Nicolai Lehnert

Research projects that are currently pursued in my group relate to the biological role of nitric oxide, the development of electrocatalysts for nitrite reduction, for biomedical applications, and nitrate reduction, for the mediation of this environmental pollutant, the synthesis and characterization of high-valent metal-oxo complexes of the late transition metals, 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 first realized 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 are relatives of 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 their biomedical relevance, nitric oxide and other NOx species (especially nitrite and nitrate) are also important intermediates 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. Furthermore, these studies allow us to discover new, biologically relevant iron-NO chemistry. Other projects related to the nitrogen cycle focus on the design and synthesis of new electrocatalysts for the reduction of nitrite to NO (for biomedical applications, especially NO delivery on demand) and nitrate to ammonia (for remediation of this critical water pollutant).

High-valent Fe-oxo complexes are key intermediates in many enzymatic processes, where O₂ is activated to functionalize organic substrates. In addition, Mn-oxo complexes are key intermediates in water oxidation, the anodic side of water splitting. Evidence is further mounting that several monocopper oxygenases, including particulate methane monooxygenase (pMMO) and lytic polysaccharide monooxygenase (LPMO), function via corresponding, formally Cu(III)-oxo intermediates. Whereas many Mn-, Fe- and V-oxo complexes have been extensively investigated, much less is known about high-valent late first-row transition metal-oxo complexes (i.e. Co-, Ni- and Cu-O species). A key open question in our understanding of high-valent transition metal-O chemistry is how the metal-oxo versus metal-oxyl character of these high-valent intermediates effects their stability and reactivity. This becomes particularly important as we move across the transition metal series to the late transition metals of groups 9-11, where bond inversion effects become pronounced. We are investigating high-valent late transition metal-oxo complexes using a plethora of spectroscopic methods, low temperature studies, quantum-chemical calculations, and we are evaluating the reactivity of these intermediates.

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 recent work focuses on the engineering of peroxidases as the next generation biocatalysts for carbene-transfer reactions that can function in an aqueous environment. In a complementary approach, we are also inserting other metallocofactors like corroles and porphycenes into Mb and other heme proteins to develop new catalysts and to gain a better understanding of how different tetrapyrrole ligands affect catalyst activity and lifetime.

Awards

• Stanley C. Israel Award for Advancing Diversity in the Chemical Sciences, American Chemical Society, Central Regional Section, 2024
• 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. B. W. Musselman, N. Lehnert, "Bridging and Axial Carbene Binding Modes in Cobalt Corrole Complexes: Effect on Carbene Transfer". Chem. Commun. 2020, 14881-14884
11. 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 
12. 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
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. D. Kass, V. A. Larson, T. Corona, U. Kuhlmann, P. Hildebrandt, T. Lohmiller, E. Bill, N. Lehnert, K. Ray, "Trapping of a phenoxyl radical at a non-haem high-spin iron(II) centre". Nature Chem. 2024, 16, 658-665.
19. V. Sosa Alfaro, H. Palomino, S. Y. Liu, C. Lemuh Njimoh, N. Lehnert, "Combined Experimental and Molecular Dynamics Approach Towards a Rational Design of the YfeX Biocatalyst for Enhanced Carbene Transferase Reactivity". Catal. Sci. Technol. 2024, 14, 5218-5233.

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