Acetyl CoA Synthase: Nature’s
Monsanto Acetic Acid Catalyst
1
By: Seth Cory and Trang Nguyen
CHEM 462 – Dr. Marcetta Y. Darensbourg
Outline
 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
2
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.
Monsanto Acetic Acid Process
Rate =
Start Here
k[[Rh(CO2)I2-]][CH3I]
E.C. = 18 e-
H 2O
CH3
CH3I
I
OC
CH3OH
Rh3+
I
CO
I
E.C. = 16 eHI
O
E.C. = 16 eO
CH3C OH
I
OC
Rh
+
I
CO
OC
I
Rh3+
I
C
CH3
I
E.C. = 18 eCO
H 2O
O
O
CH3C I
4
CO C
Rh3+
I
OC
I
I
CH3
Adapted from: Miessler, G; Spessard, G. Organometallic Chemistry. 1996.
Monsanto Acetic Acid Process
5
Jones, J. Platinum Metals Rev. 2000, 3, 94-105.
Monsanto Acetic Acid Process
 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?
6
Sunley, G; Watson, D. Catal. Today. 2000, 58, 293-307.
Sava, X; et al. Ullmann’s Encyclopedia of Industrial Chemistry. 2007.
Outline
 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
7
Natural Sources of ACS
Bacteria
 Chemoautotropic:
grow on CO2/H2 or CO
Bacteria have developed intricate
chemical processes to survive
based on their environments!
 Major role in the global
carbon (CO2/CO) cycle
8
Tan, S; et al. Biochem. 2007, 46, 11606 -11613
ACS/CODH: Overview of Structure
9
Ragsdale, S; et al. Chem. Rev. 2014, 114, 4149-4174.
ACS/CODH: Overview of Reactions
How CO is delivered from Ccluster to A-cluster?
Active site of C-cluster
10
Proposed Mechanism of C-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.
ACS/CODH: Overview of Structure
11
Ragsdale, S; et al. Chem. Rev. 2014, 114, 4149-4174.
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
12
Lindahl, P. Coordination & Bioinorganic Chemistry Lectures, Nickel Enzyme, Texas A&M
University, College Station. TX, USA, 2014
A-Cluster: Nid Site (Tight)
42-
HN
HN
cys
O
O
N
S
gly
Ni2+
Ni2+
N
S
N
S
O
S
N
O
cys
O
O
*
13
signifies an attachment to the protein backbone
Spectroscopic Properties of A-cluster
 Electronic Properties
 Oxidized = diamagnetic
 1 e- Reduced =
paramagnetic
 Under CO atmosphere gives
EPR signal
 Vibrational Properties
 νCO = 1996 cm-1
14
Macharak, P; Harrop, T. Coord. Chem. Rev. 2005, 249, 3007-3024.
Fontecilla-Camps, J; et al. Nat. Struct. Biol. 2003, 10, 217-278.
Outline
 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
15
How can we study the chemistry of the A-cluster?
 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
16
Diamagnetic Mechanism
Paramagnetic Mechanism
Ni+: d9
Ni0: d10
 Relies on Nip(0)  Ni(II) square
planar species
 NiFeC EPR signal results from
a side-reaction
17
 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.
Lindahl Mechanism (Diamagnetic)
CH3Co3+-CoFeSP
2+/1+
S
[Fe4S4]
Ni0
S
Co1+-CoFeSP
2+/1+
N
Ni2+
S
N
S
[Fe4S4] H C
3
Ni2+
S
N
Ni2+
S
O
N
O
O
CoA
H 3C
S
CO
CoAS
2+/1+
[Fe4S4]
H 3C
-
S
Ni2+
Migratory Insertion
S
N
18
S
N
[Fe4S4]
H 3C
Ni2+
O
2+/1+
S
CO
Ni2+
O
Adapted from: Lindahl, P. Met. Ions Life Sci. 2009, 6, 133-150.
Lindahl, P; Barondeau, D. J. Am. Chem. Soc. 1997, 119, 3959-3970.
S
N
Ni2+
S
N
O
Camps Mechanism (Diamagnetic)
CO
2+/1+
S
[Fe4S4]
CO
Ni0
S
2+/1+
N
S
[Fe4S4]
Ni0
S
Ni2+
S
N
Does CO withdraw
e- density from Ni0?
CoA
2+/1+
[Fe4S4]
H 3C
N
O
CH3Co3+-CoFeSP
S
CoAS
-
Co1+-CoFeSP
S
Ni2+
Migratory Insertion
S
N
O
S
N
2+/1+
S
[Fe4S4]
H 3C
Ni2+
19
S
O
O
H 3C
N
Ni2+
O
CO
Ni2+
S
N
Ni2+
S
N
Adapted from: Fontecilla-Camps, J; et al. Nat. Struct. Biol. 2003, 10, 217-278.
O
Ragsdale Mechanism (Paramagnetic)
-
Ni2+ is activated by a 1e reduction by ferredoxin
CO
2+
S
Ni1+
CO
[Fe4S4]
S
O
S
CoAS
[Fe4S4]
Ni1+
N
N
S
Ni2+
H 3C
S
2+
N
S
Ni2+
S
O
N
O
CoA
CH3Co3+-CoFeSP
Internal
e transfer
-
Co1+-CoFeSP
2+
[Fe4S4]
H 3C
S
Ni2+
2+
S
N
Ni2+
O
S
N
atory In
sertio
n
2+
S
[Fe4S4]
H 3C
Ni2+
CO
Ni3+
S
S
N
Ni2+
N
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.
O
N
Ni2+
S
CO
S
20
[Fe4S4]
H 3C
Migr
O
S
N
O
Outline
 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
21
Nip Biomimetic Complexes
S
S
Ni2+
N
 Neither complex can be reduced
N
 Sulfur lone pairs prevent reduction
 Catalytically incompetent with
respect to ACS-type activity
Ph
P
Ni2+
Ph
S
22
S
Ph
P
Ph
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.
Nip Biomimetic Complexes
CH3
CH3
Ph
S
S
Ni2+,1+
P
Ph
N
N
CH3
S
Ni2+,1+,0 Ph
S
H 3C
P
Ph
 Phosphine ligands delocalize electrons
 σ-donors to the metal
 No π-acceptors to delocalize electrons  Good π-acceptors allow for reduction to
Ni0
Catalyzes formation of acetyl group
23
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.
Functional Biomimetic Complex
N
R
R
CH3MgX
S
S
R
Ni2+,1+ S
R = i-Pr or t-Bu
R
N
N
R
CO
S
S
Ni2+
S
R
H 3C
R
R
RS
S
Ni2+
S
-
Ni0
S
R
O
C
CH3
O
SR
H 3C
•
•
•
•
24
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)
Adapted from: Holm, R; et al. J. Am. Chem. Soc. 1991, 113, 8485-8492.
Biomimetic Complexes
N
N
Ni2+
S
S
Ni2+,1+
Ph
P
Ph
P
Ph
Ph
Nid-like site: N2S2 square-planar coordinated
Nip-like site: 2 bridging thiolates with 2 phosphines
{Nip2+ Nid2+}
25
e-
{Nip+ Nid2+}
e-
{Nip0 Nid2+}
Adapted from: Schröder; et al. Chem. Commun. 2003, 24, 3012-3013.
Biomimetic Complexes
N
O
N
O
N
Ni2+
S
Ni2+
P
26
Ni0
Ph
P
Ph
S
S
S
Ni2+,1+
Ph
N
OC
CO
Ph
Nid-like site:
Nid-like site:
2 tertiary amine nitrogens
2 amide nitrogens
 Unable to reduce to Ni0
 Able to reduce to Ni0
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.
Biomimetic Complexes
O
O
N
(6)
H3C(O)CHN
(6)
Ni2+
S
(5)
R
O
N
NH2
(5)
S
Ni2+,1+,0 R
R
P
(5)
(5)
P
R
Nip-like site:
27
Nip-like site:
2 phosphine ligands
3rd bridging ligands
4 coordination sites
3 coordination sites
No ACS activity
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
Outline
 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
28
Hall’s Theoretical Model
 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 nickelassisted thioacetyl reductive
elimination
29
O
CH3
HS
HS
Fe
S
M
HS
L
N
S
Ni2+
S
N
Adapted from: Hall, M; et. al. J. Am. Chem. Soc. 2004, 126, 3410-3411.
O
Hall’s Theoretical Model
S
Ni0
S
S
S
+CH3
Ni2+
Ni2+
H 3C
S
-1
[1: 0 kcal mol ]
S
S
CO
Ni2+
Ni2+
H 3C
S
-1
Ni2+
CO S
-1
[2: 0 kcal mol ]
[3: -14.8 kcal mol ]
-1
[TS: -28.3 kcal mol ]
-25.5 kcal mol-1
+
-1
S
30
S
S
Ni2+
O
H 3C
[TS: -5.0 kcal mol ]
CH3
Ni2+
H3CS
-
S
S
SCH3
Ni2+
Ni2+
H 3C
S
H 3C
O
-1
[5: -40.3 kcal mol ]
C
C
S
O
-1
[4: -21.0 kcal mol ]
Adapted from: Hall, M; et. al. J. Am. Chem. Soc. 2004, 126, 3410-3411.
Outline
 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
31
Questions: Diamagnetic Vs. Paramagnetic
 Ni(0) has never been
 SN2 addition of methyl
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
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
Ragsdale, S; et al. Chem. Rev. 2014, 114, 4149-4174.
32
Macharak, P; Harrop, T. Coord. Chem. Rev. 2005, 249, 3007-3024.
Conclusion
 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
33
Current Work: Ni-Ni bond roles in catalysis?
34
Lindahl, P; J. Inorg. Biochem. 2012, 106, 172-178.
M., Matsumoto, et al. Proc. Nat. Acad. Sci. USA. 2009, 106, 111862–111866.
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.