MetalMetal Catalyzed Carbonylation: Catalyzed Carbonylation: MetalMetal--Catalyzed Carbonylation: Catalyzed Carbonylation: From the Industry to the Bench From the Industry to the Bench
Tom HsiehDong Research Group
Organic and Biological Seminar Series
1
Department of Chemistry, University of TorontoNovember 9, 2009
OutlineOutline
Introduction to carbon monoxide (CO)Introduction to carbon monoxide (CO)Preparation of COUses of CO in some industrial processesProperties of the CO moleculeProperties of the CO molecule
Reductive carbonylation of nitro compounds: use of CO as a stoichiometric redundant in the preparation of p pN-heterocycles
Carbonylative cross-coupling of organich lid f CO C1halides: use of CO as a C1 source in the preparation of carboxylicacid derivatives
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Preparation of Carbon MonoxidePreparation of Carbon Monoxide
Burning elemental carbon in restricted supply of oxygen gas
Reduction of carbon dioxide with coke
Dehydration of formic acid (small scale for laboratory)Dehydration of formic acid (small scale for laboratory)
Water-gas shift reaction (preparation of synthesis gas)
3Housecroft and Sharpe. Inorganic Chemisty. Prentice Hall: England 2001.
Industrial Process: FischerIndustrial Process: Fischer--Tropsch SynthesisTropsch Synthesis
Discovered in 1922Discovered in 1922
Commercialized in 1928
Heterogeneous catalysisHeterogeneous catalysisFe and Co catalysts200-300 oC and 10-60 barHi hl th iHighly exothermic
6.5 Mt / yr by 1944
Used as synthetic lubricants and
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Used as synthetic lubricants and synthetic diesel/jet fuels
Prof. Franz Fischer Dr. Hans Tropsch
Housecroft and Sharpe. Inorganic Chemisty. Prentice Hall: England 2001.
Proposed FischerProposed Fischer--Tropsch MechanismTropsch Mechanism
5Housecroft and Sharpe. Inorganic Chemisty. Prentice Hall: England 2001.
Industrial Process: HydroformylationIndustrial Process: Hydroformylation
Discovered and commercialized in 1938 by Otto Roelen at Ruhrchemie (Germany)
Important industrial homogeneous catalysisImportant industrial homogeneous catalysisCombined 7.2 Mt / yr
50% of world capacity located in Europe and 30% in USA
Propene important olefin starting material
Fi t ti t l t [HC (CO) ]
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First active catalyst: [HCo(CO)3]
Hagen. Industrial Catalysis. Wiley-VCH: Weinheim 2006.
Industrial Process: HydroformylationIndustrial Process: Hydroformylation
CatalystsCa a ys s
Co Co/phosphine Rh/phosphine
Reaction Pressure (bar) 200-300 50-100 7-25( )Reaction Temperature (°C) 140-180 180-200 90-125
L:B of aldehyde 4:1 9:1 19:1
Catalyst [HCo(CO)4] [HCo(CO)3(PBu3)][HRh(CO)(PPh3)3] / PPh3 up to 1:500
Main Products aldehydes alcohols aldehydes
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Hydrogenation to alkanes (%) 1 15 0.9
Hagen. Industrial Catalysis. Wiley-VCH: Weinheim 2006.
Hydroformylation: Catalytic CycleHydroformylation: Catalytic Cycle
β-H eliminationβ-H elimination
Migratory InsertionCoordination
Migratory Insertion
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HydrorhodationHydrorhodation
Hagen. Industrial Catalysis. Wiley-VCH: Weinheim 2006.
Use of [Rh] in HydroformylationUse of [Rh] in Hydroformylation
Advantages of using [Rh] over [Co][Rh] is 1000x more active[Rh] is 1000x more active
Excess of PPh3 allows high linear aldehyde selectivity
Use of PPh3 increases catalyst stability and prolongs its life
[Rh] has low volatility so purification of product is simpler
[Rh] process is high cost: work up, catalyst recycling and corrosiong y y g
Intensive research in developing heterogeneous [Rh] catalyst
Two-phase technology: uses water-soluble [Rh] with TPPTS
Improved L:B selectivity (> 19:1)
Ease of [Rh] catalyst separation and recycling
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Ease of [Rh] catalyst separation and recycling
Hagen. Industrial Catalysis. Wiley-VCH: Weinheim 2006.
Industrial Processes: Production of Acetic AcidIndustrial Processes: Production of Acetic Acid
Commercialized in 1970 by Monsanto
Important industrial catalytic processCombined 3.5 Mt / yr60% of world’s acetyls
One of few industrial catalytic processesOne of few industrial catalytic processes whose kinetics are fully known
Active catalyst: [RhI2(CO)2]¯
10Hagen. Industrial Catalysis. Wiley-VCH: Weinheim 2006.
The Monsanto Process: Catalytic CycleThe Monsanto Process: Catalytic Cycle
OxidativeAddition
Migratory Insertion
Ligand Exchange
Reductive Elimination
11Hagen. Industrial Catalysis. Wiley-VCH: Weinheim 2006.
The Monsanto ProcessThe Monsanto Process
Process is licensed worldwide
Mild reaction conditions: 30-40 bar and 150-200 °C
Numerous columns needed for product isolation
Stainless steel needed for all plant components due to corrosiveness of iodide
In 1996 the Cativa Process introduced by BP ChemicalsIn 1996, the Cativa Process introduced by BP ChemicalsHigher reactivity about 3xUp to 0.5 Mt / yr via this modification
12Hagen. Industrial Catalysis. Wiley-VCH: Weinheim 2006.
Carbon MonoxideCarbon Monoxide
“carbene-like” “dinitrogen-like”
Colorless and odorless gas
Highly flammable and toxic
Bond length: 112.8 pm
Bond energy: 257 kcal/mol
Di l 0 112 DDipole moment: 0.112 D
Insoluble in water (26 mg/L)
HOMO is lone pair on C ( )HOMO is lone pair on C (σ3)
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Carbon MonoxideCarbon Monoxide
C≡O N≡N HC≡CH O=O O=C=O Me2C=O2
Bond Energy (kcal/mol) 257 226 200 119 193 193
Bond LengthBond Length (pm) 112.8 109.7 120.3 121.0 116.0 121.3
Dipole Moment (D) 0.112 0 0 0 0 2.91Moment (D)
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Use of Carbon Monoxide in SynthesisUse of Carbon Monoxide in Synthesis
Aldehydes Acyl halides
Aldoximes
Ketones
Ketenes
Nitriles
Anhydrides
CarbonatesKetenes
Ketoximes
Esters
Carbonates
Carbamates
IsocyanatesCO
+Metal-Catalyzed
Lactones
Carboxylic acids
A id
Ureas
Amines
A d
+
SubstrateCarbonylation
Amides
Lactams
1,2-Dicarbonyls
Azo compounds
Heterocycles
Carbocycles
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, ca bo y s
1,4-Dicarbonyls
Ca bocyc es
Metal complexes
ReductiveReductive CarbonylationCarbonylation ofofReductiveReductive Carbonylation Carbonylation of of NitroNitro CompoundsCompounds
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Reductive CarbonylationReductive Carbonylation
The use of CO for the reduction of chemical bonds while formingThe use of CO for the reduction of chemical bonds while forming CO2, for example:
NO2 reduced to nitroso and/or nitreneCO oxidized to CO2 – a stoichiometric reductant
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First Example of Reductive CarbonylationFirst Example of Reductive Carbonylation
In 1949, Buckley and Ray reported the first reductive carbonylation
Trace amounts of reduction occurred at 200 oC or < 2500 atmNickel and cobalt catalysts had no effectNickel and cobalt catalysts had no effect
18Buckley and Ray. J. Chem. Soc. 1949, 1154.
Towards CatalysisTowards Catalysis
In 1965, Kmiecik identified Fe(CO)5 as a efficient catalyst for the reductive carbonylation of nitrobenzenereductive carbonylation of nitrobenzene
K i ik i l t d bKmiecik isolated azoxybenzene as a possible intermediate
19Kmiecik. J. Org. Chem. 1965, 30, 2014.
Synthesis of IsocyanatesSynthesis of Isocyanates
In 1967, Hardy and Bennett reported the first reduction of nitro aromatics to generate isocyanates catalyticallyaromatics to generate isocyanates catalytically
R = EDG and EWG Solvents: nonpolar Catalysts: Pd, Rh/Al, Rh/CLewis acids: FeX3, AlX3, SnCl4, CuCl2
20Hardy and Bennett. Tetrahedron Lett. 1967, 11, 961.
Advancements in Reductive CarbonylationAdvancements in Reductive Carbonylation
Since this discovery, research in this area of reductive carbonylation has greatly increasedhas greatly increased
Big push for the formation of other targets including isocyanates, b t d icarbamates, ureas, and amines
21Chem. Rev. 1996, 96, 2035. and Curr. Org. Chem. 2006, 10, 1479.
Isocyanates from PhosgenationIsocyanates from Phosgenation
> 2 Mt produced per yearTDI and MDI account for > 95% of the world’s diisocyanates madeTDI and MDI account for > 95% of the world’s diisocyanates madeImportant precursors to numerous polyurethanesPhosgene is highly toxicL t f i HCl d d
The Polyurethanes Book; Wiley: New York, NY, 2003. and Dalton Trans. 2009, 6251. 22
Large amounts of corrosive HCl produced
Reductive Carbonylation MechanismReductive Carbonylation Mechanism
23Chem. Rev. 1996, 96, 2035.
Diversity of Nitroarenes in Reductive CarbonylationDiversity of Nitroarenes in Reductive Carbonylation
Catalytic Reductive Carbonylation of Organic Nitro Compounds. Kluwer Academic Publishers: Netherlands, 1997.
Benzimidazoles via [Ru] CatalysisBenzimidazoles via [Ru] Catalysis
Entry Solvent T (oC) % A % B % C
1 Benzene 220 86 4 ---
2 Benzene 170 34 trace 47
3 (no [Ru]) Benzene 220 --- --- 85
4 CH CN 170 82 44 CH3CN 170 82 --- 4
Limited number of stable iminesC l b d ith th i i d i it
Cenini and coworkers. J. Mol. Catal. 1992, 72, 283.
Can also be done with the imine made in situ
Benzimidazoles via [Pd] CatalysisBenzimidazoles via [Pd] Catalysis
E t R Ti (h) T ( C) P ( t ) % A % BEntry R Time (h) T (oC) PCO (atm) % A % B
1 Ph 5 180 40 83 trace
2 Ph 5 180 20 81 ---2 Ph 5 180 20 81
3 Ph 5 160 40 78 11
4 Ph 5 140 40 55 10
5 p-ClC6H4 2 180 40 55 45
6 p-OMeC6H4 3 180 40 80 10
2,4,6-Trimethylbenzoic acid (TMBH) is required or else no reaction
Cenini and coworkers. J. Mol. Catal. 1994, 59, 3375.
Carbazoles via [Pd] CatalysisCarbazoles via [Pd] Catalysis
Previous forcing conditions: Ru (CO) 50 atm CO 220 oC
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Previous forcing conditions: Ru3(CO)12, 50 atm CO, 220 oCLow Catalyst loading: 0.5 mol % Pd, 3.5 mol % phen, 97% yield
Smitrovich and Davies. Org. Lett. 2004, 6, 533.
Merck’s Kinase InhibitorsMerck’s Kinase Inhibitors
Pd(TFA) (0 1 mol %)
quantitative yield
Pd(TFA)2 (0.1 mol %)TMphen (1.0 mol %)CO (1 atm)DMF, 70 oC
Conditions: Pd(OAc) (6 mol %) PPh (24 mol %) CO (4 atm)
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Conditions: Pd(OAc)2 (6 mol %), PPh3 (24 mol %), CO (4 atm)Difficult purification required development of new reaction conditions
Davies and coworkers. Tetrahedron. 2005, 61, 6425.
Substrate Scope of Merck’s ConditionsSubstrate Scope of Merck’s Conditions
Varying Conditions
Pd(OAc)2 or Pd(TFA)20.1 – 1.5 mol%
phen or TMphen0.7 – 3 mol %
CO (1 – 2 atm)
29Davies and coworkers. Tetrahedron. 2005, 61, 6425.
( )
70 – 80 oC
Proposed Mechanism for Indole FormationProposed Mechanism for Indole Formation
30Davies and coworkers. Tetrahedron. 2005, 61, 6425.
Nitroalkenes in Reductive CarbonylationNitroalkenes in Reductive Carbonylation
Proposal: extension to NitroalkenesI t t d i i i N h t lInterested in accessing various N-heterocycles
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Synthesis of NitroalkenesSynthesis of Nitroalkenes
Preparation of the model nitroalkene substrate
Preparation of symmetrical arylnitroalkenes
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Substrate ScopeSubstrate Scope
a Isolated yield. b Regioselectivity (based on 1H NMR integrations) is 47:53.
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Electron-rich substrates are tolerated
Substrate ScopeSubstrate Scope
a Isolated yield. c Regioselectivity is 42:58. d Regioselectivity is 51:49.
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Electron-poor substrates are tolerated
Regioselective CRegioselective C––H Bond AminationH Bond Amination
35Structure solved by Dr. Alan Lough
Indoles via Reduction of Nitroalkenes with COIndoles via Reduction of Nitroalkenes with CO
Tolerant of both electron-rich and electron-poor substrates – 10 examples, 58–98%
Versatile methodology for making indolesFe Rh Pt and Pd catalystsFe, Rh, Pt and Pd catalystsBidentate N- and P-based ligands
New strategy for the synthesis of nitroalkenesnitroalkenes
36Hsieh and Dong. Tetrahedron. 2009, 65, 3062 (Invited Article).
CarbonylativeCarbonylative crosscross--couplingcouplingCarbonylativeCarbonylative crosscross--coupling coupling of organic of organic halideshalides
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Biologically Active Compounds via CarbonylationBiologically Active Compounds via Carbonylation
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Biologically Active Compounds via CarbonylationBiologically Active Compounds via Carbonylation
Seeberger and coworkers. Org. Lett. 2002, 4, 2965.
39Kogen and coworkers. Tetrahedron. 2005, 61, 2075.
Biologically Active Compounds via CarbonylationBiologically Active Compounds via Carbonylation
Desmaele and coworkers. Tetrahedron Lett. 2005, 46, 2201.
40Song and coworkers. J. Org. Chem. 2001, 66, 605.
Carbonylation of Aryl HalidesCarbonylation of Aryl Halides
T i l C ditiTypical Conditions
X = Cl, Br, I, OTf, OMs and OTs
[Pd] = Pd(0) and Pd(II)[Pd] = Pd(0) and Pd(II)
L = mono- and bidentate phosphines
Base = organic and inorganic
T = 100 to 180 °C
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PCO = 1 to 40 bar
Organometallics. 2008, 27, 5402. and Angew. Chem. Int. Ed. 2009, 48, 4114.
Profen Drugs: Chiral Carboxylic AcidsProfen Drugs: Chiral Carboxylic Acids
Sub-class of the non-steroidal anti-inflammatory drugs (NSAIDs)
Compared to aryl-X, small amounts of research done with 2° alkyl-X.
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Lack of efficient methods of preparing profens enantioselectively
State of the Art: Asymmetric Profen PreparationState of the Art: Asymmetric Profen Preparation
Hydrocarboxylation and Hydroesterification
Primarily palladium catalysisPrimarily palladium catalysis
Typical enantioselectivities < 60% ee
Regioselectivity problem – linear and branched productsg y p p
Difficult to obtain high levels of both regio- and enantioselectivity
43Dalton Trans. 2008, 853. and Top Organomet. Chem. 2006, 18, 97.
Stoichiometric AlkoxycarbonylationStoichiometric Alkoxycarbonylation
90% inversion of stereochemistrystereochemistry
44Stille and coworkers. J. Am. Chem. Soc. 1974, 96, 4983.
Stereoconvergent Catalytic HydroxycarbonylationStereoconvergent Catalytic Hydroxycarbonylation
Mild conditions: rt, 4-12 h, CO (1 atm)
9 different ligands were testedL i dLow conversion and ee
No substrate scope
45Arzoumanian and coworkers. Organometallics 1988, 7, 59.
Stereospecific Catalytic HydroxycarbonylationStereospecific Catalytic Hydroxycarbonylation
Poor Regioselectivity
Significant amount of homobenzyl acid,vinylarene and alkylarene byproducts
High enantioselectivity at low conversionsHigh enantioselectivity at low conversionsBest result: 36% yield, 91% ee
High pressure of CO (43 atm)
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High pressure of CO (43 atm)
Sparacino and coworkers. J. Org. Chem. 1991, 56, 1928.
Alkoxycarbonylation of 2Alkoxycarbonylation of 2°° Alkyl HalidesAlkyl Halides
Proposal
Two possibilities for asymmetric inductionStereoconvergent: a chiral catalyst facilitates the transformation of racemic substrates to enantioenriched products
Stereospecific: an achiral catalyst facilitates the transformation of enantioenriched substrates to enantioenriched products with either retention or inversion of stereochemistry
47Charles Yeung
PdPd--Catalyzed Enantioselective AlkoxycarbonylationCatalyzed Enantioselective Alkoxycarbonylation
New catalytic transformation
Pd(0) and Pd(II) successfully catalyze this transformationNi, Rh, Ru, Pt and Fe are ineffective catalysts
Conventional bidentate ligands are ineffectivee.g. BINAP, BIPHEP, SEGPHOS and DUPHOS
Initial hit with Pd(OAc)2, Et3N, CH2Cl2, MeOHP(2 f r l) 46% GC ield
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P(2-furyl)3 – 46% GC yield
(R)-Monophos – 48% GC yield, 33% ee
Carbonylation of Benzylic BromidesCarbonylation of Benzylic Bromides
R = R' = Ph MeOH, 67%, 21% ee
R = Ar, R' = Ar' MeOH, 20%, 49% eei-PrOH, 12%, 72% ee
Ar' =Ar =
High yields with low ee and vice versa
Reactions with i-PrOH generally give higher ee than with MeOH
Product distribution differ between MeOH and i-PrOHSubstitution is the major competing pathway with MeOH
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β-H elimination is the major competing pathway with i-PrOH
Summary and ConclusionSummary and Conclusion
Carbon monoxide is used throughout synthetic chemistryIndustrial processes (Mt scale) and academic research (mg scale)p ( ) ( g )
Major advancements in reductive carbonylation1949 – no catalysis, 250 °C, and 3000 atm of COy , ,2009 – numerous catalysts (0.1 mol %), 70 °C and 1 atm of COSignificant improvements – possible industrial applications soonBeyond nitroarenes
Carbonylative cross-coupling of many R-X electrophilesAryl, vinyl, benzyl and alkylAryl, vinyl, benzyl and alkylHalides, sulfonates, acetates, carbonates, etc.Directed carbonylation of sp2 C–H is also knownEnantioselective variants are in development
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p
AcknowledgementsAcknowledgements
Prof. Vy M. Dong
Charles Yeung
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Charles Yeung
Dong Research Group