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Olefin Metathesis Catalysts for the Synthesis of Molecules and

MaterialsDecember 8, 2005

Stockholm, Sweden

New Polyethylene

Ni

1950+

n CH2=CH2AlEt3

only !

CH3-CH2-CH=CH2

Ziegler --MPI in Mulheim

1940's- war years

n CH2=CH2AlEt3 H-(CH2-CH2)n-CH=CH2

n= 1-12

n CH2=CH2n

TiCl4/AlR3

room temperaturelow pressure

1953

Crystalline - Milk bottles

Called High density polyethylene -HDPEdensity=0.97

CH2 CH2

K. Ziegler and G. Natta, Nobel Prize 1963

Discovery of a New Reaction

Ziegler catalystTiCl4/AlR3

Polymer containing unsaturation- unexpected for an addition polymer

nTruett, et al,J. Am. Chem. Soc, 1960, 2337

Co/MoOn2 CH2=CHCH3

Three carbons

CH2=CH2 CH3CH=CHCH3+

Two carbons Four carbons

Heterogeneous Catalyst

R. L.. Banks and G. C. Bailey, I & EC Product Research and Development, 1964, 170

Metathesis DiscoveryMoCl5/Et3Al

WCl6/Et3Al

n

n

Natta, et. al. J. Polymer Sci., Polymer Lett. 1964, B2, 349

WCl6/EtOH/Et3Aln

WCl6/EtOH/Et3Al+ +

Calderon, Chen, Scott, Tetrahedron Letters, 1967, 3327

Proposed MechanismsCD3CD=CDCD3

CD3CD=CHCH3CH3CH=CHCH3

+metathesis

catalystCD3CH=CHCH3

CD3CD=CDCH3

CD3CH=CHCD3

CH3CD=CDCH3

Not Observed

N. Calderon, E. A. Olfsead, J. P. Ward, W. A. Judy, K. W. Scott, J. Am. Chem. Soc., 1968,,90, 4133

Proposed intermdiate

CDCD3D3CDC

CHCH3H3CHCM

CH3CH=CH2 M=CH2+ CH2=CH2 M=CHCH3+

M=CHCH3CH3CH=CH2 + CH3CH=CHCH3 M=CH2+

CH3CH=CH2 CH2=CH2 + CH3CH=CHCH3

J. L. Herisson, Y. Chauvin Makromol. Chemie, 1971, 141, 162 Based on cross metathesisT. J. Katz, J. McGinnis, J. Am. Chem. Soc.,1975, 97,1592

M--CH2

CH3CH--CH2

Proposed Intermediate

Mechanistic Study

metathesis

catalyst+

metathesisinactive

OBSERVED

CD2

CD2+ metathesis

catalyst H2C CH2

H2C CD2

D2C CD2+

+

predicted Ratio

pairwiseChauvin1 1

2 0 (1.6)

1 1CH2

CH2

R. H. Grubbs, P. L. Burk and D. D. Carr, J. Am. Chem. Soc. 1975, 97, 3265.T. J. Katz and R. Rothchild, J. Am. Chem. Soc. 1976, 98, 2519.

Olefin Metathesis Mechanism

RHC=CHR RHC=CHR RHC CHR+ 2[M] CHR

[M] CHRRHC=CHR

[M] CHR

[M]

RHC CHR

CHR

RHC CHR

[M]

RHC CHR

CHR

RHC=CHR

RHC=CHR

RHC=CHR

[M] CHR

LnM=CHR

Carbene Catalysts

CD2 + Cp2TiCH2-AlCl(CH3)2 CH2 + Cp2TiCD2-AlCl(CH3)2

F.N. Tebbe, G. W. Parshall, G. S. Reddy, J. Am. Chem. Soc. 1978, 100, 3611

Demonstration of Exchange between Metal Methylene and an Olefin

TiCH2

AlMe2Cl

CH2=C(CH3)2+DMAP

TiCH2

CMe2CH2 + DMAP-AlMe2Cl

T. R. Howard, J. B. Lee and R. H. Grubbs, J. Am. Chem. Soc., 1980,102, 6876.

Isolation of Metallacycle in Active Metathesis System

Tebbe Reagent

Metal Alkylidenes in Organic Synthesis

Tebbe Reagent in Synthesis

Living ROMP Polymers

Schrock AlkylidenesW O-t-But-Bu-O

t-Bu-O O-t-Bu

O

+ Ta=CH-t-Bu

Cl

Me3PPMe3

Cl

Cl W=CH-t-Bu

Cl

Me3PPMe3

Cl

O

Active with AlCl3

with terminal olefins W=CH2 complex observed

R. R. Schrock, S. Rockluge, J. Wengrovius, G. Rupprecht, J. Fellmann, J. Mol. Catal. 1980, 8, 73.

W

ArNCl

ClO

OC

t-Bu

H

LiOR

-LiClW

NArRO

ROC

t-Bu

H

also Mo Analog

Activity depends on R

[(CF3)2CH3]CO- >>(CH3)3CO-

R.R.Schrock, R. T. DePue, J. Feldman, C. J. Schaverien, J. C. Deqan, A. H. Liu, J. Am. Chem. Soc. 1988, 110, 1423

(Osborn and Basset also made Active W catalylsts)

The Ruthenium Story

Synthesis of an IonophoreO O OO

n

O

O

O

RuCl3

RuCl3Benzene/Ethanol n

F. W. Michelotti, W. P. Keaveney, J. Poly. Sci., Part A, 1965, 895

O

OO

nTi, W based CatalystsNo Polymer

Ruthenium Catalyst Synthesis

Ill defined, highly active, little initiation

!Well defined, good activity, 100mg/week

Ruthenium Catalyst Synthesis Large Scale

High activity, Scale up to 15 kg/week, Mike Giardello

One Pot, 2 days, scales easily, > 15 kg in 50 gal reactor

Metal-Centered-Functional Group

Catalyst Developments at Caltech

And Nolan and Herrmann

N-Heterocycle Carbene Ligands

Mechanism

At steady state

Eric DiasMelanie SanfordJen Love

Ru Catalysis Evolution at Caltech(relative rate of polymerization of COD)

( 0 ) ( 1)

(102) (104)

Uses and Applications Resulting from Stable, Tolerant Catalysts

RuR

D

D1Cl

Cl D=2 electron donor

General Catalyst Structure

Commercial Ru CatalystsFirst Generation Second Generation

--X

3. Phosphine free

Carbon-Carbon Double Bond Forming Reactions

CMR1

R2 R1

R2

n

RCM

n

ROMP

n

ADMETn

History of Ring Closing Metathesis

Ring Closing Metathesis with Well Defined Catalysts

(CH2)X

O Ph

O Ph

SiMePhO

O

93%

92%

71%

+CH2=CH2

+CH2=CH2

+CH2=CH2

Mo PhMe

Me

N

i-Pri-Pr

RfORfO

G. C. Fu and R. H. Grubbs, J. Am. Chem. Soc., 1992, 114, 5426-5427. J. Am. Chem. Soc . 1992, 114(18), 7324-7325. , J. Am. Chem. Soc., 1993, 115, 3800-3801

Ru Ph

Ph

PCy3

PCy3

Cl

Cl

G. C. Fu, S. T. Nguyen, and R. H. Grubbs, J. Am. Chem. Soc. 1993, 115, 9856-9857

Pharmaceutical Applications

Boehringer IngelheimHepatitis C Drugs

15

T. Nicola, M. Brenner, K. Donsbach, and P. Kreye,

Organic Process and Development, 2005, 27.

HCV Serine Protease InhibitorBoehringer Ingelheim’s BILN 2061Phase II Clinical Trials in US and Europe

NHN

O

O

O

NO

OO

OS Br

OO

NHN

O

O

O

NO

OO

OS Br

OO

Ru

toluene

NHN

O

OH

O

NO

OO

O

N

S

N

N

MeO400 kg.

GSK Osteoporosis Drug

NOR1 O

NOR1 O

NOR1 O

ON

NHRO

R2

R1= amide, sulfonamide, peptideR2 = aminoacid side chain

Protease Inhibitor of cathepsin K

Synthesis of a Large Natural Product

88%Ph

Ph

Catenane Formation

NH2

+

O

O

O

O

O

O

OO

O

OPF6

–

O

O

OO

O

O

NH2

+PF6

–

O

O

O

O (52-75%)

CH2Cl2

Reflux

2

a

bc d

+NH2

+

O

O

O

O

O

O

OO

O

OPF6

–

a

b c

dd

e

e

δ

N N

Ru

PCy3

Cl

Cl

Ph2

Magic Rings

O

O

OO

O

ONH2

+PF6

–

O

O

O

Oa

bc d

+

+

LL’Cl2Ru=CHRNH2

+

O

O

O

O

O

O

OO

O

OPF6

–

a'

b'c' d'

O

O

O O

O

O

Ru

O

O

O O

O

O

NH2

+

O

O

O

O

PF6–

Ru

No Reaction

Asymmetric Ring-Closing Metathesis

• Isolated yields

• 1 equiv. NaI relative to substrate; 25 equiv. relative to catalyst

Ru

PCy3

NN

iPr

PhCl

Cl

PhPh

iPriPr

iPr

2

Ru

PCy3

NN

iPr

PhCl

Cl

PhPhiPr

1

O1 (4 mol %)

NaI (1 equiv)

THF, 40 °C2h

O

64% yield (volatile)90% ee

O1 (4 mol %)

NaI (1 equiv)

THF, 40 °C2h

O

77% yield (volatile)90% ee

OSi

2 (1 mol %)

CH2Cl2, 40 °C2h

O

81% yield92% ee

Si

O Si2 (1 mol %)

CH2Cl2, 40 °C2h

O

65% yield92% ee

Si

OSi O

Si

98% yield78% ee

1 (4 mol %)NaI (1 equiv)

THF, 40 °C2h

O 2 (2 mol %)

CH2Cl2, 40 °C2h

O

92% yield76% ee

(85%ee with 1/NaI, but 5% conv.)

Green Chemistry• Starting material

– Renewable– Simple structures

• Processing– Few/no by products– No/little solvents (Water)– Low energy input

• Products– Replace polluting materials– Replace petroleum based material

A Codevelopment Program for the Conversion of Seed Oils to

Value added Chemical

Cargill- Materia- Caltech-DOE

Replace petroleum based productswith those from renewable resources

Seed oils (corn and soy beans) are highly unsaturated (many double bonds) and

can be modified by Olefin Metathesisto

value added functional moleculesCargill anticipates that it will have commercial sales in 2006 of several million pounds of a proprietary Ruthenium-metathesis based product derived from a renewable resource that will replace a petroleum-based material.

Oleic Acid to Value Added Chemicals

RO

O

RO

O

RO

O

+

+

H2C CH2 Ru Catalyst

RO

O

R = H or Me

Ru Catalyst

Oleic Acid

Use in Polyolefins and synthetic oils

Use in coatings

Polyesters

Linear hydrocarbon

Self-Metathesis of MO: C627 (5 ppm) at 40 °C

Sample # Time (min) MO (%) 9C18 (%) 1,18MeO2-9C18 (%) Impurities (%) SM (%) TON0 0 100.0 0.0 0.0 0.0 0 0

067-007-1-10 10 49.9 25.1 24.9 0.1 100 200000067-007-1-20 20 50.3 24.9 24.8 0.0 99 198000067-007-1-30 30 51.4 24.3 24.3 0.0 97 194000067-007-1-60 60 49.9 25.0 25.1 0.0 100 200000

TON vs time(min)

0

50000

100000

150000

200000

250000

0 10 20 30 40 50 60

Time (min)

TON

Product Distribution (%) vs. time(min)

0.0

5.0

10.0

15.0

20.0

25.0

30.0

0 20 40 60

Time (min)

Prod

uct (

%)

9C181,18MeO2-9C18

TON = 200,000; TOF = 1,200,000 h-1; extremely low impurity formation

Statistical Distribution of CM Products

Pheromone by Cross MetathesisOAc

AcOOAc

+

OAc

OAc+

85%

15%

Ru Cat Ru Cat

Ru Cat

50%

-CH2=CH2 -CH2=CH2

PHEROMONE for Peach Twig BorerUsed in Mating Disruption

Catalyst removed with P(CH2OH)3No Solvents Used

OAc OH+83% 17%

Water as a Solvent

ROMP of Water-Soluble Endo-Monomer

30:1 monomer: Catalyst

D2O, 45 °CN

N(CH3)3Cl–

n

NN(CH3)3

Cl–

HH

O OO

O

RuCl

NN

OCl

OPEG-Me

Me-PEGONH N

O

N

Ru

PCy3

PhCl

Cl

N(CH3)3

N(CH3)3

Cl–

Cl–

P

Ru

PPhCl

Cl

Cross Metathesis

D2O, r. t., 24 h

RuCl

NN

OCl

OPEG-Me

5 mol%

D2O, 45 oC, 24 h

RuCl

NN

OCl

OPEG-Me

5 mol%

HO OH HO

OH

94 %

OHHO

OH

> 90%(trans:cis > 15:1)

CD3OD, 45 oC, 24 h

RuCl

NN

OCl

OPEG-Me

5 mol%

OAc

AcO

OAc

80 %

Polymer Synthesis

Mechanical PropertiesChemical Function

Dicyclopentadiene-Thermoset Polymer

PolyDCPD-9mm Ballistic Protection

Products Made With DCPD ROMP[Ru] cat.

n

DCPD poly(DCPD)

Consumer products

Truck PartsSports Equipment

www.plastictechnology.combaseball.eastonsports.com

Acknowledgements

• All my Professors and others who have provided inspiration on my journey from the American equivalent of Åmål.

• The over 200 co-workers who have contributed to my research.

• Financial support of NSF, NIH, DoD, Materia ---• Helen and the gang- Barney, Brendan and Katy.