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
H
AcO
H
Raney Ni/H2
HO
Neutral solvent
H
HO
H
OH
OH
H
H
Pd/SrCO3/H2
15%
O
RT 3 Atm. EtOH
O
OH
H
H
45%
O
Access to catalyst surface
influences stereochemistry
H
Ni/H2
CH3
87%
OH
H
OH
H
CH3
Ni/H2
75%
OH
H
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
O
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
H
OH
PtO2/H2
N
N
Catalyst Addition is in Equilibrium
H
H
PtO2/HOAc
+
R.T., 1 Atm
H
51%
H
49%
Effect of Solvent and Pressure on
Stereochemistry
H
H
+
O

Solvent







n-Hexane
DMF
tert-Butyl Alcohol
Ethanol
0.3 N HCl/Ethanol
0.3 N NaOH
H
O
H
O
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: 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
95%
Hexane
26 C, 1 Atm
Slow
Alkyne Reduction
HO
OH
OH
H
Lindlar's Catalyst/ Quinoline
Hexane RT 1 Atm
TBSO
OTBS
HO
H
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
H
50 C 100 Atm
H
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
N
N
O
H
N
N
H
O
O
O
Some Functional Group
Reductions: faster than Aromatic
R-NO2
R-NH2
R-CN
R-CH2NH2
O
OH
H
R
R
O
R
OH
R
NOH
R
H
H
R
R
H
R
NHOH
H
R
R
OR
NH2
H
R
R
Reductive Amination
OH
O
R
+
NH3
R'
R
N
NH2
R'
R
H
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
O
H
+
CH3
N
CO2H
CO2H
Pd/ H2
+
H
NH2
70%ee
CO2H
Reductive Amination
OH
O
NH2
Rh/Al2O3
H2/2-4 Atm
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, HOAc
R.T. 3 Atm
PtO2 HOAc
R. T. 3 Atm
CH3
CH3
H
H
48%
52%
Carbon-Carbon Hydrogenolysis
Ph
ROC
R
R
R
Ph
Ph
COR
COR
R
CH2OH Ph
Ph
R
Ph
Ph
Ph
COR
R
CH2OH
Ph
R
Ph
Halogen Weakens Opposite bond
Ph
Ph
Pd EtOH
RT 1 Atm
H
10%
90%
Ph
F
H
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
R
Pd/C EtOH
CO2
+
H2N
R
Carbonyl Hydrogenolysis
O
Pd/C HOAc
O
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
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
+
H
H
48%
52%
PtO2 HOAc
RT 3 Atm