Catalytic cross-coupling reactions have solved countless problems in total synthesis, pharmaceutical chemistry, and the production of fine chemicals. While these reactions have traditionally been carried out with platinum group metals (PGMs), there has been a recent push to develop methods that circumvent the need for expensive and toxic precious metal catalysts. A growing body of research has demonstrated that iron can be an excellent catalyst, effecting cross-couplings that have proven difficult for PGMs such as the coupling of alkyl halides and Grignard reagents with both high activity and selectivity. While iron-catalyzed C-C cross-coupling chemistry offers tremendous potential for sustainable, low-cost methodologies for selective C-C bond formation across the spectrum of available nucleophiles and electrophiles, a detailed molecular level understanding of these systems has remained elusive. In fact, at present there remains no single iron-catalyzed cross-coupling reaction for which a broadly accepted mechanism has been determined, hindering rational catalyst development. This limitation is in stark contrast to palladium chemistry, where detailed studies of active catalyst structure and mechanism have provided the foundation for the continued design and development of catalysts with novel and/or improved catalytic performance. Our long-term goal is to develop iron-catalyzed C-C cross-coupling to the level of understanding currently present for palladium, thus permitting the rational development of iron chemistry across the spectrum of desired C-C bond forming reactions. In the proposed grant, a novel experimental approach combining inorganic spectroscopies, density functional theory and synthesis will be utilized to develop molecular-level insight into active catalyst structure and th mechanisms involved in current leading edge iron-catalyzed C-C cross-coupling reactions, and to utilize this insight to develop new catalysts and reaction methodologies with improved catalytic performance. Following up on strong preliminary data, the specific aims of the proposal are to: (1) develop molecular-level understanding of the active iron catalysts and reaction mechanisms present in iron-bisphosphine catalyzed C-C cross-coupling, (2) develop molecular-level understanding of the active iron catalysts and reaction mechanisms present in C-C cross-coupling catalyzed by simple ferric salts, and (3) develop novel iron-based C-C cross-coupling methods driven by fundamental insight into active catalyst structure and mechanism. The research is innovative because it involves a novel physical-inorganic approach to study iron cross-coupling catalysis, advances our understanding of the active catalysts and mechanisms involved in this catalysis and leverages this fundamental insight to the design and development of new iron catalysts and reaction methodologies for cross-coupling. The proposed research is significant because it is expected to expand the number of molecules that can be made using low-cost, sustainable iron cross-coupling methods. Long term, this expansion of synthetic methods will enable discoveries in molecular biology and pharmacology of direct impact to human health.

Public Health Relevance

The iron-based cross-coupling reaction studies in this application utilize low-cost, non-toxic metals that offer the potential for the development of sustainable catalytic systems for use in the health sciences. The proposed research is relevant to public health and the mission of the NIH because it is from these low-cost, sustainable methods that affordable routes to the next generation of pharmaceuticals and molecular probes will be discovered.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM111480-03
Application #
9111982
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2014-09-05
Project End
2019-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Rochester
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Fleischauer, Valerie E; Muñoz Iii, Salvador B; Neate, Peter G N et al. (2018) NHC and nucleophile chelation effects on reactive iron(ii) species in alkyl-alkyl cross-coupling. Chem Sci 9:1878-1891
Muñoz 3rd, Salvador B; Daifuku, Stephanie L; Sears, Jeffrey D et al. (2018) The N-Methylpyrrolidone (NMP) Effect in Iron-Catalyzed Cross-Coupling with Simple Ferric Salts and MeMgBr. Angew Chem Int Ed Engl 57:6496-6500
Muñoz 3rd, Salvador B; Fleischauer, Valerie E; Brennessel, William W et al. (2018) Combined Effects of Backbone and N-Substituents on Structure, Bonding, and Reactivity of Alkylated Iron(II)-NHCs. Organometallics 37:3093-3101
Sears, Jeffrey D; Neate, Peter G N; Neidig, Michael L (2018) Intermediates and Mechanism in Iron-Catalyzed Cross-Coupling. J Am Chem Soc 140:11872-11883
Krishnan, V Mahesh; Davis, Ian; Baker, Tessa M et al. (2018) Backbone Dehydrogenation in Pyrrole-Based Pincer Ligands. Inorg Chem 57:9544-9553
Kneebone, Jared L; Brennessel, William W; Neidig, Michael L (2017) Intermediates and Reactivity in Iron-Catalyzed Cross-Couplings of Alkynyl Grignards with Alkyl Halides. J Am Chem Soc 139:6988-7003
Leclerc, Matthew C; Gabidullin, Bulat M; Da Gama, Jason G et al. (2017) Transition-Metal-Free Formation of C-E Bonds (E = C, N, O, S) and Formation of C-M Bonds (M = Mn, Mo) from N-Heterocyclic Carbene Mediated Fluoroalkene C-F Bond Activation. Organometallics 36:849-857
Carpenter, Stephanie H; Neidig, Michael L (2017) A Physical-Inorganic Approach for the Elucidation of Active Iron Species and Mechanism in Iron-Catalyzed Cross-Coupling. Isr J Chem 57:1106-1116
Kneebone, Jared L; Fleischauer, Valerie E; Daifuku, Stephanie L et al. (2016) Electronic Structure and Bonding in Iron(II) and Iron(I) Complexes Bearing Bisphosphine Ligands of Relevance to Iron-Catalyzed C-C Cross-Coupling. Inorg Chem 55:272-82
Muñoz Iii, Salvador B; Daifuku, Stephanie L; Brennessel, William W et al. (2016) Isolation, Characterization, and Reactivity of Fe8Me12(-): Kochi's S = 1/2 Species in Iron-Catalyzed Cross-Couplings with MeMgBr and Ferric Salts. J Am Chem Soc 138:7492-5

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