Research

Welcome to our research page! Our group conducts a wide range of projects on catalysis. In general, our research group aims to discover, develop and understand new transition metal-catalyzed reactions. The scope of our studies encompasses the functionalization of C-H bonds in substrates ranging from alkanes to complex natural products, the enantioselective formation of C-C, C-N and C-O bonds by additions to alkenes and allylic substitution, and even the creation of artificial metalloenzymes for applications in organic synthesis. The discovery of fundamentally new transition metal chemistry and its development into practical, catalytic synthetic methods is a theme of our research. We reach these goals by obtaining insight from detailed mechanistic studies, developing new concepts in catalysis, and merging principles of biocatalysis and chemical catalysis. The following classes of metal-catalyzed reactions are currently being investigated in our group:

Regioselective Functionalization of Alkyl and Aryl C-H Bonds

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Our group has discovered some of the most widely practiced C-H bond functionalization reactions. We discovered that metal boryl compounds react with arenes and alkanes to form functionalized products and developed this new elementary reaction into a catalytic process for the conversion of alkyl and aryl C-H bonds into C-B bonds. The C-B bonds in the product can then be converted to C-C and C-heteroatom bonds in a wide range of valuable products. We have also recently extended this type of catalysis to the formation of C-Si bonds from silane reagents. We are now seeking to apply this chemistry to the functionalization complex arenes and heteroarenes and to the discovery of catalysts that functionalize aliphatic C-H bonds in molecules with complex structures and with a range of auxiliary functionality.

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Our success on the functionalization of C-H bonds in complex molecules with boranes and silanes has led us to develop additional classes of C-H bond functionalizations. For example, we recently disclosed a combination of catalyst and reagent for the conversion of C-H bonds in natural products to the C-N bonds in alkyl azides. Reduction of the azide leads to natural product analogs containing amino groups, as well as related nitrogen-based functionality. We also discovered the direct coupling of arenes with allyl halides by a new mechanism in which the C-H bond of the arene is cleaved by a phosphine-ligated silver complex, rather than the palladium complex.

See our publications on main group-transition metal organometallics and catalytic C-H bond functionalization.

 

Olefin Hydrofunctionalization

 

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The hydrofunctionalization of olefins is a long-standing goal for transition metal catalysis. We have discovered catalysts for the first additions of N-H and O-H bonds to unactivated alkenes and have discovered catalysts for the addition of amines and alcohols to vinylarenes and dienes. Most recently, we have disclosed systems for the addition of boranes to internal alkenes enantioselectively and systems for the first anti-Markovnikov hydroarylations of unactivated alkenes with high regioselectivity. The products of the asymmetric hydroborations lead to enantioenriched amines, alcohols and alkylarenes.

This work on alkene hydrofunctionalization rests upon two discoveries of new elementary reactions for organometallic complexes. We reported the oxidative addition of ammonia to form monomeric products with late transition-metal complexes and the insertions of ethylene and alpha-olefins into transition-metal amido and transition-metal alkoxo bonds.

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See our publications on hydrofunctionalization of olefins.

Iridium-Catalyzed Allylic Substitution

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We have developed an iridium catalyst that forms chiral allylic amines, ethers, and carbonyl compounds in high enantiomeric excess from terminal allylic esters. Detailed mechanistic studies have shown that the catalyst forms by cyclometalation at a methyl C-H bond of the ligand and this observation has allowed the design of simplified, as well as improved catalysts. The scope of the reaction encompasses a wide range of nucleophiles. Current studies are focused on expanding the scope of allylic electrophiles and on approaches to control the diastereoselectivity of reactions that form C-C bonds from enolates.

See our publications on iridium-catalyzed allylic substitution.

New Classes of Cross Coupling
Palladium-Catalyzed Coupling of Aryl Halides with Heteroatom Nucleophiles

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We developed a palladium-catalyzed process that forms arylamines, aryl sulfides, and arylethers. This reaction has become one of the most widely practiced reactions by medicinal chemists. The catalytic chemistry resulted from our detailed mechanistic experiments on transition metal amide, alkoxo and thiolato complexes. One catalyst we developed leads to the formation of arylamines and aryl sulfides with turnover numbers exceeding 10,000 in many cases and ppm levels of palladium in others. This catalyst also coupled aryl halides with ammonia for the first time to form primary arylamines without any protecting or blocking groups. Another class of catalyst we developed recently contains nickel in place of palladium. This catalyst is the first nickel-based catalyst to couple primary amines with a range of aryl halides. Yet another system based on palladium catalyzes the first thermal coupling of alkyl halides, instead of aryl halides, with a nitrogen nucleophile to form alkyl-nitrogen bonds. These reactions occur preferentially with secondary and tertiary alkyl halides that undergo elimination, rather than substitution, in the absence of the catalyst.

This coupling reaction is useful for total synthesis, medicinal chemistry, and the preparation of electronically important organic materials. At least one drug is manufactured using this chemistry, and countless drug candidates have been prepared by these reactions. At the same time, the catalysis involves unprecedented reactions of transition metal compounds, principally reductive elimination to form carbon-heteroatom bonds. Thus, some students focus on novel inorganic chemistry while others use this reaction as a modular route to nitrogen heterocycles and polyanilines.

See our publications on methodology development and reaction mechanism of catalytic C-X bond formation.

Catalytic Alpha Arylation of Carbonyl Compounds

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We have developed a simple method to convert aryl halides and ketones, esters, amides, cyanoesters, malonates, nitriles, and related compounds to alpha aryl carbonyl compounds and nitriles in the presence of base and a palladium catalyst. Familiar compounds that can be generated from these products include Ibuprofen, Naproxin and Tamoxifen. The reaction occurs in a general fashion and in many cases with low catalyst loadings.

As part of our studies to understand this process, we have generated both O-bound and C-bound palladium enolate complexes. These complexes undergo reductive elimination of the alpha-aryl ketone, ester, or amide product in good yields. Studies on the effects of changing the enolate electronics on reductive elimination rate are in progress.

See our publications on methodology development and reaction mechanism of catalytic C-C bond formation.

Metal-Catalyzed Fluorination and Fluoroalkylation

The synthesis of arenes and heteroarenes containing fluorine is crucial to the discover of modern drugs and agrochemicals. These fluorine atoms impart a unique combination of steric and electronic properties and can influence the interactions of the molecules with proteins by non-covalent interactions. The fluorine atoms also modulate the metabolism of such compounds. Thus, we have sought catalytic methods for the conversion of arenes, heteroarenes, aryl halides and heteroaryl halides to products containing fluorine and fluoroalkyl groups.

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These studies have lead to a series of practical methods to prepare aryl and heteroaryl fluorides, as well as arenes containing trifluoromethyl groups and difluorocarbonyl units. Representative methods include the coupling of aryl iodides and heteroaryl bromides and iodides with a copper reagent we discovered, the fluorination of pyridine and diazine heterocycles at the C-H bond alpha to nitrogen, and the palladium-catalyzed coupling of aryl halides with difluoromethyl ketones and amides.

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These reactions raise a series of questions about fundamental organometallic chemistry. Metal-fluorides are difficult to prepare yet often unreactive. Alkyl groups containing fluorine on the alpha carbon are typically unreactive toward reductive elimination and migratory insertion. Thus, the development of this catalytic chemistry confronts the challenge of inducing reactivity from metal fluorides and metal-fluoroalkyl complexes, and raises mechanistic questions about the identity of the intermediates and individual steps of the catalytic reactions we developed. To address these questions, we have prepared copper and palladium fluoride and fluoroalkyl complexes and are studying their fundamental reactivity.

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Catalysis for renewable chemicals and fuels

The conversion of biomass to chemicals or fuels requires catalytic reductions of C-O bonds. The aromatic C-O bonds in aryl ethers are some of the strongest and least reactive C-O bonds and are one class of the C-O bonds in the lignin portion of lignocellulosic biomass. One potential renewable source of arenes are the aryl ethers contained in lignin, but methods to cleave the C-O bonds of this material are required to meet this goal.

In one set of studies, we discovered nickel complexes and nanostructured nickel materials that catalyze the hydrogenolysis of C-O bonds. These reactions occur with just one atmosphere of hydrogen at milder temperatures than required for prior catalysts. Most important, these reactions are the first reductions of the C-O bonds in aryl ethers that occur without concomitant reduction of the arene. Studies to improve the activity of the catalysts, to understand the origin of the high selectivity, to identify the nickel species that cleaves the C-O bond within the catalytic cycle, and to reduce additional classes of C-O bonds are the subject of current studies in our laboratory.

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In a second set of studies we discovered conditions to use heterogeneous palladium catalysts for the breakdown of lignin by the reagentless cleavage of the b-O-4 linkages. These reactions generate hydrogen by the dehydrogenation of alcohols and use this hydrogen to cleave the C–O bonds in the b-O-4 linkages.

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Our group is also part of the Center of Sustainable Polymers, which focuses on the synthesis of polymers from monomers that can be prepared from biomass sources, as well as polymers that can be recycled. Our work has focused on using silicon to link monomers derived from plant oils to provide a cleavable linker for recycling and to use diol and diamine monomers prepared from biomass precursors by catalytic chemistry with diesters derived from plant oils to create renewable polyesters and polyamides.

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See our publications on catalysis for renewable chemicals and fuels.

Artificial Metalloenzymes

We have begun to develop methods to combine the diversity of reactions of organometallic complexes with the selectivity of enzymes. To do so, we have followed several approaches. In one case, we have developed cooperative chemoenzymatic reactions in which a chemical organometallic catalyst and an enzyme operate together to form one product with higher yield and selectivity than would be achieved by two using the two catalysts in two separate reactions. In a second case, we have incorporated organometallic fragments into metalloenzymes in which the metal is bound to the protein sidechains. We recently replaced the zinc of carbonic anhydrase with a rhodium-alkene fragment.

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In a third set of studies, we have created artificial metalloenzymes by replacing the iron in heme proteins with noble metals. Our currently most active system is generated by replacing iron with an iridium-methyl unit. By doing so in a P450 enzyme, we have created an artificial metalloenzyme that catalyzes the insertion of carbenes into C-H bonds with activities and selectivities that rival those of natural enzymes in biosynthetic pathways. Our first studies on this topic were published in Nature and Science and signaled a new approach to create organometallic catalysts with selectivity derived from a protein matrix that can be modified in a high-throughput fashion by laboratory evolution.

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See our publications on artificial metalloenzymes

Combinatorial Catalyst Discovery

We have been developing alternative approaches to the conventional methods for catalyst discovery and development. In particular, we have used fluorescent and colorimetric assays to evaluate catalysts for carbon-carbon and carbon-nitrogen bond forming processes catalyzed by transition metal complexes. With this approach, we discovered the catalysts for hydroamination of substrates with C=C bonds discussed above and for several types of room temperature cross-coupling reactions. Most recently, we have followed an approach to discover new reactions by adding catalysts to mixture of reagents and analyzing for new products by mass spectrometry. In current studies, we are developing an informatics approach to deciphering the products formed from these systems.

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See our publications on high-throughput screening.