the art of heterogenous catalytic hydrogenation part 2 applications
TRANSCRIPT
The Art of Heterogenous The Art of Heterogenous Catalytic HydrogenationCatalytic Hydrogenation
Part 2Part 2
ApplicationsApplications
Topics to be coveredTopics to be covered
Applications of Heterogenous Catalytic Applications of Heterogenous Catalytic ReductionsReductionsSimple ReductionsSimple Reductions
Differential reductionsDifferential reductions
hydrogenolysishydrogenolysis
EquipmentEquipment
Tour of the High Pressure LabTour of the High Pressure Lab
Recommended Books:Recommended Books:
Heterogenous Catalysis for the Synthetic Heterogenous Catalysis for the Synthetic Chemist Chemist Robert L Augustine (1996)Robert L Augustine (1996)
Good for theory, kinetics, applications & Good for theory, kinetics, applications & EquipmentEquipment
Practical Catalytic Hydrogenation, Practical Catalytic Hydrogenation, Techniques and ApplicationsTechniques and ApplicationsMorris Freifelder 1971Morris Freifelder 1971
Alchemic secrets of successAlchemic secrets of success
Recommended ReferencesRecommended References
Catalytic Hydrogenation over Platinum Catalytic Hydrogenation over Platinum Metals Metals P. N. Rylander 1967P. N. Rylander 1967
Factors That Impact Reduction Factors That Impact Reduction ChoicesChoices
Functional group reducedFunctional group reduced
Local structureLocal structure
Presence of other reducible groupsPresence of other reducible groups
Products that act as inhibitors/poisonsProducts that act as inhibitors/poisons
Desirability of hydrogenolysis as one of the Desirability of hydrogenolysis as one of the actionsactions
Equipment limitationsEquipment limitations
OlefinsOlefins
Under mild conditions, ease of reduction Under mild conditions, ease of reduction can becan be correlated inversely with degree of substitution correlated inversely with degree of substitution (except when conjugated)(except when conjugated)
RHC=CH2 , RHC=CHR > RRHC=CH2 , RHC=CHR > R22C=CHR > RC=CHR > R22C=CRC=CR22
Many different catalysts reduce double bonds.Many different catalysts reduce double bonds.
The key to differentiating reduction of double The key to differentiating reduction of double bonds is monitoring equivalents hydrogen bonds is monitoring equivalents hydrogen consumed.consumed.
Olefins continuedOlefins continued
Bond migrations prior to reduction are Bond migrations prior to reduction are common and may result in scrambling of common and may result in scrambling of nearby stereochemistry (Requires Hnearby stereochemistry (Requires H22!)!)
Certain groups act as directorsCertain groups act as directors
Bond Migration: More with Ni, Pd, Bond Migration: More with Ni, Pd, less with Ptless 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 Access to catalyst surface influences stereochemistryinfluences stereochemistry
OH
OH
H
OHH
CH3
H
OH
CH3
H
Ni/H2
Ni/H2
87%
75%
Catalyst approach: OH blocks Pd Catalyst approach: OH blocks Pd but favors Nibut 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 Hydrogen Addition is from the Least Hindered SideLeast Hindered Side
O O
OO
H3C
H
CH3 CH3
HH
CH3 CH3
Pd/C EtOHRT 4 H
Selective Reduction of PolyenesSelective Reduction of Polyenes
Pd and Ni often cause bond migrationPd and Ni often cause bond migration Greatly influenced by local structureGreatly influenced by local structure Conjugated di- and polyenes give mixtures Conjugated di- and polyenes give mixtures
except in special casesexcept in special cases
CO2H CO2H
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 EquilibriumCatalyst Addition is in Equilibrium
Effect of Solvent and Pressure on Effect of Solvent and Pressure on StereochemistryStereochemistry
OO O
H
H
H
H
+
SolventSolvent Percent Percent cis cis ProductProduct Low H2 PressLow H2 Press High H2 High H2
PressPress n-Hexanen-Hexane 7777 4848 DMFDMF 8686 7575 terttert-Butyl Alcohol-Butyl Alcohol 9191 4848 EthanolEthanol 7878 4848 0.3 N HCl/Ethanol0.3 N HCl/Ethanol 9191 8080 0.3 N NaOH0.3 N NaOH 5050 5050
Alkyne ReductionAlkyne Reduction
Usual catalysts: Lindlar’s (Pd/CaCOUsual catalysts: Lindlar’s (Pd/CaCO33) )
Pd/BaSO4, Nickel boride, Cu and Co. Pd/BaSO4, Nickel boride, Cu and Co. Selectivity for cis reduction: Pd >Rh >Pt > Selectivity for cis reduction: Pd >Rh >Pt >
Ru> IrRu> Ir Quinoline commonly used as a modifier.Quinoline commonly used as a modifier.
Reduction of Alkynes: a Game of Reduction of Alkynes: a Game of Relative RateRelative Rate
Pd-Pb/CaCO3
Hexane26 C, 1 Atm
95%
Slow
Alkyne ReductionAlkyne Reduction
OTBSTBSO
H
OH
Lindlar's Catalyst/ Quinoline
Hexane RT 1 Atm
OH
HO
H
HO
Aromatic ReductionAromatic Reduction
Catalyst Activity: Rh > Ru > Pt > Ni > Pd Catalyst Activity: Rh > Ru > Pt > Ni > Pd > Co> Co
Ru minimizes C-O and C-N Ru minimizes C-O and C-N hydrogenolysis.hydrogenolysis.
C-Halide bonds do not survive aromatic C-Halide bonds do not survive aromatic reductionsreductions
Correct choice of conditions allows other Correct choice of conditions allows other functionalities to survivefunctionalities to survive
Aromatic ReductionAromatic Reduction
O
O
Rh/Al2O3 HOAcRT 3 Atm
78%
O
H
HO
H
OH
H
OHH
H50 C 100 Atm
RuO2 EtOH
90%
Phenols to Cyclohexanones: thin Phenols to Cyclohexanones: thin film on catalyst modifies productsfilm on catalyst modifies products
OHPd, NaOH
150-170 C5-15 atm
O
95%
OH OPd/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 Ring Differentiation in Aromatic ReductionReduction
OH
OH
OH
Raney Nickel, EtOH150 C, 200 Atm
Raney Nickel, EtOH/ NaOH150 C, 200 Atm
60%
65%
Ring Differentiation in Aromatic Ring Differentiation in Aromatic ReductionReduction
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 Ring Differentiation in Aromatic ReductionReduction
OH
OH
OH
Pd/C H2O/HOAc125 C 65 atm
Pd/C Cyclohexane113 C 65 atm
> 90%
53%
Other Aromatic ReductionsOther Aromatic ReductionsNH2 NH2
2H2NH
NH2NH2
NHNH
H2-NH3
Other Aromatic ReductionsOther Aromatic Reductions
HN H
N
Dicyclohexylamine
Heterocyclic ReductionsHeterocyclic Reductions
N NH
NH
HN
O
N
N
O O O
PtO2, H2, HOAc3 Atm RT
PtO2, H2, HOAc3 Atm RT
Some Functional Group Some Functional Group Reductions: faster than AromaticReductions: faster than Aromatic
R-NO2 R-NH2
R-CN R-CH2NH2
R H
O
R H
OHH
R R
O
R R
OHH
R R
NOH
R R
NHOHH
R R
NH2
HOR
Reductive AminationReductive Amination
R R'
O+ NH3
R R'
OHNH2
R R'
NH
R R'
NH2
H
R' = H or R
Reductive AminationReductive Amination
Takes advantage of relative ease of imine Takes advantage of relative ease of imine reduction.reduction.
Takes advantage of equilibrium between Takes advantage of equilibrium between imine and ketone in presence of an amine.imine and ketone in presence of an amine.
Some aldehydes produce significant Some aldehydes produce significant byproducts of diamine and polymers.byproducts of diamine and polymers.
Use of one eq. acid improves yield of Use of one eq. acid improves yield of primary amineprimary amine
Reductive AminationReductive Amination
Raney Nickel is the catalyst of choiceRaney Nickel is the catalyst of choice Palladium, Rhodium and Platinum do not Palladium, Rhodium and Platinum do not
perform as well as RaNiperform as well as RaNi Ruthenium on carbon has been used Ruthenium on carbon has been used
successfullysuccessfully Use of 1 eq. ammonium acetate or HOAc Use of 1 eq. ammonium acetate or HOAc
significantly improves resultssignificantly improves results Aromatic Halides have been reported to survive Aromatic Halides have been reported to survive
conditions (using Rhodium)conditions (using Rhodium) Can be done on sensitive aromatics, like furan.Can be done on sensitive aromatics, like furan.
Reductive AminationReductive Amination
CO2H
O+
H NH2
CH3 H
NCH3
CO2H
Pd/ H2
CO2H
H NH2+70%ee
Reductive AminationReductive Amination
OH O
Rh/Al2O3
H2/2-4 Atm
NH2
Aq. NH4OH
O
Nickel, H2, NH3Atm Press NH2
HydrogenolysisHydrogenolysis
Reductive cleavage of sigma bonds:Reductive cleavage of sigma bonds: C-C, C-N, C-O, C-S and othersC-C, C-N, C-O, C-S and others Choice of catalyst, structure of substrate, Choice of catalyst, structure of substrate,
and solvent greatly influence whether and solvent greatly influence whether double bond reduction continues on to double bond reduction continues on to hydrogenolysis.hydrogenolysis.
Carbon-Carbon HydrogenolysisCarbon-Carbon Hydrogenolysis
PtO2, HOAcR.T. 3 Atm
CH3 CH3
H H
48% 52%
PtO2 HOAcR. T. 3 Atm
Carbon-Carbon HydrogenolysisCarbon-Carbon Hydrogenolysis
RR
ROC
R
Ph
Ph CORPh
RCOR
Ph
Ph
COR
R
PhCH2OH
R
Ph
Ph
CH2OH
RPh Ph
Halogen Weakens Opposite bondHalogen Weakens Opposite bond
Ph
Ph
H
H
F
Pd EtOHRT 1 Atm
Ph
H
HCH3
Ph
90% 10%
Ph
97%
PdO EtOH
RT 1 Atm
C-O HydrogenolysisC-O Hydrogenolysis
Generally benzyl alcohols, ethers and Generally benzyl alcohols, ethers and estersesters
Often facilitated by acidOften facilitated by acid Frequently occurs in competition with Frequently occurs in competition with
aromatic ring reductionaromatic ring reduction Palladium favors hydrogenolysis while Palladium favors hydrogenolysis while
platinum favors ring reduction.platinum favors ring reduction.
C-O HydrogenolysisC-O Hydrogenolysis
CH3
NH CH3
OH
CH3
NH 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 PdContrasting Pt with Pd
OH
OH
OH
OH
PtO2 tBuOH/HOAc
RT 20 Atm
C-O HydrogenolysisC-O Hydrogenolysis
O
CO2Et
HO
CO2Et
Pd/C EtOHRT 1 Atm
C-O HydrogenolysisC-O Hydrogenolysis
OPtO2 EtOHRT 1 Atm, 94%
OH
O NH
R
O
CO2 + H2N RPd/C EtOH
Carbonyl HydrogenolysisCarbonyl HydrogenolysisO
Pd/C HOAc
O
O
Pd/C HOAc/H2SO4
80C 4 Atm
O
70%
C-N HydrogenolysisC-N HydrogenolysisCH3
NH
CH3
NH2RT 1 Atm
Pd(OH)2 EtOH
OH
OCH3
N NCuCrO Dioxane
235 C 275 Atm
OH
OCH3
90%
100%
C-N HydrogenolysisC-N Hydrogenolysis
NO2
H3CO
OH
N
NO2
H3CO
OHPd/BaSO4 EtOHRT 2 Atm
69%
Parr Shaker Demo and Parr Shaker Demo and HP Lab TourHP Lab Tour
Hydrogenolysis: Carbon-CarbonHydrogenolysis: Carbon-Carbon
PtO2 HOAcRT 3 Atm
PtO2 HOAcRT 3 Atm
CH3
H
CH3
H
+
48% 52%