Selective heterogeneous catalytic Selective heterogeneous catalytic hydrogenations for the fine hydrogenations for the fine

chemical industrychemical industryTechnical University of BudapestTechnical University of Budapest

Department of Organic Chemical TechnologyDepartment of Organic Chemical Technology

Antal TunglerAntal Tungler

Most important properties of Most important properties of catalysts:catalysts:

activityactivity

stabilitystability

selectivityselectivity

Types of selectivity:Types of selectivity:

RegioselectivityRegioselectivity ChemoselectivityChemoselectivity

NO2

Cl

NH2

ClNH

2

3H2Ni

Pd4H2

OH

OH

OH2H2

Pd, OH-

Pd, H+

Regioselectivity in the hydrogenation of Regioselectivity in the hydrogenation of polychlorinated benzenespolychlorinated benzenes

180oCCatalyst Pd/C Temp.

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl Cl

ClCl

Cl

ClCl

Cl

Cl

Cl

Cl

StereoselectivityStereoselectivity

H2

menthol

neomenthol

isomenthone

menthoneOH-

Pd

+HPd

2H2

Pd

OH

OH

O

O

OH

EnantioselectivityEnantioselectivity

In the presence of chiral auxiliaries or modifiers

O

O OCH3

O

OHO

CH3*

H2/Ni

NaBr+tartaric acid

methanol

/ PdH2

*

OO

* OEt

H

O

HOO

Et

O

OPt catalysts H2

solventcinchona alkaloids

How can be influenced How can be influenced chemoselectivity?chemoselectivity?

–Changing the solventChanging the solvent

methanol

selectivity >90%ethyl acetate

+ HCl

4H2

Pd

3H2 NH2

NH2

Cl

NO2

Cl

How can be influenced How can be influenced chemoselectivity?chemoselectivity?

Changing the catalystChanging the catalyst

COOH

NO2

Cl

COOH

NH2

Cl

COOH

NH2

Ni v. Pt3H2

Pd 4H2

+ HCl

Modifying of the catalystModifying of the catalyst

Alloying of the active metalAlloying of the active metal

Ar CO

Cl

Pd

H2

Pd-Cu

Ar CH3

Ar CO

H

The alloying can be carried out together withthe preparation of the palladium catalyst onactive carbon or with controlled metaladsorption on the Pd catalyst.

Poisoning of the catalysts with strong Poisoning of the catalysts with strong basesbases

CH CH CHO Pd/C, H2

EtOAc, pyridineCH2 CH2 CHO

selectivity ~ 65%

CH3

O2N NH2

strong base

Pd/C, H2

CH3

NO2O2N

Poisoning of the catalystPoisoning of the catalyst

NH3C CH

3

NO

NH3C CH

3

NH2

2 H2

Pd-Fe2+

water /NH3

N CH3

N CH3

H H

H2

Pd/C Cl-

water / H2SO4

Pd/C methanol

N CH3

H

Anions and cations both can increaseselectivity (and deteriorate activity).

Hydrogenation of heteroaromatic compoundsHydrogenation of heteroaromatic compounds(potencial catalyst poisons)(potencial catalyst poisons)

N OH

CH3

N OH

CH3

H2 Pd/C

HN

O

NH

Pd/C H2H

N

O

N

X-N OH

CH3

Pd/C H2+N OH

CH3

non miscible solvents

water

water and methanol

Optimizing reaction conditionsOptimizing reaction conditions

hydrogenolysis

water

Pd / C

6 H2

O

OO

O

O

OO

O

O

OO

O

Determining the optimal temperature, pressure,catalyst and substrate concentration selectivitycould be improved from 40 to 65%.

How can be influenced regioselectivity?How can be influenced regioselectivity?

Optimization of catalyst preparationOptimization of catalyst preparation

(PdCl4)

2

+CH2

CH3

CH3

CH3

NH2(PdCl4)

With tetraalkyl ammonium palladate precursorthe dispersion of the reduced metal is above 0.5

and the catalyst contains tertiary amine.The high dispersion and amine containing Pd/C

SELCAT Q-type catalyst has both higherselectivity and activity in the hydrogenation of

naphtol to aromatic tetralol.

Improvement of regioselectivity with the Improvement of regioselectivity with the use of the proper catalystuse of the proper catalyst

Pd/C, H+

Pd, OH-

2H2

OH

OH

OH Ni,

aromatic tetralol

with SELCAT Q selectivity is above 80% with respect

aliphatic tetralol

SQ

to the aromatic tetralol

The role of pH in the stereochemistry of The role of pH in the stereochemistry of hydrogenationshydrogenations

(known examples in the reduction of ketones)(known examples in the reduction of ketones)

OH

NHCOCH3

NHCOCH3

HO3 H2

SELCAT Pd

OH- water

trans-acetamino cyclohexanol

80 % stereoselectivity

The intermediate of the hydrogenation is thecyclohexanone derivative: among basicconditions equatorial alcohol is formed in

excess.

How can be influenced How can be influenced diastereoselectivity?diastereoselectivity?

Most important factors:Most important factors: -the properties of the molecule to be -the properties of the molecule to be

hydrogenated-the substituents of the hydrogenated-the substituents of the unsaturated atomsunsaturated atoms

-catalitically active metal, support, dispersion -catalitically active metal, support, dispersion of the metalof the metal

-solvent (protic-aprotic, polar-apolar)-solvent (protic-aprotic, polar-apolar) -preliminary reduction of the catalyst surface -preliminary reduction of the catalyst surface

and its saturation with hydrogenand its saturation with hydrogen pH of the reaction mixturepH of the reaction mixture

(S)-proline as chiral auxiliary(S)-proline as chiral auxiliary

H2

*

OO

enantiomeric excess 80%

CH3

O

CH

OH

CH3*

H2

enantiomeric excess 25%

Pd, stoichiometric (S)-proline, methanol assolvent

Pd, stoichiometric (S)-proline, methanol assolvent

(S)-proline is a chiral auxiliary which reacts withthe substrate giving an adduct and this adduct

is hydrogenated diastereoselectively.

Pd/C catalyst

2

*O+H2

*

+O

N COOH

*

*

*N COOH

H2

H2

chemo- and diastereoselective

diastereoselective

-H2O

oxazolidinones

2R,4S és 2S,4S

iminium salts

EZenamine

++N C

O

CO

NCOO

-

NCOO

-

N COOH

C

carbinol amine

N COOH

CHO

O

+N COOH

Enantioselective hydrogenationsEnantioselective hydrogenations

Pd black catalystmethanol as solvent

O O

*

H2

NN

H

EtOOC

(-)-dihydro vinpocetine as chiral modifier

methanol as solvent

H2Pt catalystsO

Et

O

O

OEt

H

O

HO*

ee 45%

ee 30%

Scheme of processes ofenantiodifferentiation

Similar processes can take place in Pt-cinchonaand Ni-tartaric acid mediated reactions.

Enantiomeric excess depends on equilibriumconstants and rates.

The formation of modifier-substrate adduct was verifiedby circular-dichroism spect-roscopy

*optically active

racemicO

H2/Pd

H2/Pd

+

In adsorbed state

In solution

catalyst surface

O

O

O

O

catalyst surfacecatalyst surface

NN

H

EtOOC

NN

H

EtOOC

NN

H

EtOOC

NN

H

EtOOC

Possibilities of producing enantiomerically pure Possibilities of producing enantiomerically pure products with heterogeneous catalytic products with heterogeneous catalytic

hydrogenations:hydrogenations:

Methods Chiralmodification of the

catalysts

Use of chiralauxiliaries in thereaction mixture

Forming newchiral compound

with a chiralreactant and carry

outdiastereoselective

hydrogenationExamples Pt/Al2O3

cinchonidineethyl

pyruvate

Pd/C(S)-prolineisophorone

Schiff-basesfrom a chiralamine and aprochiralketone

Optical purity good-excellent

good poor-excellent

Scope narrow narrow broad

Industrialapplicationpossibility

limited no hopeful

AcknowledgementAcknowledgement T. Máthé, K. Fodor, G. Farkas, L. Hegedüs, G. Tóth, J. Kajtár, T. Máthé, K. Fodor, G. Farkas, L. Hegedüs, G. Tóth, J. Kajtár, I. Kolossváry, I. Kolossváry, B. Herényi, R. A. Sheldon, P. Gallezot B. Herényi, R. A. Sheldon, P. Gallezot

Department of Chemical Technology, Technical University of Budapest, H-1521. b Department of Chemical Technology, Technical University of Budapest, H-1521. b Organic Chemical Technology Research Group of the Hungarian Academy of SciencesOrganic Chemical Technology Research Group of the Hungarian Academy of Sciences

Technical Analytical Research Group of HASTechnical Analytical Research Group of HAS Department of Organic Chemistry, Eötvös University, BudapestDepartment of Organic Chemistry, Eötvös University, Budapest Department of Chemical Information Technology, Technical University of Budapest Department of Chemical Information Technology, Technical University of Budapest Gedeon Richter Co., BudapestGedeon Richter Co., Budapest Laboratory of Organic Chemistry and Catalysis, Delft University of TechnologyLaboratory of Organic Chemistry and Catalysis, Delft University of Technology Institut de Recherces sur la Catalyse-CNRS, 2, Av. Albert Einstein, 69626 Institut de Recherces sur la Catalyse-CNRS, 2, Av. Albert Einstein, 69626

Villeurbanne, FranceVilleurbanne, France