olefin metathesis catalysts for the synthesis of molecules ... · olefin metathesis catalysts for...
TRANSCRIPT
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.