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An environmentally bening technology: selective liquid-

phase catalytic hydrogenation

Antal TunglerDepartment of Chemical Technology

BUTE2004

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E factor

Industrial branch Product volumen

t/y

kg byproduct/kg product

Basic materials 104-106 < (0,1)1 5

Fine chemicals 102-104 5 >50

Pharmaceuticals 10-103 25 >100

Stoichiometric Catalytic

Reduction

4 PhCOCH3 + NaBH4 + 4 H2O 4 PhCH(OH)CH3 + NaB(OH)4

AU = 122/147,5 = 82,7%

PhCOCH3 + H2 PhCH(OH)CH3

AU = 120/120 = 100%

PhNO2 + 2Fe +H2O = PhNH2 + Fe2O3

AU = 93/253 = 36,8%PhNO2 + 3H2 = PhNH2 + 2H2O

AU = 93/129 = 72%

Comparison of atom utilisation

Topics of the presentation:

Types of selectivity

Methods of improving selectivity

Asymmetric catalysis

New substrates and modifiers in enantioselective hydrogenations

Diastereoselective hydrogenations

Perspectives of the preparation of optically active compounds with hydrogenation

Results from our laboratory are highlighted!

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Catalytic asymmetric synthesesA further possibility to increase effectiveness!

Every step with 100% stereoselectivity halves the amount of required starting materials!

Homogeneous, transition

metal catalyzed reactions with chiral ligands

Heterogeneous catalytic reactions, with chiral

synthons or with chiral modifiers, primarily

liquid-phase hydrogenations

The most important properties of catalysts:

activity, stability, selectivity

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Types of selectivity in hydrogenations:

• Chemoselectivity • Regioselectivity

NO2

Cl

NH2

Cl

NH2

3 H2Ni

4 H2Pd

+ HCl

OH

OH

OHPd 2 H2

OH-

H+

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Stereoselectivity

OH

Pd

2 H2

OOH

OHO

menthone diastereoisomers

Pd H2

H+

OH-

menthol diastereoisomers

neomenthol

menthol

thymol

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Enantioselectivity

CH3C

CH2C

OCH3

O O

CH3CH C

OCH3

OH O

*Raney-nickel

Tartaric acid, NaBr

H2

COOH

OH

OH

COOH

*

*

β-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)

hydroxyester ketoester

CH3O

R

O

HO H

+

R= CH3

C2H5

H2/Ptmodifiersolvent

CH3O

R

O

HO H

CH3O

R

O

O

N

N

H

HH

OH

O

Pd H2

(S)-proline, methanol

O

*

Hydrogenation of the C=C bond of isophorone with Pd in the

presence of (S)-proline

Tungler and his co-workers, 1989

Best ee > 60%N COOHH

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Chronology of asymmetric catalysisChronology 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

N

CH3OO

ClN

O

Cl

CH3O

H2 chiral Ir complex

N

O

Cl

CH3O

H

CH3 NCH3

O

Cl

CH3O

H

aR, 1S aS, 1S

Metolachlor activeenantiomers

orPR'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!

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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

Comparison of homogeneous and heterogeneous asymmetric catalysts

Advantages Selectivity, broad scope, variability, high ee

Activity, separation

Disadvantages Sensitivity, small activity, difficult separation, complicated ligand synthesis

Poorly defined, usually small ee, only on low temperature, up till now only metal catalysts

What to do? Improve separation: two-phase systems, heterogenisation, encapsulation, increase productivity

Uniform active sites: zeolite support, better characterisation

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How can be infuenced selectivity?

NO2

Cl

NH2

Cl

NH2

Pd

ethyl acetate

methanol

3 H2

4 H2

chemoselectivity > 90%

+ HCl

Change the solvent

Replace the catalyst

COOH

Cl

NO2

COOH

NH2

Cl

COOH

NH2

Ni or Pt

3 H2

Pd4 H2

+ HCl

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Modification of the catalyst with alloying of the active metal

The alloying of the active component can be carried out during catalyst preparation or thereafter with metal adsorption on controlled potential.

The preparation of aromatic aldehydes with the hydrogenation of the corresponding acid chlorides with SELCAT RA Pd-Cu/C catalyst

CHO

CH3O

OCH3

OCH3

CHO

OH

CHO

OCOCH3

CHO

OCOCH3

Ar CCl

O Pd-Cu / C O

CH

Ar

CH3Ar

Pd / C

H2

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With poisoning of the catalyst

Both aniones and cationes can influence the catalytic activity and

selectivity!

With adjusting of pH the stereoselectivity of the hydrogenation of ketones can be influenced (see menthol!)

Trans-acetylamino cyclohexanol, 80% stereoselectivity

•The intermediate of the hydrogenation is the

cyclohexanone derivative, in basic medium the equatorial alcohol is formed in excess.

NCH3

NCH3

NCH3

H H

H

H2

Pd/C Cl-

water-H2SO4

Pd/C methanol

NH3C CH3

NO

N CH3H3C

NH2

Pd/C + Fe2+

water-NH3

2 H2

H3CCONH OH NHCOCH3

H

HO

HPd OH-

3 H2

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Influencing the selectivity with the mode of preparation, metal deposition

OH

OH

OH

Pd OH-

2 H2

Pd H+

aliphatic tetralol

aromatic tetralol

80% regioselectivity with the SELCAT Q catalyst

H2PdCl4 + C + Cl-CH3

N CH3CH3

CH2

+CH3

N CH3CH3

CH2

+

2

PdCl4 Cbase

Pd(OH)2 / CH2

Pd / C

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Extend the scope : 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

O

OMe

OMe

NH

Cl

O

ClCOOH

NOH

50 26

96.5

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Hydrogenation of isophorone in the presence of (S)-proline as a

chiral auxiliary(S)-dihydroisopforone as major product

2S,4S-oxazolidinone E= 19,762 kcal/mol, proS side towards the catalyst

2S,4R-oxazolidinone E= 20,098 kcal/mol, proR side towards the

catalyst

2

O+H2

H2

H2

-H2O

oxazolidinones

carbinol amine

2R,4S és 2S,4S

N CO

CO

diastereoselective

*

*

*N COOH

Pd/C catalyst

* +N COOH

chemo- and diastereoselective

*

O

O

+

N COOH

N COOH

CHO

*

*

A. Tungler, M. Kajtár, T. Máthé, G. Tóth, E. Fogassy, J. Petró: Catalysis Today, 5,159-171, (1989).A. Tungler, T. Máthé, J. Petró, T. Tarnai: J. of Molecular Catal. 61, 259-267, (1990).

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Search for new catalysts, modifiers and substrates

Catalyst: Pd Modifier: cinchonidine

COOH

R

COOH

R=Me, EtO

OH

O

Ee % 72 52 82

Catalyst: Pd Modifier: dihydroapovincaminic

acid ethyl ester

O

( )n

n = 1, 2, 3O

55

54

H OH

N

HN

OH

Pd black catalyst Ee % 40/21

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Diastereoselective hydrogenations

N

O

O

C

C

NH

CCH

CH3

CONH

CH2 CHCONH

CO

N

CH3

NH

C O

H2/Pd

*

N C

O

N

COOMe

H2/katalizátoroldószer N C

OH

N

COOMe

* - MeOHN

CN

C

O

O

*

N

CH3

C

O

CH3OSO3

N

COOMe

H2/katalizátor

oldószer N

CH3

C

O

H N

COOMe

*

CH3OSO3

NaOH

N

CH3

C

O

* N

COOMe

de 68%

de 79%

de 98%

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Perspectives of different hydrogenation methods for the preparation of optically active

compoundsMethods 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 acidDIPAMP/PTAAl2O3

Ethyl pyruvatePt/cinchonidine

Isophorone Pd-(S)-proline

Schiff’s basesPicolinic acid amidePd/C

Optical purity

goodexcellent

goodexcellent

goodexcellent

good poor excellent

Chemical yield

excellent good good poor acceptable

Scope broad increasing increasing narrow broad

Industrial application

good promising limited no hopeful

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Acknowledgement• The author gratefully acknowledge the financial support of the

Commission of European Communities, COST PECO 12382 and the support of the Hungarian OTKA Foundation, I am grateful to Gedeon Richter Co. for supplying vinpocetin.

• Prof. Roger Sheldon, Dir. Pierre Gallezot, Michel Besson Dr. for co-operation

– Farkas Gabriella -Kajtár Márton– Fodor Karina -Tóth Gábor– Fogassy Gabriella -Szepesy László– Fürcht Ákos -Tarnai Tibor– Háda Viktor– Hegedűs László– Máthé Tibor– Sípos Éva