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By: Seth Cory and Trang Nguyen CHEM 462 – Dr. Marcetta Y. Darensbourg 1
Acetyl CoA Synthase: Nature’s Monsanto Acetic Acid Catalyst
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Outline
2
Industrial Process: Monsanto Acetic Acid Catalysis Reaction Mechanism Advantages & Other Routes
Biological Mechanism: ACS/CODH Catalysis Overview of Structure Proposed Mechanisms & Biomimetic Complexes Survey of Mechanisms at the A-Cluster Analysis of Synthetic Biomimetic Complexes Computational Analysis
Conclusion Current Directions Summary
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Monsanto Acetic Acid Process Acetic acid used by many chemists Converted to acetic anhydride and used for synthesis of
acetate films and aspirin
Mid 1960s: BASF cobalt catalyst used for methanol carbonylation Reaction conditions: 250 oC and 680 bar
Late 1960s: Monsanto rhodium catalyst discovered Reaction conditions: 150-200 oC and 30-60 bar
3 Miessler, G; Spessard, G. Organometallic Chemistry. 1996. Jones, J. Platinum Metals Rev. 2000, 3, 94-105.
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HI
H2O
CH3IRh3+
COI
OC II
CH3
Rh3+CI
OC II
O
CH3
Rh3+CI
OC II
O
CH3CO
Rh+ COI
OC I
CH3CO
I
H2O
CH3CO
OH
CO
CH3OH
Start HereMonsanto Acetic Acid Process
4
Rate = k[[Rh(CO2)I2-]][CH3I]
Adapted from: Miessler, G; Spessard, G. Organometallic Chemistry. 1996.
E.C. = 18 e-
E.C. = 16 e-
E.C. = 18 e-
E.C. = 16 e-
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Monsanto Acetic Acid Process
5 Jones, J. Platinum Metals Rev. 2000, 3, 94-105.
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6
Benefits: Uses a more efficient metal complex to synthesize a C-C bond Increased yield selectivity to >99% based upon methanol Milder conditions needed for the synthesis
(150-200 oC and 30-60 bar) Plant capacity: 500,000 tons annually
Challenges: Rhodium: expensive and precipitates under low water concentrations Large production of high boiling point by-products
Replaced by an Iridium catalyst in the late 1990s by BP Chemicals
How can nature do this chemistry at atmospheric pressures and low temperatures?
Monsanto Acetic Acid Process
Sunley, G; Watson, D. Catal. Today. 2000, 58, 293-307. Sava, X; et al. Ullmann’s Encyclopedia of Industrial Chemistry. 2007.
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Outline
7
Industrial Process: Monsanto Acetic Acid Catalysis Reaction Mechanism Advantages & Other Routes
Biological Mechanism: ACS/CODH Catalysis Overview of Structure Proposed Mechanisms & Biomimetic Complexes Survey of Mechanisms at the A-Cluster Analysis of Synthetic Biomimetic Complexes Computational Analysis
Conclusion Current Directions Summary
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8
Natural Sources of ACS
Chemoautotropic: grow on CO2/H2 or CO
Major role in the global carbon (CO2/CO) cycle
Tan, S; et al. Biochem. 2007, 46, 11606 -11613
Bacteria
Bacteria have developed intricate chemical processes to survive based on their environments!
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ACS/CODH: Overview of Structure
9 Ragsdale, S; et al. Chem. Rev. 2014, 114, 4149-4174.
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ACS/CODH: Overview of Reactions
10
Active site of C-cluster Proposed Mechanism of C-cluster
How CO is delivered from C-cluster to A-cluster?
Macharak, P; Harrop, T. Coord. Chem. Rev. 2005, 249, 3007-3024. Lindahl, P. Met. Ions Life Sci. 2009, 6, 133-150. Wolfgang, K; Schwederski, B; Klein, A. Bioinorganic Chemistry: Inorganic Elements in the Chemistry of Life. 2013.
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ACS/CODH: Overview of Structure
11 Ragsdale, S; et al. Chem. Rev. 2014, 114, 4149-4174.
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12
A Cluster: active site of ACS reaction
Proximal Ni: (trigonal planar) + where substrate binds + very labile can be removed by phenanthroline
Proximal Ni: (trigonal pyramid) can be replaced by Zn and Cu inactivates ACS activity
Ni
Lindahl, P. Coordination & Bioinorganic Chemistry Lectures, Nickel Enzyme, Texas A&M University, College Station. TX, USA, 2014
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A-Cluster: Nid Site (Tight)
13
Ni2+
N
S N
S
HN
O
Ni2+
O
O
2-
*signifies an attachment to the protein backbone
N
S N
S
HN
O
O
O
4-
cys
gly
cys
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Spectroscopic Properties of A-cluster
14
Electronic Properties Oxidized = diamagnetic 1 e- Reduced =
paramagnetic Under CO atmosphere gives
EPR signal
Vibrational Properties νCO = 1996 cm-1
Macharak, P; Harrop, T. Coord. Chem. Rev. 2005, 249, 3007-3024. Fontecilla-Camps, J; et al. Nat. Struct. Biol. 2003, 10, 217-278.
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Outline
15
Industrial Process: Monsanto Acetic Acid Catalysis Reaction Mechanism Advantages & Other Routes
Biological Mechanism: ACS/CODH Catalysis Overview of Structure Proposed Mechanisms & Biomimetic Complexes Survey of Mechanisms at the A-Cluster Analysis of Synthetic Biomimetic Complexes Computational Analysis
Conclusion Current Directions Summary
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How can we study the chemistry of the A-cluster?
16
Goals: Provide mechanistic insight at the A-Cluster Use the model to synthesize acetyl-CoA from CH3 and CO
Biophysical Methods Starting materials: How to obtain the A-cluster of ACS/CODH enzyme? Protein biochemistry: purify proteins from living organisms Active-site mimicking organometallic complexes
Experimental techniques: How to study the activity of A-cluster? Biophysical Techniques: X-ray Crystallography & Spectroscopy Organometallic synthesis coupled with spectroscopy and redox studies Structural & Spectroscopic vs. Functional
Computationally using DFT calculations
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Diamagnetic Mechanism Paramagnetic Mechanism
17
Relies on Nip(0) Ni(II) square planar species
NiFeC EPR signal results from a side-reaction
Relies on Nip (I) Ni(III) square pyramidal species
NiFeC EPR signal results from a Ni(I)-CO species
Crabtree, R. The Organometallic Chemistry of the Transition Metals. 2005. Ragsdale, S; et al. Chem. Rev. 2014, 114, 4149-4174.
Ni0: d10
Ni+: d9
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18
Lindahl Mechanism (Diamagnetic)
Adapted from: Lindahl, P. Met. Ions Life Sci. 2009, 6, 133-150. Lindahl, P; Barondeau, D. J. Am. Chem. Soc. 1997, 119, 3959-3970.
Ni2+N
S N
S
O
Ni0S
2+/1+[Fe4S4]
Ni2+N
S N
S
O
Ni2+S2+/1+[Fe4S4]
Ni2+N
S N
S
O
Ni2+
S2+/1+[Fe4S4]
Ni2+N
S N
S
O
Ni2+
S2+/1+[Fe4S4]
CO
CH3Co3+-CoFeSP Co1+-CoFeSP
CO
H3C
Migratory InsertionH3C
O
CoAS-
H3C S
O
CoA
H3C
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Camps Mechanism (Diamagnetic)
19 Adapted from: Fontecilla-Camps, J; et al. Nat. Struct. Biol. 2003, 10, 217-278.
Ni2+N
S N
S
O
Ni0S
2+/1+[Fe4S4]
Ni2+N
S N
S
O
Ni0S
2+/1+[Fe4S4]
Ni2+N
S N
S
O
Ni2+
S2+/1+[Fe4S4]
Ni2+N
S N
S
O
Ni2+
S2+/1+[Fe4S4]
CO
CH3Co3+-CoFeSP
Co1+-CoFeSP
CO
CO
H3C
Migratory InsertionH3C
O
H3C S
O
CoA
CoAS-
Does CO withdraw e- density from Ni0?
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Ragsdale Mechanism (Paramagnetic)
20
Ragsdale, S; Murakami, J. Biol. Chem. 2000, 275, 4699-4707. Ragsdale, S; et al. Biochemistry. 2002, 41, 1807-1819. Adapted from: Ragsdale, S; et. al. Chem. Rev. 2014, 114, 4149-4174.
Ni2+N
S N
S
O
Ni1+S2+[Fe4S4]
Ni2+N
S N
S
O
Ni1+S2+[Fe4S4]
Ni2+N
S N
S
O
Ni2+
S2+[Fe4S4]
Ni2+N
S N
S
O
Ni3+S
2+[Fe4S4]
CO
CH3Co3+-CoFeSP
Co1+-CoFeSP
CO
CO
H3CMigratory Insertion
H3C
O
CoAS-
H3C
S
O
CoA
Ni2+ is activated by a 1e-
reduction by ferredoxin
Ni2+N
S N
S
O
Ni2+S
2+[Fe4S4]
CO
H3C
Internal e- transfer
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Outline
21
Industrial Process: Monsanto Acetic Acid Catalysis Reaction Mechanism Advantages & Other Routes
Biological Mechanism: ACS/CODH Catalysis Overview of Structure Proposed Mechanisms & Biomimetic Complexes Survey of Mechanisms at the A-Cluster Analysis of Synthetic Biomimetic Complexes Computational Analysis
Conclusion Current Directions Summary
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Nip Biomimetic Complexes
Neither complex can be reduced Sulfur lone pairs prevent reduction Catalytically incompetent with
respect to ACS-type activity
22
Ni2+
S
N
S
N
Adapted from: Darensbourg, M; et al. Inorg. Chem. 1990, 29, 4366-4368. Adapted from: Darensbourg, M; et al. Organomettalics. 1993, 12, 870-875. Lindahl, P; J. Biol. Inorg. Chem. 2004, 9, 516-524.
Ni2+
P S
S P
Ph
Ph
Ph Ph
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Ni2+,1+,0
P S
S P
Ph
Ph
Ph Ph
CH3
H3C
Nip Biomimetic Complexes
23
Ni2+,1+
S
N
S
N
CH3 CH3
σ-donors to the metal No π-acceptors to delocalize electrons
Phosphine ligands delocalize electrons Good π-acceptors allow for reduction to Ni0
Catalyzes formation of acetyl group Adapted from: Darensbourg, M; et al. Inorg. Chem. 1990, 29, 4366-4368. Adapted from: Darensbourg, M; et al. Organomettalics. 1993, 12, 870-875. Lindahl, P; J. Biol. Inorg. Chem. 2004, 9, 516-524.
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Functional Biomimetic Complex
24 Adapted from: Holm, R; et al. J. Am. Chem. Soc. 1991, 113, 8485-8492.
Ni2+,1+
N
SS
S RR
RCH3MgX
Ni2+
N
SS
S RR
R
H3C
CO
Ni2+
N
SS
S RR
R
CO CH3
H3CSR
O
Ni0RS
-
• Can be reduced to Ni1+
• Thioethers cannot stabilize low oxidation state of Ni • After reductive elimination, the Ni0 dissociates and precipitates • v(CO) = 2026 cm-1 (only when CO binds first)
R = i-Pr or t-Bu
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Biomimetic Complexes
25 Adapted from: Schröder; et al. Chem. Commun. 2003, 24, 3012-3013.
Nid-like site: N2S2 square-planar coordinated
Nip-like site: 2 bridging thiolates with 2 phosphines
{Nip2+ Nid2+} {Nip+ Nid2+} {Nip0 Nid2+} e- e-
Ni2+,1+
Ni2+
P P
S S
Ph
Ph Ph
Ph
NN
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Biomimetic Complexes
26 Adapted from: Schröder; et al. Chem. Commun. 2003, 24, 3012-3013. Adapted from: Rauchfuss, T; et al. J. Am. Chem. Soc. 2003, 125, 8700-8701.
Ni2+
N
S
N
S
O O
Ni0
OC CO
Nid-like site:
2 amide nitrogens
Able to reduce to Ni0
Nid-like site:
2 tertiary amine nitrogens
Unable to reduce to Ni0
Ni2+,1+
Ni2+
P P
S S
Ph
Ph Ph
Ph
NN
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Biomimetic Complexes
27
Nip-like site:
3rd bridging ligands
3 coordination sites
Nip-like site:
2 phosphine ligands
4 coordination sites
No ACS activity
(6) (6)
(5)
(5)
(5)
(5)
Adapted from: Riordan, C; Krishnan, R. J. Am. Chem. Soc. 2004, 126, 4484-4485. Lindahl, P. Coordination & Bioinorganic Chemistry Lectures, Nickel Enzyme, Texas A&M University, College Station. TX, USA, 2014
Ni2+,1+,0
P
S
P
S
Ni2+
N N
O
O
R
R
R
R
NH2
O
H3C(O)CHN
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Outline
28
Industrial Process: Monsanto Acetic Acid Catalysis Reaction Mechanism Advantages & Other Routes
Biological Mechanism: ACS/CODH Catalysis Overview of Structure Proposed Mechanisms & Biomimetic Complexes Survey of Mechanisms at the A-Cluster Analysis of Synthetic Biomimetic Complexes Computational Analysis
Conclusion Current Directions Summary
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Hall’s Theoretical Model
29
Calculated Cu1+(CO)(CH3) as unstable and CO likely dissociates upon CH3 addition in a competitive mechanism
Showed CH3 addition to Ni0 prior to CO retains thiolate ligands
Calculated an unstable Ni3+(CO )(CH3) that dissociates from thiolate ligands
Provided insight on a nickel-assisted thioacetyl reductive elimination
Adapted from: Hall, M; et. al. J. Am. Chem. Soc. 2004, 126, 3410-3411.
MS
L
S
S
N
N
O
O
Ni2+
CH3
Fe
HS
HSHS
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Hall’s Theoretical Model
30 Adapted from: Hall, M; et. al. J. Am. Chem. Soc. 2004, 126, 3410-3411.
S Ni0S
S
Ni2+
+CH3
[1: 0 kcal mol-1]
S
Ni2+
S
S
Ni2+
[2: 0 kcal mol-1]
H3C
CO S
Ni2+
S
S
Ni2+
[3: -14.8 kcal mol-1]
H3C CO
S
Ni2+
S
S
Ni2+
[4: -21.0 kcal mol-1]
C
[TS: -5.0 kcal mol-1]
O
H3CSCH3
S
Ni2+
S
S
Ni2+
[5: -40.3 kcal mol-1]
COH3C
H3CS
[TS: -28.3 kcal mol-1] -25.5 kcal mol-1
H3CS CH3
O
+-
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Outline
31
Industrial Process: Monsanto Acetic Acid Catalysis Reaction Mechanism Advantages & Other Routes
Biological Mechanism: ACS/CODH Catalysis Overview of Structure Proposed Mechanisms & Biomimetic Complexes Survey of Mechanisms at the A-Cluster Analysis of Synthetic Biomimetic Complexes Computational Analysis
Conclusion Summary Current Directions
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Ni(0) has never been observed
Ni(0) in a highly electropositive environment formed by Nid2+ and [Fe4S4]2+
Reduction potential for Ni2+−CO/Ni+− CO is already negative, below −550 mV
SN2 addition of methyl cation to the Nip+ should result in a Nip3+
Nip3+ state is highly oxidizing and unstable
Further reduced to a more stable state Nip2+
Requires e- transfer from a redox carrier protein, which has not also been observed
32
Questions: Diamagnetic Vs. Paramagnetic
Ragsdale, S; et al. Chem. Rev. 2014, 114, 4149-4174. Macharak, P; Harrop, T. Coord. Chem. Rev. 2005, 249, 3007-3024.
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Conclusion
33
The closed state is required to promote the oxidative
addition of a Ni0/1+ to form Ni2+/3+(CO)CH3 followed by a
methyl migration to form an acetyl C-C bond formation
Reductive elimination drives the formation of acetyl-CoA
Similar to Monsanto Acetic Acid Process
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34
Current Work: Ni-Ni bond roles in catalysis?
Lindahl, P; J. Inorg. Biochem. 2012, 106, 172-178. M., Matsumoto, et al. Proc. Nat. Acad. Sci. USA. 2009, 106, 111862–111866.
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Harvesting the Power of ACS
35 Dalton. Trans. 2010,12, 2949-3136. M., Matsumoto, et al. Proc. Nat. Acad. Sci. USA. 2009, 106, 111862–111866.