The Art of Heterogeneous

Catalytic Hydrogenation

Part 2

Applications

by Bill Boulanger

Adjunct Professor, Department of Chemistry

University of Illinois at Urbana-Champaign

wboulang@illinois.edu

Topics to be covered

Applications of Heterogeneous Catalytic

Reductions

Simple Reductions

Differential reductions

hydrogenolysis

Equipment

Tour of the High Pressure Lab

Recommended Books:

Heterogeneous Catalysis for the Synthetic

Chemist

Robert L Augustine (1996)

Good for theory, kinetics, applications &

Equipment

Practical Catalytic Hydrogenation,

Techniques and Applications

Morris Freifelder 1971

Alchemic secrets of success

Recommended References

Catalytic Hydrogenation over Platinum

Metals

P. N. Rylander 1967

Factors That Impact Reduction

Choices

Functional group reduced

Local structure

Presence of other reducible groups

Products that act as inhibitors/poisons

Desirability of hydrogenolysis as one of the

actions

Equipment limitations

Olefins

Under mild conditions, ease of reduction can be

correlated inversely with degree of substitution

(except when conjugated)

RHC=CH2 , RHC=CHR > R2C=CHR > R2C=CR2

Many different catalysts reduce double bonds.

The key to differentiating reduction of double

bonds is monitoring equivalents hydrogen

consumed.

Olefins continued

Bond migrations prior to reduction are

common and may result in scrambling of

nearby stereochemistry (Requires H2!)

Certain groups act as directors

Bond Migration: More with Ni, Pd,

less with Pt

AcOH

C8H17

Pd black/H2

AcOH

C8H17

HHO

Raney Ni/H2

Neutral solventH

HO

O

Pd/SrCO3/H2

RT 3 Atm. EtOH O

OH

HH

O

OH

HH

15%

45%

OH

Access to catalyst surface

influences stereochemistry

OH

OH

H

OHH

CH3

H

OH

CH3

H

Ni/H2

Ni/H2

87%

75%

Catalyst approach: OH blocks Pd

but favors Ni

H3C

Pd

Ni

HOH

Pd/H2

Ni/H2

H

H3C

CH3

H

H

OH

H

OH

76%

87%

Hydrogen Addition is from the

Least Hindered Side

O O

OO

H3C

H

CH3 CH3

HH

CH3 CH3

Pd/C EtOHRT 4 H

Selective Reduction of Polyenes

Pd and Ni often cause bond migration

Greatly influenced by local structure

Conjugated di- and polyenes give mixtures

except in special cases

CO2HCO2H

PtO2/H2

HOH

H

OH

HOH

H

OH

PtO2/EtOH

N N

PtO2/H2

H

H

H

H51% 49%

+PtO2/HOAc

R.T., 1 Atm

Catalyst Addition is in Equilibrium

Effect of Solvent and Pressure on

Stereochemistry

OO O

H

H

H

H

+

Solvent Percent cis Product

Low H2 Press High H2 Press

n-Hexane 77 48

DMF 86 75

tert-Butyl Alcohol 91 48

Ethanol 78 48

0.3 N HCl/Ethanol 91 80

0.3 N NaOH 50 50

Alkyne Reduction

Usual catalysts: Lindlar’s (Pd/CaCO3)

Pd/BaSO4, Nickel boride, Cu and Co.

Selectivity for cis reduction: Pd >Rh >Pt >

Ru> Ir

Quinoline commonly used as a modifier.

Reduction of Alkynes: a Game of

Relative Rate

Pd-Pb/CaCO3

Hexane26 C, 1 Atm

95%

Slow

Alkyne Reduction

OTBSTBSO

H

OH

Lindlar's Catalyst/ Quinoline

Hexane RT 1 Atm

OH

HO

H

HO

Aromatic Reduction

Catalyst Activity: Rh > Ru > Pt > Ni > Pd

> Co

Ru minimizes C-O and C-N

hydrogenolysis.

C-Halide bonds do not survive aromatic

reductions

Correct choice of conditions allows other

functionalities to survive

Aromatic Reduction

O

O

Rh/Al2O3 HOAcRT 3 Atm

78%

O

H

H

O

H

OH

H

OHH

H50 C 100 Atm

RuO2 EtOH

90%

Phenols to Cyclohexanones: thin

film on catalyst modifies products OH

Pd, NaOH

150-170 C5-15 atm

O

95%

OHO

Pd/C, Cyclohexane NaOH

120 C 50 Atm

OH

OH

O

O

Raney Ni, H2O/NaOH

50 C , 100 Atm

85%

85-95%

Ring Differentiation in Aromatic

Reduction

OH

OH

OH

Raney Nickel, EtOH150 C, 200 Atm

Raney Nickel, EtOH/ NaOH150 C, 200 Atm

60%

65%

Ring Differentiation in Aromatic

Reduction

OCH3

OCH3

OCH3

Raney Nickel, EtOH130 C, 200 Atm

Raney Nickel, EtOH/ NaOH130 C, 200 Atm

95%

70%

Raney Nickel , EtOH150 C 100-200 Atm

Ring Differentiation in Aromatic

Reduction

OH

OH

OH

Pd/C H2O/HOAc125 C 65 atm

Pd/C Cyclohexane113 C 65 atm

> 90%

53%

Other Aromatic Reductions

NH2 NH22H2

NH

NH2NH2

NHNH

H2

-NH3

Other Aromatic Reductions

HN H

N

Dicyclohexylamine

Heterocyclic Reductions

N NH

NH

HN

O

N

N

O O O

PtO2, H2, HOAc3 Atm RT

PtO2, H2, HOAc3 Atm RT

Some Functional Group

Reductions: faster than Aromatic R-NO2 R-NH2

R-CN R-CH2NH2

R H

O

R H

OH

H

R R

O

R R

OH

H

R R

NOH

R R

NHOH

H

R R

NH2

HOR

Reductive Amination

R R'

O+ NH3

R R'

OHNH2

R R'

NH

R R'

NH2

H

R' = H or R

Reductive Amination

Takes advantage of relative ease of imine

reduction.

Takes advantage of equilibrium between

imine and ketone in presence of an amine.

Some aldehydes produce significant

byproducts of diamine and polymers.

Use of one eq. acid improves yield of

primary amine

Reductive Amination

Raney Nickel is the catalyst of choice

Palladium, Rhodium and Platinum do not perform as well as RaNi

Ruthenium on carbon has been used successfully

Use of 1 eq. ammonium acetate or HOAc significantly improves results

Aromatic Halides have been reported to survive conditions (using Rhodium)

Can be done on sensitive aromatics, like furan.

Reductive Amination

CO2H

O+

H NH2

CH3 H

N

CH3

CO2H

Pd/ H2

CO2H

H NH2+70%ee

Reductive Amination

OH O

Rh/Al2O3

H2/2-4 Atm

NH2

Aq. NH4OH

O

Nickel, H2, NH3

Atm Press NH2

Hydrogenolysis

Reductive cleavage of sigma bonds:

C-C, C-N, C-O, C-S and others

Choice of catalyst, structure of substrate,

and solvent greatly influence whether

double bond reduction continues on to

hydrogenolysis.

Carbon-Carbon Hydrogenolysis

PtO2, HOAcR.T. 3 Atm

CH3 CH3

H H

48% 52%

PtO2 HOAcR. T. 3 Atm

Carbon-Carbon Hydrogenolysis

RR

ROC

R

Ph

Ph COR

Ph

R

CORPh

Ph

COR

R

Ph

CH2OH

R

Ph

Ph

CH2OH

R

Ph Ph

Halogen Weakens Opposite bond

Ph

Ph

H

H

F

Pd EtOHRT 1 Atm

Ph

H

H

CH3

Ph

90% 10%

Ph

97%

PdO EtOH

RT 1 Atm

C-O Hydrogenolysis

Generally benzyl alcohols, ethers and

esters

Often facilitated by acid

Frequently occurs in competition with

aromatic ring reduction

Palladium favors hydrogenolysis while

platinum favors ring reduction.

C-O Hydrogenolysis

CH3

N

H CH3

OH

CH3

N

H CH3

Pd H2O/H2SO4

60 C 3.5 Atm

NH2

OH

CO2Et

NHAc

Difficult to reduce

OAc

Pd/BaSO4 EtOH/ Et3N

70 C 3.5 Atm

CO2Et

NHAc

Contrasting Pt with Pd

OH

OH

OH

OH

PtO2 tBuOH/HOAc

RT 20 Atm

C-O Hydrogenolysis

O

CO2Et

HO

CO2Et

Pd/C EtOHRT 1 Atm

C-O Hydrogenolysis

O

PtO2 EtOHRT 1 Atm, 94%

OH

O NH

R

O

CO2 + H2N R

Pd/C EtOH

Carbonyl Hydrogenolysis

O

Pd/C HOAc

O

O

Pd/C HOAc/H2SO4

80C 4 Atm

O

70%

C-N Hydrogenolysis

CH3

NH

CH3

NH2RT 1 Atm

Pd(OH)2 EtOH

OH

OCH3

N NCuCrO Dioxane

235 C 275 Atm

OH

OCH3

90%

100%

C-N Hydrogenolysis

NO2

H3CO

OH

N

NO2

H3CO

OH

Pd/BaSO4 EtOHRT 2 Atm

69%

Parr Shaker Demo and

HP Lab Tour

Hydrogenolysis: Carbon-Carbon

PtO2 HOAcRT 3 Atm

PtO2 HOAcRT 3 Atm

CH3

H

CH3

H

+

48% 52%