Nicolai Lehnert

Research projects that are currently pursued in my group relate to the biological role of nitric oxide (bioinorganic chemistry and biophysics), the development of heterogeneous catalysts for the generation of the sustainable energy carrier hydrogen (solar energy conversion and catalysis), and enzyme engineering for the development of artificial enzymes that catalyze organometallic reactions (biocatalysis and bioorganometallic chemistry).

Historically, nitric oxide (nitrogen monoxide, NO) has always been viewed as an environmental pollutant, generated from the burning of fossil fuels, due to its toxic and corrosive properties. This general view of NO as an environmental pollutant and toxin changed dramatically in the 1980’s when it was realized first that humans are capable of NO biosynthesis for the purpose of immune defense and signaling. In humans, NO is generated by the nitric oxide synthase (NOS) isozymes, which belong to the cytochrome P450 family. For the purpose of signaling, NO is produced by endothelial (e-) NOS in the endothelial cells that line the inner surface of arteries (blood pressure control), or by neuronal (n-) NOS in the brain for nerve signal transduction. The important cardiovascular and neuronal regulation by NO is then mediated by soluble guanylate cyclase (sGC), which serves as the general biological NO sensor/receptor protein in mammals. NO is also produced in macrophages by inducible (i ) NOS for immune defense. 

Besides it biomedical relevance, nitric oxide is also an important metabolite in the nitrogen cycle. The nitrogen cycle is one of the most important biogeochemical cycles on Earth, because nitrogen is a key nutrient for all life forms, from bacteria to plants all the way to humans. Although the carbon cycle receives more attention in news media, it is actually the nitrogen cycle that has been altered the most by human activities. The reason for this is that nitrogen is a major component of fertilizer in agriculture, and hence plays a key role in human food production to feed an ever increasing global population. One important process in the nitrogen cycle is denitrification, the stepwise reduction of nitrate to dinitrogen, which is mediated by soil-born bacteria and fungi as an anaerobic form of respiration. A key step in denitrification is the reduction of NO to N₂O by NO reductase (NOR) enzymes, generating large quantities of the important greenhouse gas and ozone-depleting agent N₂O that are subsequently released to a large extend into the atmosphere. We are therefore very interesting in the molecular mechanisms of N₂O production by bacterial (NorBC) and fungal (Cyt P450nor) NORs, which contain heme/non-heme and {heme-thiolate} active sites, respectively. Besides these respiratory NORs that are found in the nitrogen cycle, another class of scavenging NORs was more recently discovered in certain pathogenic bacteria. These microbes use flavodiiron NO reductase (FNOR) enzymes, which contain non-heme diiron active sites, as a protection against exogenous NO, produced by our immune system as a response to bacterial infection. Hence, these enzymes play important roles in bacterial pathogenesis, and constitute potential drug targets. Despite these environmental and medical impacts of NORs, the mechanisms of these enzymes are not well understood. In order to elucidate the molecular mechanisms of NORs, we are probing the reactivity of both heme and non-heme iron model complexes in different oxidation states with NO. Using a plethora of spectroscopic methods, we are studying the detailed electronic structures of these complexes and relate them back to their biologically relevant reactivity. In this way, we are mapping out the chemical reactivity landscape of heme and non-heme iron centers with NO. In this way, mechanistic proposals for NORs can be tested, and new, biologically relevant iron-NO chemistry can be discovered.

Political leaders around the world are calling to move from the total reliance on fossil fuel to an energy economy based on alternatives to petroleum. In this respect, hydrogen is the ultimate clean fuel with the highest achievable energy density, and its use as primary energy carrier is therefore desirable, in particular in combination with solar energy. In addition, hydrogen is an important chemical feedstock for ammonia (fertilizer) production and oil refining, and 40 – 50 million metric tons of H₂ are annually produced for this purpose. However, ~95% of the current hydrogen production stems from natural gas reforming, and hence, from fossil fuels. Engineering of solar-powered catalyst systems for hydrogen production is therefore of critical importance not only to the advancement of the global energy economy, but also to generate cheap hydrogen as a chemical feedstock. Heterogeneous catalyst manifolds that are most promising for photocatalysis are those that boast versatile and cheap, stable components. Our previous work has generated heterogeneous H₂ production systems based on inexpensive (molecular) Co-bis(benzenedithiolate) H₂ production catalysts, functional in aqueous solutions (the medium of choice for practi­cal applications) with high O₂ stability, af­ford­ed straight-forwardly by ad­sorbing these compounds on graphitic surfaces (via pi-stacking inter­ac­tions). We are currently working on applying this strategy to gallium phosphide (GaP) and other 3-5 semiconductors.

Synthetic organic compounds are important for the production of plastics, drugs, food preservatives, and many other applications. Many important C-C and C-H bond-forming reactions that are used to build these compounds are catalyzed by small-molecule transition metal complexes. Despite the high turnover numbers and rates that have been achieved for these small molecule catalysts, significant improvements are needed for the next generation of “greener” organometallic catalysts. In biology, metalloenzymes catalyze reactions in aqueous media with high stereo- and enantioselectivity and high turnover numbers. Small, readily obtained proteins that can be engineered and mutated in a straight-forward way may allow for a new category of stereoselective, water-based organometallic catalysts. Heme proteins, such as the O₂ storage protein myoglobin (Mb), are particularly interesting to study for these applications as they often allow for easy removal of the native heme and reconstitution of the apo-protein with other porphyrins and planar molecules. Through these techniques, increased activity or new reactivity (compared to the natural function of the protein) in the same protein scaffold can be achieved. Our approach is to combine Ru, Rh and Ir porphyrins with modified Mb to prepare robust, stereoselective carbene-transfer catalysts that can function in an aqueous environment. For example, we have prepared Ruthenium mesoporphyrin IX (RuMpIX) and reconstituted this porphyrin into Mb and several His64 Mb mutants in order to increase the size and hydrophobicity of the active site and allow for more facile substrate access. With our most active Mb mutant (H64A) reconstituted with RuMpIX, we were able to catalyze the N-H insertion of aniline with ethyl diazoacetate with 52% yield, and the cyclopropanation of vinyl anisole with the same carbene source in 36% yield. In a complementary approach, we are also inserting other metallocofactors like corroles and porphycenes into Mb to develop new catalysts and to gain a better understanding of how different tetrapyrrole ligands affect catalyst activity and lifetime.

Awards

• Carol Hollenshead Inspire Award for Excellence in Promoting Equity & Social Change, University of Michigan, 2021
• Harold R. Johnson Diversity Service Award, University of Michigan, 2018
• LS&A John Dewey Teaching Award, 2016
• LS&A Award for Outstanding Contributions to Undergraduate Education, 2014
• 3M Nontenured Faculty Grant, 2011
• NSF Career Award, 2009
• Japan Society for the Promotion of Science Invitation Fellowship, 2008
• Dow Corning Assistant Professor of Chemistry, 2007

Representative Publications

1. C. J. White, A. L. Speelman, C. Kupper, S. Demeshko, F. Meyer, J. P. Shanahan, E. E. Alp, M. Hu, J. Zhao, N. Lehnert, "The Semireduced Mechanism for Nitric Oxide Reduction by Non-Heme Diiron Complexes that Model Flavodiiron NO Reductases". J. Am. Chem. Soc. 2018, 140, 2562-2574
2. A. L. Speelman, C. J. White, B. Zhang, E. E. Alp, J. Zhao, M. Hu, C. Krebs, J. Penner-Hahn, N. Lehnert, "Non-Heme High-Spin {FeNO}^6-8 Complexes: One Ligand Platform Can Do It All". J. Am. Chem. Soc. 2018, 140, 11341-11359
3. N. Lehnert, H. T. Dong, J. B. Harland, A. P. Hunt, C. J. White, "Reversing Nitrogen Fixation". Nat. Rev. Chem. 2018, 2, 278-289, DOI: 10.1038/s41570-018-0041-7
4. H. T. Dong, C. J. White, B. Zhang, C. Krebs, N. Lehnert, "Non-Heme Diiron Model Complexes Can Mediate Direct NO Reduction: Mechanistic Insight into Flavodiiron NO Reductases". J. Am. Chem. Soc. 2018, 140, 13429-13440
5. A. B. McQuarters, E. J. Blasei, E. E. Alp, J. Zhao. M. Hu, C. Krebs, N. Lehnert, "Synthetic Model Complex of the Key Intermediate in Cytochrome P450 Nitric Oxide Reductase (P450nor)". Inorg. Chem. 2019, 58, 1398-1413
6. A. P. Hunt, N. Lehnert, "The Thiolate Trans Effect in Heme {FeNO}⁶ Complexes and Beyond: Insight into the Nature of the Push Effect". Inorg. Chem. 2019, 58, 11317-11332 (selected for Journal cover: Issue 17, Sept. 02, 2019)
7. A. P. Hunt, A. E. Batka, M. Hosseinzadeh, J. Gregory, H. Haque, H. Ren, M. E. Meyerhoff, N. Lehnert, "Nitric Oxide Generation On Demand for Biomedical Applications via Electrocatalytic Nitrite Reduction by Copper BMPA- and BEPA-Carboxylate Complexes". ACS Catal. 2019, 6, 7746-7758
8. H. T. Dong, A. L. Speelman, C. E. Kozemchak, D. Sil, C. Krebs, N. Lehnert, "The Fe₂(NO)₂ Diamond Core: A Unique Structural Motif in Non-Heme Iron-NO Chemistry". Angew. Chem. Int. Ed. 2019, 58, 17695-17699
9. V. A. Larson, B. Battistella, K. Ray, N. Lehnert, W. Nam, "Iron and manganese oxo complexes, oxo wall and beyond". Nat. Rev. Chem. 2020, 4, 404-419
10. H. T. Dong, M. J. Chalkley, P. H. Oyala, J. Zhao, E. E. Alp, M. Y. Hu, J. C. Peters, N. Lehnert, "Exploring the Limits of Dative Boratrane Bonding: Iron as a Strong Lewis Base in Low-Valent Non-Heme Iron-Nitrosyl Complexes". Inorg. Chem. 2020, 59, 14967-14982
11. B. W. Musselman, N. Lehnert, "Bridging and Axial Carbene Binding Modes in Cobalt Corrole Complexes: Effect on Carbene Transfer". Chem. Commun. 2020, 14881-14884
12. J. Yang, H. T. Dong, M. S. Seo, V. A. Larson, Y.-M. Lee, J. Shearer, N. Lehnert, W. Nam, "The Oxo Wall Remains Intact: A Tetrahedrally-Distorted Co(IV)-Oxo Complex". J. Am. Chem. Soc. 2021, 143, 16943-16959 
13. N. Lehnert, E. Kim, H. T. Dong, J. B. Harland, A. P. Hunt, E. C. Manickas, K. M. Oakley, J. Pham, G. C. Reed, V. Sosa Alfaro,"The Biologically Relevant Coordination Chemistry of Iron and Nitric Oxide: Electronic Structure and Reactivity". Chem. Rev. 2021, 121, 14682-14905
14. C. J. White, M. O. Lengel, A. J. Bracken, J. W. Kampf, A. L. Speelman, E. E. Alp, M. Hu, J. Zhao, N. Lehnert, "Distortion of the [FeNO]₂ Core in Flavodiiron Nitric Oxide Reductase Models Inhibits N-N Bond Formation and Promotes Formation of Unusual Dinitrosyl Iron Complexes: Implications for Catalysis and Reactivity". J. Am. Chem. Soc. 2022, 144, 3804-3820.
15. V. Sosa Alfaro, S. O. Waheed, H. Palomino, A. Knorrscheidt, M. Weissenborn, C. Z. Christov, N. Lehnert, "YfeX - A New Platform for Carbene Transferase Development with High Intrinsic Reactivity". Chem. Eur. J. 2022, 28, e202201474.
16. H. T. Dong, S. Camarena, D. Sil, M. O. Lengel, J. Zhao, M. Y. Hu, E. E. Alp, C. Krebs, N. Lehnert, "What is the Right Level of Activation of a High-Spin {FeNO}7 Complex to Enable Direct N-N Coupling? Mechanistic Insight into Flavodiiron Nitric Oxide Reductases". J. Am. Chem. Soc. 2022, 144, 16395-16409.
17. D. G. Karmalkar, V. A. Larson, D. D. Malik, Y.-M. Lee, M. S. Seo, J. Kim, D. Vasiliauskas, J. Shearer, N. Lehnert, W. Nam, "Preparation and Characterization of a Formally Ni^IV-Oxo Complex with a Triplet Ground State and Application in Oxidation Reactions". J. Am. Chem. Soc. 2022, 144, 22698-22712.
18. E. C. Manickas, A. B. LaLonde, M. Y. Hu, E. E. Alp, N. Lehnert, "Stabilization of a Heme-HNO Model Complex Using a Bulky Bis-Picket Fence Porphyrin and Reactivity Studies with NO". J. Am. Chem. Soc. 2023, 145, 23014-23026.
19. V. A. Larson, N. Lehnert, "Covalent Attachment of Cobalt Bis(Benzylaminedithiolate) to Reduced Graphene Oxide as a Thin Film Electrocatalyst for Hydrogen Production with Remarkable Dioxygen Tolerance". ACS Catal. 2024, 14, 192-210.

Research Areas(s)

• Bioinorganic Chemistry
  Biophysical Chemistry
  Energy Science
  Inorganic Chemistry
  Bioorganometallic Chemistry
  Sustainable Chemistry
  Physical Inorganic Chemistry & Spectroscopy
  Nitric oxide
  Heme enzymes and model complexes