Olefin Metathesis Catalysts for the Synthesis of Molecules and - - PowerPoint PPT Presentation

Olefin Metathesis Catalysts for the Synthesis of Molecules and Materials

December 8, 2005 Stockholm, Sweden

New Polyethylene

Ni 1950+ n CH2=CH2 AlEt3

• nly !

CH3-CH2-CH=CH2 Ziegler --MPI in Mulheim 1940's- war years n CH2=CH2 AlEt3 H-(CH2-CH2)n-CH=CH2 n= 1-12 n CH2=CH2 n TiCl4/AlR3 room temperature low pressure 1953

Crystalline - Milk bottles

Called High density polyethylene -HDPE density=0.97 CH2 CH2

• K. Ziegler and G. Natta, Nobel Prize 1963

Discovery of a New Reaction

Ziegler catalyst TiCl4/AlR3 Polymer containing unsaturation- unexpected for an addition polymer n Truett, et al,J. Am. Chem. Soc, 1960, 2337 Co/MoOn 2 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 Discovery

MoCl5/Et3Al WCl6/Et3Al n n Natta, et. al. J. Polymer Sci., Polymer Lett. 1964, B2, 349 WCl6/EtOH/Et3Al n WCl6/EtOH/Et3Al + + Calderon, Chen, Scott, Tetrahedron Letters, 1967, 3327

Proposed Mechanisms

CD3CD=CDCD3 CD3CD=CHCH3 CH3CH=CHCH3 + metathesis catalyst CD3CH=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 CDCD3 D3CDC CHCH3 H3CHC M

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

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

M--CH2 CH3CH--CH2 Proposed Intermediate

Mechanistic Study

metathesis catalyst + metathesis inactive

OBSERVED

CD2 CD2 + metathesis catalyst H2C CH2 H2C CD2 D2C CD2 + + predicted Ratio pairwise Chauvin 1 1 2 0 (1.6) 1 1 CH2 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] CHR RHC=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 Ti CH2 AlMe2 Cl CH2=C(CH3)2 + DMAP Ti CH2 CMe2 CH2 + 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 Alkylidenes

W O-t-Bu t-Bu-O t-Bu-O O-t-Bu O + Ta=CH-t-Bu Cl Me3P PMe3 Cl Cl W=CH-t-Bu Cl Me3P PMe3 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 ArN Cl Cl O O C t-Bu H LiOR

• LiCl

W NAr RO RO C 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 Ionophore

O O O O n O O O

RuCl3

RuCl3 Benzene/Ethanol n

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

O O O n Ti, W based Catalysts No 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 Dias Melanie Sanford Jen Love

Ru Catalysis Evolution at Caltech

(relative rate of polymerization of COD) ( 0 ) ( 1) (102) (104)

Uses and Applications Resulting from Stable, Tolerant Catalysts

Ru R D D1 Cl Cl D=2 electron donor General Catalyst Structure

Commercial Ru Catalysts

First Generation Second Generation

• -X
• 3. Phosphine free

Carbon-Carbon Double Bond Forming Reactions

CM

R1 R2 R1 R2 n

RCM

n

ROMP

n

ADMET

n

History of Ring Closing Metathesis

Ring Closing Metathesis with Well Defined Catalysts

(CH2)

X O Ph O Ph SiMePh O O 93% 92% 71% +CH2=CH2 +CH2=CH2 +CH2=CH2

Mo Ph Me Me N i-Pr i-Pr RfO RfO

• 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 Ingelheim Hepatitis C Drugs

15

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

Organic Process and Development, 2005, 27. HCV Serine Protease Inhibitor Boehringer Ingelheim’s BILN 2061 Phase II Clinical Trials in US and Europe

N H N O O O N O O O O S Br O O N H N O O O N O O O O S Br O O Ru toluene N H N O OH O N O O O O N S N N MeO

400 kg.

GSK Osteoporosis Drug

N O R1 O N O R1 O N O R1 O O N NHR O R2

R1= amide, sulfonamide, peptide R2 = aminoacid side chain

Protease Inhibitor of cathepsin K

Synthesis of a Large Natural Product

88%

Ph Ph

Catenane Formation

N H2

+

O O O O O O O O O O PF6– O O O O O O N H2

+

PF6– O O O O

(52-75%)

CH2Cl2 Reflux 2 a b c d

+

N H2

+

O O O O O O O O O O PF6–

a b c d d

e

e δ

N N Ru PCy3 Cl Cl Ph

2

Magic Rings

O O O O O O N H2

+

PF6– O O O O a b c d

+ + LL’Cl2Ru=CHR

N H2

+

O O O O O O O O O O PF6– a' b' c' d' O O O O O O

Ru

O O O O O O N H2

+

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 N N iPr Ph Cl Cl Ph Ph iPr iPr iPr 2 Ru PCy3 N N iPr Ph Cl Cl Ph Ph iPr 1 O 1 (4 mol %) NaI (1 equiv) THF, 40 °C 2h O 64% yield (volatile) 90% ee O 1 (4 mol %) NaI (1 equiv) THF, 40 °C 2h O 77% yield (volatile) 90% ee O Si 2 (1 mol %) CH2Cl2, 40 °C 2h O 81% yield 92% ee Si O Si 2 (1 mol %) CH2Cl2, 40 °C 2h O 65% yield 92% ee Si O Si O Si 98% yield 78% ee 1 (4 mol %) NaI (1 equiv) THF, 40 °C 2h O 2 (2 mol %) CH2Cl2, 40 °C 2h O 92% yield 76% 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 products with those from renewable resources

Seed oils (corn and soy beans) are highly unsaturated (many double bonds) and can be modified by Olefin Metathesis to value added functional molecules

Cargill 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 (%) TON 100.0 0.0 0.0 0.0 067-007-1-10 10 49.9 25.1 24.9 0.1 100 200000 067-007-1-20 20 50.3 24.9 24.8 0.0 99 198000 067-007-1-30 30 51.4 24.3 24.3 0.0 97 194000 067-007-1-60 60 49.9 25.0 25.1 0.0 100 200000 TON vs time(min)

50000 100000 150000 200000 250000 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 20 40 60 Time (min)

Product (%) 9C18 1,18MeO2-9C18

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

Statistical Distribution of CM Products

Pheromone by Cross Metathesis

OAc AcO OAc + OAc OAc + 85% 15% Ru Cat Ru Cat Ru Cat 50%

• CH2=CH2
• CH2=CH2

PHEROMONE for Peach Twig Borer Used in Mating Disruption

Catalyst removed with P(CH2OH)3 No Solvents Used

OAc OH +

83% 17%

Water as a Solvent

ROMP of Water-Soluble Endo-Monomer

30:1 monomer: Catalyst D2O, 45 °C N N(CH3)3 Cl– n N N(CH3)3 Cl– H H O O O O

Ru Cl N N O Cl OPEG-Me

Me-PEGO N H N O N Ru PCy3 Ph Cl Cl

N(CH3)3 N(CH3)3 Cl– Cl– P Ru P Ph Cl Cl

Cross Metathesis

D2O, r. t., 24 h

Ru Cl N N O Cl OPEG-Me

5 mol% D2O, 45 oC, 24 h

Ru Cl N N O Cl OPEG-Me

5 mol%

HO OH HO OH

94 %

OH HO OH

> 90% (trans:cis > 15:1) CD3OD, 45 oC, 24 h

Ru Cl N N O Cl OPEG-Me

5 mol%

OAc AcO OAc

80 %

Polymer Synthesis

Mechanical Properties Chemical Function

Dicyclopentadiene-Thermoset Polymer

PolyDCPD-9mm Ballistic Protection

Products Made With DCPD ROMP

[Ru] cat. n DCPD poly(DCPD)

Consumer products Truck Parts Sports Equipment www.plastictechnology.com baseball.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.