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 Ziegler --MPI in Mulheim 1940's- war years AlEt 3 H-(CH 2 -CH 2 ) n -CH=CH 2 n CH 2 =CH 2 n= 1-12 1950 + AlEt 3 CH 3 -CH 2 -CH=CH 2 n CH 2 =CH 2 Ni only ! 1953 TiCl 4 /AlR 3 n CH 2 =CH 2 CH 2 CH 2 Called High density n room temperature polyethylene -HDPE low pressure density=0.97 Crystalline - Milk bottles K. Ziegler and G. Natta, Nobel Prize 1963

Discovery of a New Reaction Ziegler Polymer containing unsaturation- catalyst unexpected for an addition polymer TiCl 4 /AlR 3 n Truett, et al, J. Am. Chem. Soc , 1960, 2337 Co/MoO n 2 CH 2 =CHCH 3 CH 2 =CH 2 + CH 3 CH=CHCH 3 Three carbons Two carbons Four carbons Heterogeneous Catalyst R. L.. Banks and G. C. Bailey , I & EC Product Research and Development , 1964, 170

Metathesis Discovery MoCl 5 /Et 3 Al n WCl 6 /Et 3 Al n Natta, et. al. J. Polymer Sci., Polymer Lett. 1964, B2, 349 WCl 6 /EtOH/Et 3 Al n WCl 6 /EtOH/Et 3 Al + + Calderon, Chen, Scott, Tetrahedron Letters, 1967, 3327

Proposed Mechanisms CD 3 CD=CDCD 3 metathesis + CD 3 CH=CHCH 3 CD 3 CD=CHCH 3 CH 3 CH=CHCH 3 catalyst CD 3 CD=CDCH 3 D 3 CDC CDCD 3 CD 3 CH=CHCD 3 M CH 3 CD=CDCH 3 H 3 CHC CHCH 3 Not Observed Proposed intermdiate N. Calderon, E. A. Olfsead, J. P. Ward, W. A. Judy, K. W. Scott, J. Am. Chem. Soc., 1968, ,90, 4133 CH 3 CH=CH 2 CH 2 =CH 2 + CH 3 CH=CHCH 3 M--CH 2 CH 3 CH--CH 2 CH 3 CH=CH 2 M=CH 2 M=CHCH 3 + CH 2 =CH 2 + Proposed Intermediate CH 3 CH=CH 2 + CH 3 CH=CHCH 3 + M=CH 2 M=CHCH 3 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

Mechanistic Study metathesis + catalyst metathesis inactive predicted Ratio CD 2 pairwise Chauvin 1 1 D 2 C CD 2 CD 2 + + metathesis 2 0 (1.6) H 2 C CD 2 CH 2 + catalyst H 2 C CH 2 1 1 CH 2 R. H. Grubbs, P. L. Burk and D. D. Carr, J. Am. Chem. Soc. 1975 , 97, 3265. OBSERVED T. J. Katz and R. Rothchild, J. Am. Chem. Soc. 1976 , 98, 2519.

Olefin Metathesis Mechanism RHC=CHR [M] CHR RHC=CHR [M] CHR + RHC=CHR RHC=CHR 2 RHC CHR [M] CHR [M] CHR LnM=CHR RHC CHR RHC=CHR RHC=CHR [M] CHR [M] CHR RHC CHR RHC CHR

Carbene Catalysts Demonstration of Exchange between Metal Methylene and an Olefin CH 2 CD 2 + Cp 2 TiCD 2 -AlCl(CH 3 ) 2 + Cp 2 TiCH 2 -AlCl(CH 3 ) 2 F.N. Tebbe, G. W. Parshall, G. S. Reddy, J. Am. Chem. Soc. 1978, 100, 3611 Isolation of Metallacycle in Active Metathesis System Cl DMAP Ti CH 2 AlMe 2 CH 2 CH 2 =C(CH 3 ) 2 + Ti CH 2 CMe 2 + DMAP-AlMe 2 Cl T. R. Howard, J. B. Lee and R. H. Grubbs, J. Am. Chem. Soc., 1980 , 102 , 6876.

Tebbe Reagent Metal Alkylidenes in Organic Synthesis

Tebbe Reagent in Synthesis

Living ROMP Polymers

Schrock Alkylidenes Cl Cl O O Cl t-Bu-O W O-t-Bu W=CH-t-Bu Ta=CH-t-Bu Me 3 P Me 3 P + O-t-Bu t-Bu-O Cl Cl PMe 3 PMe 3 Active with AlCl 3 with terminal olefins W=CH 2 complex observed R. R. Schrock, S. Rockluge, J. Wengrovius, G. Rupprecht, J. Fellmann, J. Mol. Catal. 1980, 8, 73. ArN NAr Cl t-Bu RO O W LiOR t-Bu C W Cl C O H -LiCl RO H Activity depends on R also Mo Analog [(CF 3 ) 2 CH 3 ]CO - >>(CH 3 ) 3 CO - 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 Ti, W based Catalysts O n No Polymer RuCl 3 O O O RuCl 3 n Benzene/Ethanol F. W. Michelotti, W. P. Keaveney, J. Poly. Sci., Part A, 1965, 895

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) (10 2 ) (10 4 )

Uses and Applications Resulting from Stable, Tolerant Catalysts D Cl D=2 electron donor Ru Cl R D 1 General Catalyst Structure

Commercial Ru Catalysts First Generation Second Generation -- X 3. Phosphine free

Carbon-Carbon Double Bond Forming Reactions CM R 1 R 1 R 2 R 2 n RCM ROMP n ADMET n n

History of Ring Closing Metathesis

Ring Closing Metathesis with Well Defined Catalysts O Ph 93% +CH 2 =CH 2 X O Ph (CH 2 ) 92% +CH 2 =CH 2 O 71% +CH 2 =CH 2 SiMePh O PCy 3 Cl i- Pr i- Pr Ph Ru N Cl Ph R f O Mo Ph PCy 3 Me R f O Me 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 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 O O O O S Br Br S O O O O Ru H O H O N N N N toluene O O O O O O 15 N O N O 400 kg. HCV Serine Protease Inhibitor MeO Boehringer Ingelheim’s BILN 2061 N Phase II Clinical Trials in US and Europe N N T. Nicola, M. Brenner, K. Donsbach, and P. Kreye, S O O Organic Process and Development , 2005, 27. H OH N N O O O N O

GSK Osteoporosis Drug O R 1 R 2 O O R 1 O O R 1 N N O NHR O N N O R 1 = amide, sulfonamide, peptide R 2 = aminoacid side chain Protease Inhibitor of cathepsin K

Synthesis of a Large Natural Product Ph 88% Ph

Catenane Formation O O O O O O O O O O PF 6– PF 6– 2 O + O c O + O d b N N CH 2 Cl 2 H 2 H 2 O O O O + O O O O a Reflux O O O e O PF 6– + N H 2 (52-75%) O O O O b c N N a Cl d Ru d e Cl Ph PCy 3 2 δ

Magic Rings + O O PF 6– PF 6– c' O + O d' d c + b' N LL’Cl 2 Ru=CHR b H 2 N O O O O O O H 2 No Reaction O O O O a' + a O O O O O O Ru Ru – PF 6 O + O N O O H 2 O O O O O O O O O O O O

Asymmetric Ring-Closing Metathesis 1 (4 mol %) O O NaI (1 equiv) Ph Ph Ph Ph i Pr i Pr i Pr THF, 40 °C N N N N 2h Cl Cl i Pr i Pr Ru Ru 64% yield (volatile) i Pr Ph Ph Cl Cl 90% ee PCy 3 PCy 3 1 (4 mol %) O O 1 2 NaI (1 equiv) THF, 40 °C 2h O Si Si O 2 (1 mol %) 77% yield (volatile) 90% ee CH 2 Cl 2 , 40 °C 2h O O 2 (2 mol %) 65% yield 92% ee CH 2 Cl 2 , 40 °C 1 (4 mol %) 2h Si NaI (1 equiv) 92% yield Si O 76% ee O (85%ee with 1 /NaI, but 5% conv.) THF, 40 °C 2h O Si Si 98% yield O 78% ee 2 (1 mol %) • Isolated yields CH 2 Cl 2 , 40 °C 2h • 1 equiv. NaI relative to substrate; 25 equiv. relative to catalyst 81% yield 92% ee

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 Oleic Acid RO O R = H or Me H 2 C CH 2 Ru Catalyst Ru Catalyst O Polyesters RO Use in Polyolefins and synthetic oils RO + + RO O Use in coatings O Linear hydrocarbon

Self-Metathesis of MO: C627 (5 ppm) at 40 °C Sample # Time (min) MO (%) 9C 18 (%) 1,18MeO 2 -9C 18 (%) Impurities (%) SM (%) TON 0 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 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 Product Distribution (%) vs. time(min) TON vs time(min) 30.0 250000 25.0 200000 20.0 Product (%) 150000 9C18 15.0 TON 1,18MeO2-9C18 100000 10.0 5.0 50000 0.0 0 0 20 40 60 0 10 20 30 40 50 60 Time (min) Time (min) TON = 200,000; TOF = 1,200,000 h -1 ; extremely low impurity formation

Statistical Distribution of CM Products

Pheromone by Cross Metathesis OAc -CH 2 =CH 2 -CH 2 =CH 2 Ru Cat Ru Cat OAc + AcO Ru Cat OAc 85% + Catalyst removed with P(CH 2 OH) 3 OAc No Solvents Used 15% 50% OH OAc + 83% 17% PHEROMONE for Peach Twig Borer Used in Mating Disruption

Water as a Solvent

ROMP of Water-Soluble Endo-Monomer H n H 30:1 monomer: Catalyst O O O N N D 2 O, 45 °C N(CH 3 ) 3 O Cl – N(CH 3 ) 3 Cl – OPEG-Me N N Cl Ru Cl O O Me-PEGO N H N N Cl Ru Ph Cl PCy 3 Cl – N(CH 3 ) 3 P Cl Ru Ph Cl P N(CH 3 ) 3 Cl –