Non-Precious Metal Catalysis in Organic Synthesis
Transition metal catalysis has solved countless problems in total synthesis, pharmaceutical chemistry, and the production of fine chemicals. While these reactions have traditionally used platinum group metals, there has been a recent push to develop methods that circumvent the need for expensive and toxic precious metal catalysts. Towards this goal, over the past 15 years a dramatic expansion of iron-based systems for reactions including cross-couplings, direct C-H functionalizations and hydrogenations have been reported. Despite the success of iron-based catalysts in organic chemistry, a detailed molecular level understanding of these systems has remained largely elusive. In fact, at the outset of our research program there existed no single iron-catalyzed cross-coupling or direct C-H functionalization reaction for which a broadly accepted mechanism had been determined, hindering rational catalyst development. Our long-term goal is to develop iron-catalyzed C-C cross-coupling and C-H functionalization reactions to the level of understanding that currently exists for palladium. The objective of our research program is to utilize a novel experimental approach using inorganic spectroscopies, density functional theory and synthesis combined with kinetic studies to develop molecular-level insight into active catalyst structure and the mechanisms involved in current leading-edge iron-catalyzed C-C cross-coupling and iron- and cobalt-catalyzed direct C-H functionalization reactions that can be utilized to inspire and facilitate the development of new catalysts and reaction methodologies.
(1) Iron-Catalyzed Cross-Coupling
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. Thus, iron-catalyzed C-C cross-coupling chemistry offers tremendous potential for sustainable, low-cost methodologies for selective C-C bond formation across the breadth of available nucleophiles and electrophiles. Despite the success of iron-based catalysts for cross-coupling, a detailed molecular level understanding of these systems has remained elusive.
Studies in iron-catalyzed cross-coupling in our group currently focus on three distinct sub-groups of iron catalysts: (1) iron-bisphosphines, (2) simple iron salts and (3) iron-N-heterocyclic carbenes (iron-NHCs). In the area of iron-bisphosines, we have established that a combination of Mössbauer, MCD and DFT methods was demonstrated to be a highly impactful methodology for the investigation of the iron-catalyzed Kumada coupling of MesMgBr and primary alkyl halides. These studies permitted the identification of FeMes2(SciOPP) as the active catalyst and in-situ studies of the reaction of FeMes2(SciOPP) with primary alkyl halides using freeze-trapped Mössbauer and MCD spectroscopies was shown to generate FeXMes(SciOPP) (X = halide) along with the formation of mesityldecane, consistent with the proposal by Nakamura of an iron(II)/iron(III) catalytic mechanism. Lastly, these studies also defined the effects of key reaction protocol details, including the role of the slow Grignard addition method and the addition of excess SciOPP ligand, in leading to high product yields and selectivities. Currently, we are expanding these studies to additional iron-bisphosphine-catalyzed cross-couplings. In the area of simple ferric salt catalysis, we have also recently reported the synthesis and characterization of [FeMe4][(THF)5MgBr] from reaction of FeCl3 with MeMgBr in THF (e.g. catalytically relevant conditions and reagents). This iron species has a distorted square planar geometry and a S = 3/2 ground-state (from EPR and further supported by DFT). Importantly, this species is an intermediate in the initial reduction pathway and, upon warming to -40 °C, conversion to the S = 1/2 previously observed by Kochi which he proposed to represent the active species in catalysis.
(2) Iron- and Cobalt-Catalyzed Direct C-H Functionalization
The development of sustainable, more efficient and selective catalysis remains one of the key fundamental research goals in chemistry. Towards this goal, iron- and cobalt-based catalysts are particularly attractive due to the low cost, non-toxic nature and rich oxidation chemistry of these base metals. Of particular note are recent developments in iron- and cobalt-catalyzed direct C-H functionalization that have exhibited highly promising catalytic performance in a variety of reactions including C(sp2)-H and C(sp3)-H alkylations and arylations as well as C(sp2)-H aminations. However, molecular level insight into the nature of the active catalyst species operating in-situ, including detailed electronic structure-activity relationships, and the underlying catalytic cycles remain poorly defined. Several factors contribute to this challenge, including a limited understanding of electronic structure and bonding in low valent iron- and cobalt-organometallics including Co-N-heterocyclic carbenes and the use of in-situ generated iron and cobalt catalysts from simple metal salts and ligand additives to yield the most effective catalytic systems. We utilize an approach combining multiple inorganic spectroscopies (magnetic circular dichroism, Mössbauer, electron paramagnetic resonance, resonance Raman), density functional theory, synthesis and kinetic and reaction studies in order to elucidate detailed electronic structure and bonding insight in iron- and cobalt-organometallics. These spectroscopies are equally applicable to freeze-trapped intermediates and, combined with stopped-flow/rapid-freeze quench methods, permit the identification of key intermediates and the molecular mechanisms of catalysis. Ultimately, the development of such fundamental insight into structure, bonding and mechanism in iron- and cobalt-catalyzed direct C-H functionalization is critical to inspire and facilitate the rational design and development of systems with improved catalytic performance.
Structure, Bonding and Mechanism in f-Element Chemistry
Detailed insight into electronic structure and bonding in heavy element chemistry remains poorly developed despite the critical role of actinide and lanthanides compounds in environmental, non-proliferation and energy issues. Furthermore, such insight into electronic structure in heavy element systems is critical in order to define the origins of their unique chemical properties as well as to broaden our understanding of fundamental quantum chemistry. The objective of our research program in this area is to develop and apply advanced inorganic spectroscopic methods to actinide chemistry, including well-defined compounds, in-situ generated complexes and transient species in order to advance our understanding of electronic structure, bonding and reactivity in heavy element systems up to the level currently available for transition metals such as iron and palladium. Towards this goal, C-term magnetic circular dichroism spectroscopy are being applied to well-defined heavy element complexes with an emphasis on actinide compounds to elucidate electronic structure including ground and excited states, determine polarizations of electronic transitions and, importantly, obtain insight into spin-orbit coupling effects. In addition, freeze-trapped spectroscopic methods will be developed to study unstable and transient species as well as for detailed molecular level insight into the reaction pathways of actinide complexes. Importantly, freeze-trapped spectroscopic methods can be applied across the breath of actinide molecular chemistry, including determination of electronic structure, bonding and reactivity of low stability actinide organometallic complexes, identification of transient species in redox reactions, and the identification of intermediates in reactions to form actinide-ligand bonds. Overall, these physical-inorganic methods will enable a deeper understanding of electronic structure and bonding in actinide complexes as well as detailed insight into the reactivity of these species.