The Art of Heterogenous Catalytic Hydrogenation Part 2 Applications.

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%


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


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


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


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.


CO2H

O+

H NH2

CH3 H

NCH3

CO2H

Pd/ H2

CO2H

H NH2+70%ee


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.


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


O

CO2Et

HO

CO2Et

Pd/C EtOHRT 1 Atm


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%

The Art of Heterogenous Catalytic Hydrogenation Part 2 Applications.

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Transcript of The Art of Heterogenous Catalytic Hydrogenation Part 2 Applications.