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8/10/2019 Art He t Erogenous Catalytic Hydrogen at i on 2
http://slidepdf.com/reader/full/art-he-t-erogenous-catalytic-hydrogen-at-i-on-2 1/48
The Art of HeterogenousCatalytic Hydrogenation
Part 2 Applications
8/10/2019 Art He t Erogenous Catalytic Hydrogen at i on 2
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Topics to be covered
Applications of Heterogenous Catalytic
Reductions
Simple Reductions
Differential reductions
hydrogenolysis
Equipment
Tour of the High Pressure Lab
8/10/2019 Art He t Erogenous Catalytic Hydrogen at i on 2
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Recommended Books:
Heterogenous Catalysis for the Synthetic
Chemist
Robert L Augustine (1996)
Good for theory, kinetics, applications &
Equipment
Practical Catalytic Hydrogenation,
Techniques and ApplicationsMorris Freifelder 1971
Alchemic secrets of success
8/10/2019 Art He t Erogenous Catalytic Hydrogen at i on 2
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Recommended References
Catalytic Hydrogenation over Platinum
Metals
P. N. Rylander 1967
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Factors That Impact Reduction
Choices
Functional group reduced
Local structure
Presence of other reducible groupsProducts that act as inhibitors/poisons
Desirability of hydrogenolysis as one of the
actionsEquipment limitations
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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.
8/10/2019 Art He t Erogenous Catalytic Hydrogen at i on 2
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Olefins continued
Bond migrations prior to reduction are
common and may result in scrambling of
nearby stereochemistry (Requires H2!)
Certain groups act as directors
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Bond Migration: More with Ni, Pd,
less with Pt
AcOH
C8H17
Pd black/H2
AcOH
C8H17
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HHO
Raney Ni/H2
Neutral solventH
HO
O
Pd/SrCO3/H2
RT 3 Atm. EtOH O
OH
HH
O
OH
HH
15%
45%
OH
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Access to catalyst surface
influences stereochemistry
OH
OH
H
OHH
CH3
H
OH
CH3
H
Ni/H2
Ni/H2
87%
75%
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Catalyst approach: OH blocks Pd
but favors Ni
H3C
Pd
Ni
HO H
Pd/H2
Ni/H2
H
H3C
CH3
H
H
OH
H
OH
76%
87%
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Hydrogen Addition is from the
Least Hindered Side
OO
OO
H3C
H
CH3 CH3
HH
CH3 CH3
Pd/C EtOHRT 4 H
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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/H
2
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HOH
H
OH
HOH
H
OH
PtO2/EtOH
N N
PtO2/H2
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H
H
H
H51% 49%
+PtO2/HOAc
R.T., 1 Atm
Catalyst Addition is in Equilibrium
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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
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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.
8/10/2019 Art He t Erogenous Catalytic Hydrogen at i on 2
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Reduction of Alkynes: a Game of
Relative Rate
Pd-Pb/CaCO3
Hexane
26 C, 1 Atm
95%
Slow
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Alkyne Reduction
OTBSTBSO
H
OH
Lindlar's Catalyst/ Quinoline
Hexane RT 1 Atm
OH
HO
H
HO
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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
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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%
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Ring Differentiation in Aromatic
Reduction
OH
OH
OH
Raney Nickel, EtOH150 C, 200 Atm
Raney Nickel, EtOH/ NaOH150 C, 200 Atm
60%
65%
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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 , EtOH
150 C 100-200 Atm
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Ring Differentiation in Aromatic
Reduction
OH
OH
OH
Pd/C H2O/HOAc125 C 65 atm
Pd/C Cyclohexane113 C 65 atm
> 90%
53%
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Other Aromatic Reductions
NH2 NH22H2
NH
NH2NH2
NHNH
H2
-NH3
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Other Aromatic Reductions
HN H
N
Dicyclohexylamine
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Heterocyclic Reductions
N NH
N
H
HN
O
N
N
O O O
PtO2, H2, HOAc3 Atm RT
PtO2, H2, HOAc3 Atm RT
8/10/2019 Art He t Erogenous Catalytic Hydrogen at i on 2
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Some Functional Group
Reductions: faster than AromaticR-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
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Reductive Amination
R R'
O+ NH3
R R'
OHNH2
R R'
NH
R R'
NH2
H
R' = H or R
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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
8/10/2019 Art He t Erogenous Catalytic Hydrogen at i on 2
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Reductive Amination
Raney Nickel is the catalyst of choice
Palladium, Rhodium and Platinum do notperform as well as RaNi
Ruthenium on carbon has been usedsuccessfully
Use of 1 eq. ammonium acetate or HOAcsignificantly improves results
Aromatic Halides have been reported to surviveconditions (using Rhodium)
Can be done on sensitive aromatics, like furan.
8/10/2019 Art He t Erogenous Catalytic Hydrogen at i on 2
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Reductive Amination
CO2H
O+
H NH2
CH3H
N
CH3
CO2H
Pd/ H2
CO2H
H NH2+70%ee
8/10/2019 Art He t Erogenous Catalytic Hydrogen at i on 2
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Reductive Amination
OH O
Rh/Al2O3
H2/2-4 Atm
NH2
Aq. NH4OH
O
Nickel, H2, NH3
Atm Press NH2
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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.
8/10/2019 Art He t Erogenous Catalytic Hydrogen at i on 2
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Carbon-Carbon Hydrogenolysis
PtO2, HOAcR.T. 3 Atm
CH3 CH3
H H
48% 52%
PtO2 HOAcR. T. 3 Atm
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Carbon-Carbon Hydrogenolysis
RR
ROC
R
Ph
Ph COR
Ph
R
CORPh
Ph
COR
R
Ph
CH2OH
R
Ph
Ph
CH2OH
R
Ph Ph
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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
8/10/2019 Art He t Erogenous Catalytic Hydrogen at i on 2
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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.
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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
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Contrasting Pt with Pd
OH
OH
OH
OH
PtO2 tBuOH/HOAc
RT 20 Atm
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C-O Hydrogenolysis
O
CO2Et
HO
CO2Et
Pd/C EtOH
RT 1 Atm
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C-O Hydrogenolysis
O
PtO2 EtOHRT 1 Atm, 94%
OH
O NH
R
O
CO2 + H
2N R
Pd/C EtOH
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Carbonyl Hydrogenolysis
O
Pd/C HOAc
O
O
Pd/C HOAc/H2SO4
80C 4 Atm
O
70%
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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%
8/10/2019 Art He t Erogenous Catalytic Hydrogen at i on 2
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C-N Hydrogenolysis
NO2
H3CO
OH
N
NO2
H3CO
OH
Pd/BaSO4 EtOHRT 2 Atm
69%
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Parr Shaker Demo and
HP Lab Tour