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The Art of Heterogenous

Catalytic Hydrogenation
Part 2
Applications

Topics to be covered
Applications of Heterogenous Catalytic
Reductions
Simple Reductions
Differential reductions
hydrogenolysis

Equipment
Tour of the High Pressure Lab

Recommended Books:
Heterogenous 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
C8H17
C8H17

Pd black/H2

AcO

AcO

Raney Ni/H2
HO

Neutral solvent

HO

OH

OH

Pd/SrCO3/H2
15%
O

RT 3 Atm. EtOH

O
OH
H

H
45%

Access to catalyst surface


influences stereochemistry
H

Ni/H2

CH3
87%

OH

OH
H
CH3

Ni/H2

75%
OH

OH

Catalyst approach: OH blocks Pd


but favors Ni
H

Pd/H2

Pd

H3C

H
76%

OH
H3C
HO

Ni

H
CH3
Ni/H2

H
H
OH

87%

Hydrogen Addition is from the


Least Hindered Side
O
O

CH3

Pd/C EtOH
RT 4 H
H

CH3

H
H3C

O
H
CH3

CH3

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
CO2H

CO2H
PtO2/H2

OH

OH

PtO2/EtOH
H

H
OH

H
OH

PtO2/H2
N

Catalyst Addition is in Equilibrium


H

H
PtO2/HOAc

R.T., 1 Atm
H

51%

49%

Effect of Solvent and Pressure on


Stereochemistry
H

H
+

Solvent

n-Hexane
DMF
tert-Butyl Alcohol
Ethanol
0.3 N HCl/Ethanol
0.3 N NaOH

Percent cis Product


Low H2 Press
High H2 Press
77
48
86
75
91
48
78
48
91
80
50
50

Alkyne Reduction
Usual

catalysts: Lindlars (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
95%

Hexane
26 C, 1 Atm

Slow

Alkyne Reduction
HO

OH
OH
H

Lindlar's Catalyst/ Quinoline


Hexane RT 1 Atm

TBSO

OTBS

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
O

Rh/Al2O3 HOAc
RT 3 Atm
78%

H
H
O

OH

RuO2 EtOH

50 C 100 Atm
H

OH
H
90%

Phenols to Cyclohexanones: thin


film on catalyst modifies products
O

OH
Pd, NaOH
150-170 C
5-15 atm

OH

95%

O
Pd/C, Cyclohexane NaOH
120 C 50 Atm
85%
O

OH
Raney Ni, H2O/NaOH
50 C , 100 Atm
OH

O
85-95%

Ring Differentiation in Aromatic


Reduction
OH

Raney Nickel, EtOH


150 C, 200 Atm

OH

60%

OH
Raney Nickel, EtOH/ NaOH
150 C, 200 Atm
65%

Ring Differentiation in Aromatic


Reduction
OCH3

Raney Nickel, EtOH


130 C, 200 Atm

OCH3

95%
Raney Nickel, EtOH/ NaOH
130 C, 200 Atm

Raney Nickel , EtOH


150 C 100-200 Atm
OCH3

70%

Ring Differentiation in Aromatic


Reduction
Pd/C H2O/HOAc
125 C 65 atm
OH
> 90%
OH

OH

Pd/C Cyclohexane
113 C 65 atm
53%

Other Aromatic Reductions


NH2

NH2

2H2

NH

H2
-NH3

NH

NH2
NH

NH2

Other Aromatic Reductions


H
N

H
N

Dicyclohexylamine

Heterocyclic Reductions
PtO2, H2, HOAc
3 Atm RT
N
H

N
PtO2, H2, HOAc
3 Atm RT

H
N

N
H

Some Functional Group


Reductions: faster than Aromatic
R-NO2

R-NH2

R-CN

R-CH2NH2

OH
H

O
R

OH
R

NOH
R

H
H

H
R

NHOH
H
R
R

OR

NH2
H
R
R

Reductive Amination
OH

O
R

NH3

R'

NH2
R'

R'

R' = H or R
NH2
H
R
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
CH3
H
NH2

CH3
N

CO2H

CO2H

Pd/ H2

NH2
70%ee
CO2H

Reductive Amination
OH

NH2

Rh/Al2O3
H2/2-4 Atm
Aq. NH4OH

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, HOAc
R.T. 3 Atm

PtO2 HOAc
R. T. 3 Atm

CH3

CH3

48%

52%

Carbon-Carbon Hydrogenolysis
Ph

ROC

Ph
Ph

COR

COR
R

CH2OH Ph
Ph

Ph

Ph
Ph

COR
R

CH2OH
Ph
R

Ph

Halogen Weakens Opposite bond


Ph

Ph

Pd EtOH
RT 1 Atm

10%

90%
Ph
F

Ph

H
CH3
H

PdO EtOH
Ph

RT 1 Atm
97%

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
OH
CH3
N
H

CH3

CH3

Pd H2O/H2SO4
N

60 C 3.5 Atm
H
O

OH

CH3

Ac
CO2Et

NH2
Difficult to reduce

NHAc

Pd/BaSO4 EtOH/ Et3N


70 C 3.5 Atm

CO2Et
NHAc

Contrasting Pt with Pd
PtO2 tBuOH/HOAc
OH

OH

OH

RT 20 Atm

OH

C-O Hydrogenolysis
CO2Et
O

Pd/C EtOH
RT 1 Atm

CO2Et
HO

C-O Hydrogenolysis
O

OH

PtO2 EtOH
RT 1 Atm, 94%

O
O

N
H

Pd/C EtOH
CO2

H2N R

Carbonyl Hydrogenolysis
O
Pd/C HOAc

O
Pd/C HOAc/H2SO4
O

80C 4 Atm
70%

C-N Hydrogenolysis
CH3

CH3
Pd(OH)2 EtOH

N
H

NH2

RT 1 Atm

100%
OH
OH
N

OCH3

CuCrO Dioxane
235 C 275 Atm
OCH3

90%

C-N Hydrogenolysis
OH
H3CO

OH
N

Pd/BaSO4 EtOH
RT 2 Atm

H3CO

69%
NO2

NO2

Parr Shaker Demo and


HP Lab Tour

Hydrogenolysis: Carbon-Carbon
PtO2 HOAc
RT 3 Atm

CH3

CH3
+

48%

52%

PtO2 HOAc
RT 3 Atm