The Biologically Relevant Coordination Chemistry of Iron and Nitric Oxide: Electronic Structure and Reactivity.

Nitric oxide (NO) is an important signaling molecule that is involved in a wide range of physiological and pathological events in biology. Metal coordination chemistry, especially with iron, is at the heart of many biological transformations involving NO. A series of heme proteins, nitric oxide synthases (NOS), soluble guanylate cyclase (sGC), and nitrophorins, are responsible for the biosynthesis, sensing, and transport of NO. Alternatively, NO can be generated from nitrite by heme- and copper-containing nitrite reductases (NIRs). The NO-bearing small molecules such as nitrosothiols and dinitrosyl iron complexes (DNICs) can serve as an alternative vehicle for NO storage and transport. Once NO is formed, the rich reaction chemistry of NO leads to a wide variety of biological activities including reduction of NO by heme or non-heme iron-containing NO reductases and protein post-translational modifications by DNICs. Much of our understanding of the reactivity of metal sites in biology with NO and the mechanisms of these transformations has come from the elucidation of the geometric and electronic structures and chemical reactivity of synthetic model systems, in synergy with biochemical and biophysical studies on the relevant proteins themselves. This review focuses on recent advancements from studies on proteins and model complexes that not only have improved our understanding of the biological roles of NO but also have provided foundations for biomedical research and for bio-inspired catalyst design in energy science.

Passive acoustic monitoring using smartphones reveals an alarming gibbon decline in a protected area in the central Annamite Mountains, Vietnam.

Monitoring populations is critical for understanding how they respond to anthropogenic disturbance and for management of protected areas. The use of passive acoustic monitoring can improve monitoring efforts as it allows for collection of data on vocal animals at spatial and temporal scales that are difficult using only human observers. In this study, we used a multiseason occupancy model to monitor occurrence, apparent extinction, and colonization probabilities of a northern yellow-cheeked gibbon, Nomascus annamensis population with acoustic data collected from mobile smartphones in Dakrong Nature Reserve, Vietnam. Forty-five sites were randomly selected for repeated surveys in 2019 and 2022. At each site, a mobile smartphone was attached to a tree and recorded sounds for 4.2 days and 3.89 days on average, in 2019 and 2022, respectively. We manually annotated spectrograms for the presence of gibbon calls, and we detected gibbons at 24 and 12 recording posts in 2019 and 2022, respectively. Estimated local apparent extinction from occupancy models was high with 67% of occupied sites in 2019 becoming unoccupied in 2022. Apparent colonization was low with ~25% of unoccupied sites in 2019 becoming occupied in 2022. As a result, the apparent occurrence probability declined from 0.58 in 2019 to 0.30 in 2022. If the absence of calls indicates that cells are unoccupied this would mean an alarming decline of the gibbon population in the nature reserve. We suggest that in the areas with high hunting pressure, monitoring intervals should be shortened to at least yearly. In addition, urgent actions, such as patrolling, or gun confiscation, should be implemented to conserve the gibbon populations in Dakrong Nature Reserve and other protected areas with the same management context.

What Is the Right Level of Activation of a High-Spin {FeNO}7 Complex to Enable Direct N-N Coupling? Mechanistic Insight into Flavodiiron NO Reductases.

Flavodiiron nitric oxide reductases (FNORs), found in pathogenic bacteria, are capable of reducing nitric oxide (NO) to nitrous oxide (N2O) to detoxify NO released by the human immune system. Previously, we reported the first FNOR model system that mediates direct NO reduction (Dong, H. T.; J. Am. Chem. Soc. 2018, 140, 13429-13440), but no intermediate of the reaction could be characterized. Here, we present a new set of model complexes that, depending on the ligand substitution, can either mediate direct NO reduction or stabilize a highly activated high-spin (hs) {FeNO}7 complex, the first intermediate of the reaction. The precursors, [{FeII(MPA-(RPhO)2)}2] (1, R = H and 2, R = tBu, Me), were prepared first and fully characterized. Complex 1 (without steric protection) directly reduces NO to N2O almost quantitatively, which constitutes only the second example of this reaction in model systems. Contrarily, the reaction of sterically protected 2 with NO forms the stable mononitrosyl complex 3, which shows one of the lowest N-O stretching frequencies (1689 cm-1) observed so far for a mononuclear hs-{FeNO}7 complex. This study confirms that an N-O stretch ≤1700 cm-1 represents the appropriate level of activation of the FeNO unit to enable direct NO reduction. The higher activation level of these hs-{FeNO}7 complexes required for NO reduction compared to those formed in FNORs emphasizes the importance of hydrogen bonding residues in the active sites of FNORs to activate the bound NO ligands for direct N-N coupling and N2O formation. The implications of these results for FNORs are further discussed.

The Oxo-Wall Remains Intact: A Tetrahedrally Distorted Co(IV)-Oxo Complex.

In this paper, we report the preparation, spectroscopic and theoretical characterization, and reactivity studies of a Co(IV)-oxo complex bearing an N4-macrocyclic coligand, 12-TBC (12-TBC = 1,4,7,10-tetrabenzyl-1,4,7,10-tetraazacyclododecane). On the basis of the ligand and the structure of the Co(II) precursor, [CoII(12-TBC)(CF3SO3)2], one would assume that this species corresponds to a tetragonal Co(IV)-oxo complex, but the spectroscopic data do not support this notion. Co K-edge XAS data show that the treatment of the Co(II) precursor with iodosylbenzene (PhIO) as an oxidant at -40 °C in the presence of a proton source leads to a distinct shift in the Co K-edge, in agreement with the formation of a Co(IV) intermediate. The presence of the oxo group is further demonstrated by resonance Raman (rRaman) spectroscopy. Interestingly, the EPR data of this complex show a high degree of rhombicity, indicating structural distortion. This is further supported by the EXAFS data. Using DFT calculations, a structural model is developed for this complex with a ligand-protonated structure that features a Co═O···HN hydrogen bond and a four-coordinate Co center in a seesaw-shaped coordination geometry. Magnetic circular dichroism (MCD) spectroscopy further supports this finding. The hydrogen bond leads to an interesting polarization of the Co-oxo π-bonds, where one O(p) lone-pair is stabilized and leads to a regular Co(d) interaction, whereas the other π-bond shows an inverted ligand field. The reactivity of this complex in hydrogen atom and oxygen atom transfer reactions is discussed as well.

Exploring the Limits of Dative Boratrane Bonding: Iron as a Strong Lewis Base in Low-Valent Non-Heme Iron-Nitrosyl Complexes.

We previously reported the synthesis and preliminary characterization of a unique series of low-spin (ls) {FeNO}8-10 complexes supported by an ambiphilic trisphosphineborane ligand, [Fe(TPB)(NO)]+/0/-. Herein, we use advanced spectroscopic techniques and density functional theory (DFT) calculations to extract detailed information as to how the bonding changes across the redox series. We find that, in spite of the highly reduced nature of these complexes, they feature an NO+ ligand throughout with strong Fe-NO π-backbonding and essentially closed-shell electronic structures of their FeNO units. This is enabled by an Fe-B interaction that is present throughout the series. In particular, the most reduced [Fe(TPB)(NO)]- complex, an example of a ls-{FeNO}10 species, features a true reverse dative Fe → B bond where the Fe center acts as a strong Lewis-base. Hence, this complex is in fact electronically similar to the ls-{FeNO}8 system, with two additional electrons "stored" on site in an Fe-B single bond. The outlier in this series is the ls-{FeNO}9 complex, due to spin polarization (quantified by pulse EPR spectroscopy), which weakens the Fe-NO bond. These data are further contextualized by comparison with a related N2 complex, [Fe(TPB)(N2)]-, which is a key intermediate in Fe(TPB)-catalyzed N2 fixation. Our present study finds that the Fe → B interaction is key for storing the electrons needed to achieve a highly reduced state in these systems, and highlights the pitfalls associated with using geometric parameters to try to evaluate reverse dative interactions, a finding with broader implications to the study of transition metal complexes with boratrane and related ligands.

Electronic Structures of an [Fe(NNR2)]+/0/- Redox Series: Ligand Noninnocence and Implications for Catalytic Nitrogen Fixation.

The intermediacy of metal-NNH2 complexes has been implicated in the catalytic cycles of several examples of transition-metal-mediated nitrogen (N2) fixation. In this context, we have shown that triphosphine-supported Fe(N2) complexes can be reduced and protonated at the distal N atom to yield Fe(NNH2) complexes over an array of charge and oxidation states. Upon exposure to further H+/e- equivalents, these species either continue down a distal-type Chatt pathway to yield a terminal iron(IV) nitride or instead follow a distal-to-alternating pathway resulting in N-H bond formation at the proximal N atom. To understand the origin of this divergent selectivity, herein we synthesize and elucidate the electronic structures of a redox series of Fe(NNMe2) complexes, which serve as spectroscopic models for their reactive protonated congeners. Using a combination of spectroscopies, in concert with density functional theory and correlated ab initio calculations, we evidence one-electron redox noninnocence of the "NNMe2" moiety. Specifically, although two closed-shell configurations of the "NNR2" ligand have been commonly considered in the literature-isodiazene and hydrazido(2-)-we provide evidence suggesting that, in their reduced forms, the present iron complexes are best viewed in terms of an open-shell [NNR2]•- ligand coupled antiferromagnetically to the Fe center. This one-electron redox noninnocence resembles that of the classically noninnocent ligand NO and may have mechanistic implications for selectivity in N2 fixation activity.

Stable Ferrous Mononitroxyl {FeNO}8 Complex with a Hindered Hydrotris(pyrazolyl)borate Coligand: Structure, Spectroscopic Characterization, and Reactivity Toward NO and O2.

The iron(II)-nitroxyl complex [Fe(NO)(L3)] (1) (with L3- = a hindered hydrotris(pyrazolyl)borate ligand), a high-spin (hs)-{FeNO}8 complex in the Enemark-Feltham notation, is surprisingly stable and is the first of its kind that could be structurally characterized. We further studied this compound using a variety of spectroscopic methods. These results indicate a hs iron(II) center with a bound 3NO- ligand where the spins are antiferromagnetic coupled ( St = 1). Vibrational data show that this complex has a very strong Fe-NO bond. DFT calculations support this result and link it to very strong π-donation from the 3NO- ligand to the iron(II) center. Furthermore, a very unusual equilibrium between the hs-{FeNO}8 complex and a dinitrosyl iron complex (DNIC) of {Fe(NO)2}9 type is observed. The O2 reactivity of the complex is finally reported.

The Fe2 (NO)2 Diamond Core: A Unique Structural Motif In Non-Heme Iron-NO Chemistry.

Non-heme high-spin (hs) {FeNO}8 complexes have been proposed as important intermediates towards N2 O formation in flavodiiron NO reductases (FNORs). Many hs-{FeNO}8 complexes disproportionate by forming dinitrosyl iron complexes (DNICs), but the mechanism of this reaction is not understood. While investigating this process, we isolated a new type of non-heme iron nitrosyl complex that is stabilized by an unexpected spin-state change. Upon reduction of the hs-{FeNO}7 complex, [Fe(TPA)(NO)(OTf)](OTf) (1), the N-O stretching band vanishes, but no sign of DNIC or N2 O formation is observed. Instead, the dimer, [Fe2 (TPA)2 (NO)2 ](OTf)2 (2) could be isolated and structurally characterized. We propose that 2 is formed from dimerization of the hs-{FeNO}8 intermediate, followed by a spin state change of the iron centers to low-spin (ls), and speculate that 2 models intermediates in hs-{FeNO}8 complexes that precede the disproportionation reaction.

Non-Heme Diiron Model Complexes Can Mediate Direct NO Reduction: Mechanistic Insight into Flavodiiron NO Reductases.

Flavodiiron nitric oxide reductases (FNORs), a common enzyme family found in various types of pathogenic bacteria, are capable of reducing nitric oxide (NO) to nitrous oxide (N2O) as a protective detoxification mechanism. Utilization of FNORs in pathogenic bacteria helps them survive and proliferate in the human body, thus causing chronic infections. In this paper, we present a new diiron model complex, [Fe2((Py2PhO2)MP)(OPr)2](OTf), with bridging propionate ligands (OPr-) that is capable of directly reducing NO to N2O in quantitative yield without the need to (super)reduce the complex. We first prepared the diferric precursor and characterized it by UV-vis, IR, NMR and Mössbauer spectroscopies, cyclic voltammetry, and mass spectrometry. This complex can then conveniently be reduced to the diferrous complex using CoCp2. Even though this diferrous complex is highly reactive, we have successfully isolated and characterized this species using X-ray crystallography and various spectroscopic techniques. Most importantly, upon reacting this diferrous complex with NO gas, we observe quantitative formation of N2O via IR gas headspace analysis, the first demonstration of direct NO reduction by a non-heme diiron model complex. This finding directly supports recent mechanistic proposals for FNORs.

A distance sampling approach to estimate density and abundance of gibbon groups.

All 18 species of gibbons are considered threatened with extinction and listed on the IUCN Red List of Threatened Species. Because gibbons (Hylobatidae) are one of the most threatened primate families, a great need exists to determine and monitor their status effectively. To meet this need, we employed distance sampling methods to estimate the density and number of gibbon groups. We focused on southern yellow-cheeked crested gibbon in the Nam Cat Tien sector of Cat Tien National Park, Vietnam, from July to October, 2016. We used an auditory point count method at 48 listening posts to detect gibbon groups. We estimated our detection probability of calling groups of gibbons within 1,200 m of a listening post was 0.63 (95% CI: 0.54-0.74). In addition, we estimated the daily calling probability of a gibbon group to be 0.46 (95% CI: 0.33-0.59) and interpreted this as the probability that a group was available to be detected. We adjusted our group density and abundance estimates by both detection and availability probabilities. Ultimately we estimated 325 (95% CI: 232-455) gibbon groups in the Nam Cat Tien sector. Our results suggest that Cat Tien National Park contains one of the largest populations of southern yellow-cheeked crested gibbon in Vietnam. Our methods are one way of avoiding underestimation of gibbon group density and abundance by incorporating uncertainty in gibbon group availability and detection.

Exploring second coordination sphere effects in flavodiiron nitric oxide reductase model complexes.

Flavodiiron nitric oxide reductases (FNORs) equip pathogens with resistance to nitric oxide (NO), an important immune defense agent in mammals, allowing these pathogens to proliferate in the human body, potentially causing chronic infections. Understanding the mechanism of how FNORs mediate the reduction of NO contributes to the greater goal of developing new therapeutic approaches against drug-resistant strains. Recent density functional theory calculations suggest that a second coordination sphere (SCS) tyrosine residue provides a hydrogen bond that is critical for the reduction of NO to N2O at the active site of FNORs [J. Lu, B. Bi, W. Lai and H. Chen, Origin of Nitric Oxide Reduction Activity in Flavo-Diiron NO Reductase: Key Roles of the Second Coordination Sphere, Angew. Chem., Int. Ed., 2019, 58, 3795-3799]. Specifically, this H-bond stabilizes the hyponitrite intermediate and reduces the energetic barrier for the N-N coupling step. At the same time, the role of the Fe⋯Fe distance and its effect on the N-N coupling step has not been fully investigated. In this study, we equipped the H[BPMP] (= 2,6-bis[[bis(2-pyridylmethyl)amino]methyl]-4-methylphenol) ligand with SCS amide groups and investigated the corresponding diiron complexes with 0-2 bridging acetate ligands. These amide groups can form hydrogen bonds with the bridging acetate ligand(s) and potentially the coordinated NO groups in these model complexes. At the same time, by changing the number of bridging acetate ligands, we can systematically vary the Fe⋯Fe distance. The reactivity of these complexes with NO was then investigated, and the formation of stable iron(II)-NO complexes was observed. Upon one-electron reduction, these NO complexes form Dinitrosyl Iron Complexes (DNICs), which were further characterized using IR and EPR spectroscopy.

Synthesis and characterization of a model complex for flavodiiron NO reductases that stabilizes a diiron mononitrosyl complex.

Flavodiiron NO reductases (FNORs) are important enzymes in microbial pathogenesis, as they equip microbes with resistance to the human immune defense agent nitric oxide (NO). DFT calculations predict that a network of second coordination sphere (SCS) hydrogen bonds is critical for the key NN coupling step in the NO reduction reaction catalyzed by FNORs. In this study, we report the synthesis of a model complex of FNORs with pendant hydrogen bond donors. For this purpose, the ligand H[BPMP] (= 2,6-bis[[bis(2-pyridylmethyl)amino]methyl]-4-methylphenol) was modified with two amide groups in the SCS. Reaction of the precursor complex [Fe2(BPMP(NHCOtBu)2)(OAc)](OTf)2 (1) (OTf- = triflate anion) with NO in the presence of base led to the surprising isolation of a diiron mononitrosyl complex, [Fe2(BPMP(NHCOtBu)(NCOtBu))(OAc)(NO)](OTf) (2) and a triiron decomposition product, [Fe3(BPMP(NHCOtBu)2)(OAc)2(µ-O)2(ONO)](OTf) (3), which were both structurally characterized. Complex 2 models the corresponding mononitrosyl adduct in FNORs. This result points towards a strategy that can be used to stabilize mononitrosyl diiron complexes, using the SCS.

A cobalt-nitrosyl complex with a hindered hydrotris(pyrazolyl)borate coligand: detailed electronic structure, and reactivity towards dioxygen.

The cobalt-nitrosyl complex [Co(NO)(L3)] is supported by a highly hindered tridentate nitrogen ligand, hydrotris(3-tertiary butyl-5-isopropyl-1-pyrazolyl)borate (denoted as L3-), and shows a linear Co-N-O unit. This complex was prepared by the reaction of the potassium salt of L3- with the cobalt-nitrosyl precursor [Co(NO)2(tmeda)](BPh4) (tmeda = N,N,N,'N'-tetramethylethylenediamine). The obtained cobalt-nitrosyl complex as well as the corresponding products from the reaction with dioxygen, [Co(η2-O2N)(L3)] and [Co(η2-O2NO)(L3)], were characterised by X-ray crystallography and a number of spectroscopic methods including IR/far-IR, UV-Vis, and NMR spectroscopy. We also performed MCD measurements and DFT calculations to further elucidate the electronic structure of [Co(NO)(L3)] and the optical properties of the complex. The MCD spectra reveal two NO-to-Co charge-transfer transitions with strong excited state displacements that give rise to vibrational progressions in the MCD spectra, indicative of a very covalent Co-NO bond. These results provide new insight into the properties of the Co-NO bond and the electron distribution in the complex, which is best described as [CoII(NO-)(L3)].