Acetyl CoA Synthase: Nature s Monsanto Acetic Acid Catalyst. By: Seth Cory and Trang Nguyen CHEM 462 Dr. Marcetta Y. Darensbourg

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1 Acetyl CoA ynthase: ature s Monsanto Acetic Acid Catalyst 1 By: eth Cory and Trang guyen CHEM 462 Dr. Marcetta Y. Darensbourg

2 utline Industrial Process: Monsanto Acetic Acid Catalysis Reaction Mechanism Advantages & ther Routes Biological Mechanism: AC/CDH Catalysis verview of tructure Proposed Mechanisms & Biomimetic Complexes urvey of Mechanisms at the A-Cluster Analysis of ynthetic Biomimetic Complexes Computational Analysis Conclusion Current Directions ummary 2

3 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: BAF cobalt catalyst used for methanol carbonylation Reaction conditions: 250 o C and 680 bar Late 1960s: Monsanto rhodium catalyst discovered Reaction conditions: o C and bar 3 Miessler, G; pessard, G. rganometallic Chemistry Jones, J. Platinum Metals Rev. 2000, 3,

4 Monsanto Acetic Acid Process Rate = k[[rh(c 2 )I 2- ]][CH 3 I] tart Here H 2 CH 3 I I CH C 3 H HI E.C. = 16 e - I Rh + C CH 3 C H C I CH 3 Rh 3+ I E.C. = 18 e - C I E.C. = 16 e - I Rh C 3+ CH 3 C I I E.C. = 18 e - C 4 H 2 C I Rh C CH 3+ CH 3 3 C I C I I Adapted from: Miessler, G; pessard, G. rganometallic Chemistry

5 Monsanto Acetic Acid Process 5 Jones, J. Platinum Metals Rev. 2000, 3,

6 Benefits: Monsanto Acetic Acid Process 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 ( o C and 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 unley, G; Watson, D. Catal. Today. 2000, 58, ava, X; et al. Ullmann s Encyclopedia of Industrial Chemistry

7 utline Industrial Process: Monsanto Acetic Acid Catalysis Reaction Mechanism Advantages & ther Routes Biological Mechanism: AC/CDH Catalysis verview of tructure Proposed Mechanisms & Biomimetic Complexes urvey of Mechanisms at the A-Cluster Analysis of ynthetic Biomimetic Complexes Computational Analysis Conclusion Current Directions ummary 7

8 atural ources of AC Bacteria Chemoautotropic: grow on C 2 /H 2 or C Major role in the global carbon (C 2 /C) cycle Bacteria have developed intricate chemical processes to survive based on their environments! 8 Tan, ; et al. Biochem. 2007, 46,

9 AC/CDH: verview of tructure 9 Ragsdale, ; et al. Chem. Rev. 2014, 114,

10 AC/CDH: verview of Reactions How C is delivered from C- cluster to A-cluster? Active site of C-cluster Proposed Mechanism of C-cluster 10 Macharak, P; Harrop, T. Coord. Chem. Rev. 2005, 249, Lindahl, P. Met. Ions Life ci. 2009, 6, Wolfgang, K; chwederski, B; Klein, A. Bioinorganic Chemistry: Inorganic Elements in the Chemistry of Life

11 AC/CDH: verview of tructure 11 Ragsdale, ; et al. Chem. Rev. 2014, 114,

12 A Cluster: active site of AC reaction Proximal i: (trigonal planar) + where substrate binds + very labile can be removed by phenanthroline Proximal i: (trigonal pyramid) can be replaced by Zn and Cu inactivates AC activity i 12 Lindahl, P. Coordination & Bioinorganic Chemistry Lectures, ickel Enzyme, Texas A&M University, College tation. TX, UA, 2014

13 A-Cluster: i d ite (Tight) H 4-2- cys H gly i 2+ i 2+ cys * signifies an attachment to the protein backbone 13

14 pectroscopic Properties of A-cluster Electronic Properties xidized = diamagnetic 1 e - Reduced = paramagnetic Under C atmosphere gives EPR signal Vibrational Properties ν C = 1996 cm Macharak, P; Harrop, T. Coord. Chem. Rev. 2005, 249, Fontecilla-Camps, J; et al. at. truct. Biol. 2003, 10,

15 utline Industrial Process: Monsanto Acetic Acid Catalysis Reaction Mechanism Advantages & ther Routes Biological Mechanism: AC/CDH Catalysis verview of tructure Proposed Mechanisms & Biomimetic Complexes urvey of Mechanisms at the A-Cluster Analysis of ynthetic Biomimetic Complexes Computational Analysis Conclusion Current Directions ummary 15

16 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 CH 3 and C Biophysical Methods tarting materials: How to obtain the A-cluster of AC/CDH 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 & pectroscopy rganometallic synthesis coupled with spectroscopy and redox studies tructural & pectroscopic vs. Functional Computationally using DFT calculations 16

17 Diamagnetic Mechanism Paramagnetic Mechanism i 0 : d 10 i + : d 9 Relies on i p (0) i(ii) square planar species ifec EPR signal results from a side-reaction Relies on i p (I) i(iii) square pyramidal species ifec EPR signal results from a i(i)-c species 17 Crabtree, R. The rganometallic Chemistry of the Transition Metals Ragsdale, ; et al. Chem. Rev. 2014, 114,

18 Lindahl Mechanism (Diamagnetic) CH 3 Co 3+ -CoFeP Co 1+ -CoFeP 2+/1+ [Fe4 4] i 0 i 2+ 2+/1+ [Fe4 4] H 3 C i 2+ i 2+ H 3 C CoA CoA - C 2+/1+ [Fe4 4] H 3 C i 2+ i 2+ Migratory Insertion 2+/1+ [Fe4 4] H 3 C i 2+ C i Adapted from: Lindahl, P. Met. Ions Life ci. 2009, 6, Lindahl, P; Barondeau, D. J. Am. Chem. oc. 1997, 119,

19 Camps Mechanism (Diamagnetic) 2+/1+ [Fe4 4] i 0 i 2+ C 2+/1+ [Fe4 4] i 0 C i 2+ H 3 C CoA Does C withdraw e- density from i 0? CH 3 Co 3+ -CoFeP CoA - Co 1+ -CoFeP 2+/1+ [Fe4 4] H 3 C i 2+ i 2+ Migratory Insertion 2+/1+ [Fe4 4] H 3 C i 2+ C i Adapted from: Fontecilla-Camps, J; et al. at. truct. Biol. 2003, 10,

20 Ragsdale Mechanism (Paramagnetic) i 2+ is activated by a 1e- reduction by ferredoxin H 3 C 2+ [Fe4 4] i 1+ i 2+ C 2+ [Fe4 4] i 1+ C i 2+ CoA CoA - Internal e - transfer CH 3 Co 3+ -CoFeP Co 1+ -CoFeP 2+ [Fe4 4] H 3 C i 2+ i 2+ Migratory Insertion 2+ [Fe4 4] H 3 C i 2+ C i [Fe4 4] H 3 C i 3+ C i Ragsdale, ; Murakami, J. Biol. Chem. 2000, 275, Ragsdale, ; et al. Biochemistry. 2002, 41, Adapted from: Ragsdale, ; et. al. Chem. Rev. 2014, 114,

21 utline Industrial Process: Monsanto Acetic Acid Catalysis Reaction Mechanism Advantages & ther Routes Biological Mechanism: AC/CDH Catalysis verview of tructure Proposed Mechanisms & Biomimetic Complexes urvey of Mechanisms at the A-Cluster Analysis of ynthetic Biomimetic Complexes Computational Analysis Conclusion Current Directions ummary 21

22 i p Biomimetic Complexes i 2+ either complex can be reduced ulfur lone pairs prevent reduction Catalytically incompetent with respect to AC-type activity Ph P Ph i 2+ Ph P Ph 22 Adapted from: Darensbourg, M; et al. Inorg. Chem. 1990, 29, Adapted from: Darensbourg, M; et al. rganomettalics. 1993, 12, Lindahl, P; J. Biol. Inorg. Chem. 2004, 9,

23 i p Biomimetic Complexes CH 3 CH 3 i 2+,1+ Ph Ph P i 2+,1+,0 CH 3 Ph H 3 C P Ph σ-donors to the metal o π-acceptors to delocalize electrons Phosphine ligands delocalize electrons Good π-acceptors allow for reduction to i 0 Catalyzes formation of acetyl group 23 Adapted from: Darensbourg, M; et al. Inorg. Chem. 1990, 29, Adapted from: Darensbourg, M; et al. rganomettalics. 1993, 12, Lindahl, P; J. Biol. Inorg. Chem. 2004, 9,

24 Functional Biomimetic Complex R R i 2+,1+ R = i-pr or t-bu R CH 3MgX R R H 3 C i 2+ R C R R i 2+ C CH 3 R R - H 3 C R i 0 Can be reduced to i 1+ Thioethers cannot stabilize low oxidation state of i After reductive elimination, the i 0 dissociates and precipitates v(c) = 2026 cm -1 (only when C binds first) 24 Adapted from: Holm, R; et al. J. Am. Chem. oc. 1991, 113,

25 Biomimetic Complexes i 2+ Ph P i 2+,1+ P Ph Ph Ph i d -like site: 2 2 square-planar coordinated i p -like site: 2 bridging thiolates with 2 phosphines {i p 2+ i d 2+ } {i p + i d 2+ } {i p 0 i d 2+ } e- e- 25 Adapted from: chröder; et al. Chem. Commun. 2003, 24,

26 Biomimetic Complexes i 2+ i 2+ Ph Ph i 2+,1+ P P Ph Ph i d -like site: 2 tertiary amine nitrogens Unable to reduce to i 0 i 0 C C i d -like site: 2 amide nitrogens Able to reduce to i 0 26 Adapted from: chröder; et al. Chem. Commun. 2003, 24, Adapted from: Rauchfuss, T; et al. J. Am. Chem. oc. 2003, 125,

27 Biomimetic Complexes (6) H 3C()CH (6) (5) i 2+ (5) H 2 (5) (5) R R P i 2+,1+,0 P R R i p -like site: i p -like site: 3 rd bridging ligands 3 coordination sites 2 phosphine ligands 4 coordination sites o AC activity 27 Adapted from: Riordan, C; Krishnan, R. J. Am. Chem. oc. 2004, 126, Lindahl, P. Coordination & Bioinorganic Chemistry Lectures, ickel Enzyme, Texas A&M University, College tation. TX, UA, 2014

28 utline Industrial Process: Monsanto Acetic Acid Catalysis Reaction Mechanism Advantages & ther Routes Biological Mechanism: AC/CDH Catalysis verview of tructure Proposed Mechanisms & Biomimetic Complexes urvey of Mechanisms at the A-Cluster Analysis of ynthetic Biomimetic Complexes Computational Analysis Conclusion Current Directions ummary 28

29 Hall s Theoretical Model Calculated Cu 1+ (C)(CH 3 ) as unstable and C likely dissociates upon CH 3 addition in a competitive mechanism howed CH 3 addition to i 0 prior to C retains thiolate ligands Calculated an unstable i 3+ (C )(CH 3 ) that dissociates from thiolate ligands Provided insight on a nickelassisted thioacetyl reductive elimination H Fe H H CH 3 M L i Adapted from: Hall, M; et. al. J. Am. Chem. oc. 2004, 126,

30 Hall s Theoretical Model i 0 i 2+ +CH 3 H 3 C i 2+ i 2+ C H 3 C i 2+ C i 2+ [1: 0 kcal mol -1 ] [2: 0 kcal mol -1 ] [3: kcal mol -1 ] [T: kcal mol -1 ] kcal mol -1 + H 3 C CH3 i 2+ H 3 C C H3 C i 2+ - CH 3 H 3 C C i 2+ i 2+ [T: -5.0 kcal mol -1 ] [5: kcal mol -1 ] [4: kcal mol -1 ] 30 Adapted from: Hall, M; et. al. J. Am. Chem. oc. 2004, 126,

31 utline Industrial Process: Monsanto Acetic Acid Catalysis Reaction Mechanism Advantages & ther Routes Biological Mechanism: AC/CDH Catalysis verview of tructure Proposed Mechanisms & Biomimetic Complexes urvey of Mechanisms at the A-Cluster Analysis of ynthetic Biomimetic Complexes Computational Analysis Conclusion ummary Current Directions 31

32 Questions: Diamagnetic Vs. Paramagnetic i(0) has never been observed i(0) in a highly electropositive environment formed by i 2+ d and [Fe 4 4 ] 2+ Reduction potential for i 2+ C/i + C is already negative, below 550 mv 2 addition of methyl cation to the i + p should result in a i 3+ p i 3+ p state is highly oxidizing and unstable Further reduced to a more stable state i 2+ p Requires e- transfer from a redox carrier protein, which has not also been observed 32 Ragsdale, ; et al. Chem. Rev. 2014, 114, Macharak, P; Harrop, T. Coord. Chem. Rev. 2005, 249,

33 Conclusion The closed state is required to promote the oxidative addition of a i 0/1+ to form i 2+/3+ (C)CH 3 followed by a methyl migration to form an acetyl C-C bond formation Reductive elimination drives the formation of acetyl-coa imilar to Monsanto Acetic Acid Process 33

34 Current Work: i-i bond roles in catalysis? 34 Lindahl, P; J. Inorg. Biochem. 2012, 106, M., Matsumoto, et al. Proc. at. Acad. ci. UA. 2009, 106,

35 Harvesting the Power of AC 35 Dalton. Trans. 2010,12, M., Matsumoto, et al. Proc. at. Acad. ci. UA. 2009, 106,