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

Reducible functional groups 1.

Reducible functional groups 2.

Horiuti-Polányi mechanism of

hydrogenation

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

Liquid phase hydrogenation reactors

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

Investigation of a hydrogenation in an

autoclave

Gas dissolution at different mixing modes

Biazzi hydrogenation reactor mixing system

Scheme of a continuous hydrogenation plant

Reaction heat for one mole hydrogen

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

Nitrobenzene reduction products

Production of nitrobenzene — continuous process

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.

Hydrodesulphurisation of Benzotiophene

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

Most important properties of catalysts:

activity

stability

selectivity

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

(-)-dihydroapovincaminic acid ethyl

ester

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

Chemoselectivity in the industry

Regioselective hydrogenation of N-

heteroaromatic compounds

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

Cycle of the Wilkinson catalyst

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

Monsanto L-DOPA process

Selke ligand

Chiral ligands for enantioselective

hydrogenations

Prochiral olefines hydrogenation

• Ferrocene type ligands

• Lonza biotine process

Prochiral olefines hydrogenation

DUPHOS ligand

Pfizer Candoxatril process

Monophos ligand

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

Heterogeneous catalysts with ligands

with covalent bonds

Ligands with ionic bonds

Heteropoly acids as glues

Augustine and coworkers,

Heteropoly acid – metal ion interaction

Rh-DIPAMP with HPA-clay

– Acetamide-acrylic acid hydrogenation 97% ee, TON 270, TOF 400 h-1

Rh-monophos ligand attached to aluminaum