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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

2

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

4

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) ]

6

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

7

Hydrogenation to alkanes (%) 1 15 0.9


Hydroformylation: Catalytic CycleHydroformylation: Catalytic Cycle

β-H eliminationβ-H elimination

Migratory InsertionCoordination

Migratory Insertion

8

HydrorhodationHydrorhodation


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

9

Ease of [Rh] catalyst separation and recycling


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


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


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)

13

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)

14

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

15

, ca bo y s

1,4-Dicarbonyls

Ca bocyc es

Metal complexes

ReductiveReductive CarbonylationCarbonylation ofofReductiveReductive Carbonylation Carbonylation of of NitroNitro CompoundsCompounds

16

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

17

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

27

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)

28

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

31

Synthesis of NitroalkenesSynthesis of Nitroalkenes

Preparation of the model nitroalkene substrate

Preparation of symmetrical arylnitroalkenes

32

Substrate ScopeSubstrate Scope

a Isolated yield. b Regioselectivity (based on 1H NMR integrations) is 47:53.

33

Electron-rich substrates are tolerated

Substrate ScopeSubstrate Scope

a Isolated yield. c Regioselectivity is 42:58. d Regioselectivity is 51:49.

34

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

37

Biologically Active Compounds via CarbonylationBiologically Active Compounds via Carbonylation

38


Seeberger and coworkers. Org. Lett. 2002, 4, 2965.

39Kogen and coworkers. Tetrahedron. 2005, 61, 2075.


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

41

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.

42

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)

46

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

48

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

49

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

50

p

AcknowledgementsAcknowledgements

Prof. Vy M. Dong

Charles Yeung

51

Charles Yeung

Dong Research Group

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