tubular-)
Granules, tabletts,
monolith structures
fluid bed Fine powders
gas + liquid Mixed batch Fine powders
Bubble column Fine powders
loop Fine powders
Mixed continuous Course particles
Trickle bed monolith structures
Requirements in liquid phase hydrogenations
-intensive mixing oft he three phases
-increasing of the rate of gas dissolution
into the liquid
-complete conversion and possible best
selectivity
-limited pressure and temperature
-complete removal oft he catalyst
-corrosion and abrasion resistant devices,
often acidic reaction medium
Possible rate limiting steps:
gas dissolution in the liquid,
diffusion of soluted reactants through the liquid film
around catalyst particles,
diffusion of soluted reactants in the pores of the
catalyst,
adsorption of the reactants,
chemical reaction on the surface,
desorption of the products,
diffusion of products in the pores of the catalyst,
product diffusion through the liquid film around
catalyst particles.
Basic Autoclave Equation
(hydrogenation reactions)
kr rate coefficient of the catalytic reaction
km rate coefficient of the hydrogen transport
h, h/ho ration of hydrogen concentrations on the catalyst surface
and on the liquid/gas surface
x catalyst concentration.
r kr h, x km (1 - h, )
r =kr km x
kr x + km
1 / r 1 / km + 1 / kr x
Industrial examples
Petrochemistry: hydrodesulphurisation,
hydrocrack, hydrodezalkylation, purification of
ethylene
Large volume organic compounds : methanol,
benzene, phenol, butenale, 2-ethyl-hexenale,
nitrobenzene
Inorganic chemicals : ammonia, hydrogenation
of nitric acid to hydroxylamine.
Food industry : hardening of fats and oils
Lonza process, which is operated by First Chemical Corp., a homogenized
feed of hydrogen and nitrobenzene is passed over a fixed-bed catalyst of
copper on pumice with an inlet temperature of about 200 °C.
Bayer operates conventional fixed-bed reactors using a palladium catalyst on a
alumina support, modified in its activity by the addition of vanadium and lead
BASF operates a vapor-phase, fluidized-bed process, catalyst is copper
(» 15 wt %) on a silica support promoted with chromium, zinc, and barium.
Nitrobenzene and hydrogen molar ratio is of 1 : 100 to 1 : 200!!
DuPont hydrogenates nitrobenzene in liquid phase using a platinum –
palladium catalyst on a carbon support with iron as modifier. The modifier
provides good catalyst life, high activity, and protection against hydrogenation
of the aromatic ring.
Catalytic hydrogenation of 2-ethyl-hexenale
Ni/Al2O3 cat.
Gas-phase, tubular reactor with water
cooling under pressure
Examples from the pharmaceutical
industry
Preparation of amines from nitriles and nitro
compounds or with reductive alkylation
Papaverin-synthesis
Reduction of carbonyle or S-S bond, preparation of
ACE-inhibitors, Captopril, Enalapril, Lizinopril
C=N bond saturation in Vinpocetin-synthesis
C=C and CC bond saturation in steroid synthesis
Types of selectivity:
Regioselectivity Chemoselectivity
N O 2
C l
N H 2
C l
N H 2
3 H 2 N i
P d 4 H 2
O H
O H
O H 2 H 2
P d , O H -
P d , H +
Regioselectivity in the hydrogenation of
polychlorinated benzenes
1 8 0 o C C a t a l y s t P d / C T e m p .
C l
C l
C l
C l
C l
C l
C l
C l
C l
C l C l
C l C l
C l
C l C l
C l
C l
C l
C l
Stereoselectivity
H 2
m e n t h o l
n e o m e n t h o l
i s o m e n t h o n e
m e n t h o n e O H -
P d
+ H P d
2 H 2
P d
O H
O H
O
O
O H
Enantioselectivity
In the presence of chiral auxiliaries or modifiers
O
O O C H
3 O
O H O
C H 3 *
H 2 / N i
N a B r + t a r t a r i c a c i d
m e t h a n o l
/ P d H 2
*
O O
* O E t
H
O
H O O
E t
O
O
P t c a t a l y s t s H 2
s o l v e n t
c i n c h o n a a l k a l o i d s
How can be influenced
chemoselectivity?
–Changing the solvent
m e t h a n o l
s e l e c t i v i t y > 9 0 %
e t h y l a c e t a t e
+ H C l
4 H 2
P d
3 H 2 N H 2
N H 2
C l
N O 2
C l
How can be influenced
chemoselectivity?
Changing the catalyst
C O O H
N O 2
C l
C O O H
N H 2
C l
C O O H
N H 2
N i v . P t
3 H 2
P d 4 H 2
+ H C l
Modifying of the catalyst
Alloying of the active metal
A r C O
C l
P d
H 2
P d - C u
A r C H 3
A r C O
H
The alloying can be carried out together with the preparation of the palladium catalyst on active carbon or with controlled metal adsorption on the Pd catalyst.
Poisoning of the catalysts with strong
bases
C H C H C H O P d / C , H 2
E t O A c , p y r i d i n e
C H 2 C H 2 C H O
s e l e c t i v i t y ~ 6 5 %
C H 3
O 2 N N H 2
s t r o n g b a s e
P d / C , H 2
C H 3
N O 2 O 2 N
(S)-proline as chiral auxiliary
H 2
*
O O
enantiomeric excess < 80%
C H 3
O
C H
O H
C H 3 *
H 2
enantiomeric excess < 25%
Pd, stoichiometric (S)-proline, methanol assolvent
Pd, stoichiometric (S)-proline, methanol assolvent
(S)-proline is a chiral auxiliary which reacts with the
substrate giving an adduct and this adduct is
hydrogenated diastereoselectively, moreover a
kinetic resolution of TMCH takes place.
O
N
COOH
H+
COOH
NOH +
OH
N
COOHCO
NO O
N
CO-H2O
+H2 racemicPd
+
CO
NO
CO
NO
-H2O
>> COOH
N>>
Pd +H2
r1
O
N
COOH
HCO
NO O
N
CO
>>
Pd +H2
+H2O
r2R
r2S
Pd
+H2 4r
N
COOHr3R
r3S
Pd +H2
HN
COOH
O
O
kinetic resolution
asymmetric hydrogenation of isophorone
(1)
(2)
(3)
(4) (5)
(6)
(6)
(7)
Enantioselective hydrogenations
P d b l a c k c a t a l y s t
m e t h a n o l a s s o l v e n t
O O
*
H 2
N N
H
E t O O C
( - ) - d i h y d r o v i n p o c e t i n e a s c h i r a l m o d i f i e r
m e t h a n o l a s s o l v e n t
H 2 P t c a t a l y s t s O
E t
O
O
O E t
H
O
H O
*
e e 4 5 %
e e 3 0 %
Scheme of processes ofenantiodifferentiation
Similar processes can take place in Pt-cinchonaand Ni-tartaric acid mediated reactions.
Enantiomeric excess depends on equilibriumconstants and rates.
T h e f o r m a t i o n o f m o d i f i e r -
s u b s t r a t e a d d u c t w a s v e r i f i e d
b y c i r c u l a r - d i c h r o i s m s p e c t -
r o s c o p y
* o p t i c a l l y a c t i v e
r a c e m i c O
H 2 / P d
H 2 / P d
+
I n a d s o r b e d s t a t e
I n s o l u t i o n
c a t a l y s t s u r f a c e
O
O
O
O
c a t a l y s t s u r f a c e c a t a l y s t s u r f a c e
N N
H
E t O O C
N N
H
E t O O C
N N
H
E t O O C
N N
H
E t O O C
Chronology of asymmetric catalysis
Homogeneous reactions
First attempt: 1966 Cu II catalyzed addition of diazoaceticacid ester to styrene, ~ 10% ee
First good enantioselectivity: 1972, with DIOP ligand
First (published) large scale industrial application: 1991 Takasago menthol process
1996 Novartis-Dual herbicide production, C=N enantioselective reduction
Nobel prize 2001: Knowles, Noyori, Sharpless
Heterogeneous reactions
First attempt: 1922 bromine
addition on cinnamic acid by
ZnO/fructose Erlenmeyer
First good enantioselectivity:
1960 beta-ketoester
hydrogenation with tartaric
acid modified Raney-nickel
Best system: 1976 alpha-
ketoester hydrogenation with
cinchonidine modified Pt-on-
alumina catalyst
High-tech asymmetric catalytic process
(Novartis)
N
CH3O
O
ClN
O
Cl
CH3O
H2 chiral Ir complex
N
O
Cl
CH3O
H
CH3 NCH3
O
Cl
CH3O
H
aR, 1S aS, 1S
Metolachlor active
enantiomers
or
PR'2
PR2
CH3
Josiphos
R = phenyl R' = 3,5-xylil
Fe
50 oC, 80 bar, ee 80%,
ton 2'000'000, tof 400'000 h-1
This is nearly the ideal process!
Development took more than 20 years!
Comparison of homogeneous and heterogeneous catalysts
Characteristics Homogeneous Heterogeneous
Advantages Selectivity, scope,
variability, well defined
Activity, separation,
stability, recovery
Disadvantages Sensitivity, small
stability and activity,
difficult separation
Difficult preparation,
poorly defined,
transport limitations
What to do? Improve separation:
two-phase systems,
heterogenisation,
encapsulation,
increase productivity
Uniform active sites:
zeolites, better
characterisation
Izumi and his co-workers, 1960 Best ee > 95%
CH3
CCH2
COCH3
O O
CH3CH C
OCH3
OH O
*Raney-nickel
Tartaric acid, NaBr
H2
COOH
OH
OH
COOH
*
*
Beta-ketoester hydrogenation with
tartaric acid modified Raney-nickel
catalyst
The hydrogenation of -ketoester with cinchona alkaloid modified platinum
catalyst
Orito and his co-workers in 1978 Best ee > 98%
(S)(R)
hydroxyesterketoester
CH3
OR
O
HO H
+
R= CH3
C2H5
H2/Pt
modifiersolvent
CH3
OR
O
HO H
CH3
OR
O
O
N
N
H
HH
OH
New substrates in Pt/cinchona mediated reactions
COOH
O
CF3
O
O
O
O
CH3CH3
Enantiomeric excesses %: 82 79 61
NH R
O
O
R=H, Et, iPR,
CH2CF3
NH
O
O
EtOOCCOOEt
O O
O
60 47 43 39
R=alkyl, aryl
OMe
O
R
OOO
R1,R2=H, Me, PhR3=H, Me, Na
R1
C(R2)COOR3
Ee % 30 20 12 12
New substrates and modifiers in Pt and Pd
mediated reactions
O
OMe
OMe
NH
Cl
O
ClCOOH
NOH
96.5 50 26
X
NHO
NH2
N
N
NN
H
EtOOC
Modifiers
New catalysts, modifiers and
substrates
Catalyst: Pd Modifier: cinchonidine
O
OH
O
Ee % 72 52 82
Modifier: dihydroapovincaminic acid ethyl ester
O
( )n
n = 1, 2, 3
O
55
54
Catalyst: Pd Catalyst: Pd
Modifier: cinchonidine
New catalysts, modifiers and
substrates
CH3 COOC2H5
OO
Pt/Al2O3 catalyst Ee % 25/10 Pd black catalyst
Ee % 40/21
(S)-,-diphenyl-2-pyrrolidinemethanol
(S)-,-dinaphtyl-2-pyrrolidinemethanol
H OH
N
HN
OH
Competitive adsorption reactions
Pd
Pd
NN
H
EtOOC
NN
H
EtOOC
NN
H
EtOOC
catalyst surfacecatalyst surface
O
O
O
O
catalyst surface
In solution
In adsorbed stat e
+
O
racemic
optically ac tive
*HN
N
EtOOC
+
H+
H+
H+
H+
H2
H
H
Diastereoselective heterogeneous catalytic
hydrogenation of aminocinnamic acid
derivatives
Substrates Reaction
time (h)
Conv.
(%)
de
(%)
R1=methyl, HR2=(S)-
proline dimethyl amide
7 75 36
R1=methyl, HR2=(S)-
prolinanilide
8 80 68
R1=phenyl, HR2=(S)-
prolinanilide
8 70 50
Conditions: 1.0 g substrate, 0.2 g 10% Pd/C (Selcat), 50 ml toluene, 10 bar, room temperature.
Perspectives of different hydrogenation methods for the
preparation of optically active compounds
Methods Homogeneous
transition
metal complex
catalysis
Anchored
homogeneous
catalysis
Chiral
modification of
heterogeneous
catalysts
Use of chiral
auxiliaries in
the reaction
mixture
Diastereo
selective
hydrogenation
Examples Metolachlor/
Josiphos
Dehydroamino
acid
DIPAMP/PTA
Al2O3
Ethyl pyruvate
Pt/cinchonidine
Isophorone
Pd-(S)-proline
Schiff’s bases
Picolinic acid
amide
Pd/C
Optical
purity
good
excellent
good
excellent
good
excellent
good poor
excellent
Chemical
yield
excellent good good poor acceptable
Scope broad increasing increasing narrow broad
Industrial
application
good promising limited no hopeful
Chemoselectivity in the industry
Hydrogenation of cinnamic aldehyde to cinnamil alcohol
Reduction of carboxylic acids to aldehydes
Raney-Ni-tartaric acid-NaBr
industrial application
Drawbacks: high amount of poisoning wastes, small activity.
Tetrahydrolipstatine intermedier – Hoffman-La Roche development
» 100% yield, e.e. 90-92%
Pt-cinkona alkaloid rendszer
Szubsztrátumok: -helyzetben funkciós csoporttal rendelkező ketonok
1979-ben Orito és munkatársai fedezték fel
Módosító: leggyakrabban alkalmazott két cinkona alkaloid a cinkonidin és ennek kvázi enantiomere a cinkonin. – Etil-piruvát hidrogénezésében cinkonidin jelenlétében az (R)-(+)-etil-laktát
keletkezik feleslegben, míg a cinkonin az (S)-(-)-etil-laktát feleslegét eredményezi.
Reakciókörülmények – RT
– 10-70 bar
Katalizátor: Pt/Al2O3
– katalizátor hidrogénben való előkezelése megkétszerezte az enatiomerfelesleget
Oldószer: AcOH vagy toluol
O
O
O
OH
O
O
O
O
O
O
O
O
OR
OR
O
CF3
Szubsztrátum Oldószer Sz/M Sz/Pt e.e.
(%)
AcOH 1540 1640 97
EtOH/H2O 350 440 82
Toluol 296000 1040 91
Etil-acetát 143 66 94
AcOH 1050 1320 97
Toluol/TFA 290 180 91
-Ketoesters enantioselektive
hydrogenation industrial application
Benazepril, ACE inhibitor intermediate compound production
– Yield 98%, e.e. 79-82%
COOEt
O
COOEt
HO H
Pt/Al2O3, H2
dihidricinkonidin
ee=80-85%
OCH2COOH
NH
H
COOEt
benazepril
Homogeneous hydrogenation
catalysts
1965: Wilkinson catalystkatalizátor
– Rhodium-tris(triphenilphosphine)
Complex
– Central metal atom or ion
– Ligands
– Anion
Ru, Rh, Ir
Practical application of homogeneous
complexes
Selectivity
Aktivity TOF>10000 h-1
Stability TON>50000
Separation from the reaction mixture
– Two-phase catalysis
– Heterogenized complexes
» Anchored on the surface with chemical bond or with adsorption
» Supported liquid-phase catalysis
Asymmetric hydrogenation
ketones
Ru-BINAP
– Broad choice of substrates
– High pressure, temperature, long reaction time
Imipenem: antibiotics intermedier, 120 t/y
New generation Ru-BINAP
(diamine) ligands
Hydrogen transfer eased by the ligand
(R)-1-phenil-ethanol production
– Takasago
– 99% ee
– 4 bar hydrogen
Hydrogenation of Imines
(S)-metolachlor – Herbicid, Syngenta (former Ciba-Geigy), 10 000 t/y, TOF 400 000 h-1,
TON 2x106, Jodine and acetic acid promotores, 80% ee