# Multi-nuclear Iron Clusters as Biomimics of Nitrogenase Enzyme Metallocofactors

> **NIH NIH F32** · HARVARD UNIVERSITY · 2022 · $67,174

## Abstract

Project Summary/Abstract
Entry of nitrogen into the biosphere is crucial for the development and sustainability of life, as this element is
utilized in the development of proteins, nucleic acids, and other cell constituents. Nature uses nitrogenase
enzymes to mediate the transformation of the bioinactive atmospheric N2 into more reactive nitrogen sources
such as NH3. Ubiquitous to all nitrogenase enzymes are multi-nuclear transition metal cofactors which act as the
active site for N2 binding, reduction, and transformation into its reduced substrates. Despite the foundational role
of the N2 fixation cycle to biology, the detailed mechanism of how nitrogenase enzyme metallocofactors facilitate
N2 fixation is largely uncertain. Synthetic chemists are actively pursuing mechanistic elucidation of the N2 fixation
by nitrogenase metallocofactors by using coordination chemistry to design molecular architectures which can
bind and reduce N2. Significant progress has been made in this regard, especially in terms of the reduction of N2
with mononuclear transition metal compounds, but it is in question whether mononuclear systems provide
accurate models for polynuclear metallocofactor sites. To this end, the use of polynuclear high-spin transition
metal complexes as functional models for nitrogenase metallocofactors have been much less explored. The
research program described herein involves the synthesis, characterization, and reactivity of new all monovalent
[Fe3] molecular architectures which we propose could be functional models to explore the mechanism of the Fe-
Mo cofactor (FeMoco) of nitrogenase. Initially, a new trianionic, hexadentate, ligand scaffold [NPL]3- will be
synthesized which can support three monovalent first-row transition metal ions. The trimetallation of [NPL]3- with
monovalent Fe(I) will be carried out to form the proposed monovalent tri-iron complex, (NPL)Fe3. Single-crystal
X-ray diffraction, SQUID magnetometry, EPR spectroscopy, and cyclic voltammetry will be used to determine
the structure, spin-state, and redox properties of (NPL)Fe3. The reactivity of the new [Fe3] cluster will be evaluated
by reacting (NPL)Fe3 with simple chemical oxidants and nitrogenase substrates (i.e. N2 and CO). Compound
(NPL)Fe3 will be subjected to reactions with oxidative N-group transfer reagents or N2 surrogates to establish the
N-bound intermediates involved on the way to full N2 conversion. The oxidative group transfer reactivity of
(NPL)Fe3 will also be explored using S-, O-, and C- group transfer reagents where the proposed sulfide complex,
[(NPL)Fe3(µ3-S)]-, will be used to model the role of sulfide ligands in the N2 fixation of FeMoco. We will synthesize
mono- and poly-hydride complexes, (NPL)Fe3H1-3, which could act as synthetic models for the E4 state of FeMoco,
which is the intermediate proposed to bind N2. The reactivity of the hydride complexes will be explored with
nitrogenase substrates such as N2, CO, and acetylene and the formation of t...

## Key facts

- **NIH application ID:** 10536804
- **Project number:** 1F32GM145088-01A1
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Trevor Latendresse
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,174
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536804

## Citation

> US National Institutes of Health, RePORTER application 10536804, Multi-nuclear Iron Clusters as Biomimics of Nitrogenase Enzyme Metallocofactors (1F32GM145088-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10536804. Licensed CC0.

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