Transition metal catalysis has solved countless problems in total synthesis, pharmaceutical chemistry, and the production of fine chemicals. While these reactions have traditionally been performed using 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 across a wide variety of organic transformations, including reactions that have proven difficult for PGMs, such as the cross-coupling of alkyl halides and Grignard reagents with both high activity and selectivity. While iron-catalyzed C-C cross-couplings and olefin aminofunctionalizations offer tremendous potential for sustainable, low-cost methods for selective C-C and C-N bond formation in organic synthesis, a detailed molecular-level understanding of these systems has remained elusive, thus, 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 carbon-carbon and carbon-heteroatom bond forming reactions to the level of understanding currently present for palladium, thus permitting the rational development of iron chemistry across the spectrum of desired C-C, C-N and C-X (X = B, F, etc.) bond forming reactions.! In the proposed grant, a novel experimental approach combining inorganic spectroscopies, density functional theory, synthesis and kinetic studies will be utilized to provide molecular-level insight into the active iron catalysts and reaction mechanisms involved in iron- catalyzed C-C cross-coupling and olefin aminofunctionalization. These insights can be utilized to inspire and facilitate the development of new catalysts and reaction methodologies with improved catalytic performance. Following our successful work in the prior grant period, the specific aims of the proposal are to: (1) expand molecular-level understanding of the active iron catalysts and reaction mechanisms present in iron-ligand catalyzed C-C cross-coupling, (2) expand molecular-level understanding of the active iron catalysts and reaction mechanisms present in C-C cross-couplings with simple ferric salts, and (3) develop molecular-level understanding of the active iron catalysts and reaction mechanisms present in iron-catalyzed olefin aminofunctionalizations. The research is innovative because it involves a novel physical-inorganic approach to study iron-catalyzed organic reactions and advances our understanding of the active iron species and mechanisms involved in catalysis to inspire and facilitate the development of improved methodologies. The proposed research is significant because it is expected to expand the number of molecules that can be made using low-cost, sustainable iron catalysis. 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 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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Brown, Patrick
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University of Rochester
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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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