Fu-Te Tsai

Relative Binding Affinity of Thiolate, Imidazolate, Phenoxide, and Nitrite Toward the {Fe(NO)2} Motif of Dinitrosyl Iron Complexes (DNICs): The Characteristic Pre-Edge Energy of {Fe(NO)2}9 DNICs

The synthesis, characterization, and transformation of the anionic {Fe(NO)(2)}(9) dinitrosyl iron complexes (DNICs) [(NO)(2)Fe(ONO)(2)](-) (1), [(NO)(2)Fe(OPh)(2)](-) (2), [(NO)(2)Fe(OPh)(C(3)H(3)N(2))](-) (3) (C(3)H(3)N(2) = imidazolate), [(NO)(2)Fe(OPh)(-SC(4)H(3)S)](-) (4), [(NO)(2)Fe(p-OPhF)(2)](-) (5), and [(NO)(2)Fe(SPh)(ONO)](-) (6) were investigated. The binding affinity of ligands ([SPh](-), [-SC(4)H(3)S](-), [C(3)H(3)N(2)](-), [OPh](-), and [NO(2)](-)) toward the {Fe(NO)(2)}(9) motif follows the ligand-displacement series [SPh](-) approximately [-SC(4)H(3)S](-) > [C(3)H(3)N(2)](-) > [OPh](-) > [NO(2)](-). The findings, the pre-edge energy derived from the 1s --> 3d transition in a distorted T(d) environment of the Fe center falling within the range of 7113.4-7113.8 eV for the anionic {Fe(NO)(2)}(9) DNICs, implicate that the iron metal center of DNICs is tailored to minimize the electronic changes accompanying changes in coordinated ligands. Our results bridging the ligand-substitution reaction study and X-ray absorption spectroscopy study of the electronic richness of the {Fe(NO)(2)}(9) core may point the way to understanding the reasons for natures choice of combinations of cysteine, histidine, and tyrosine in protein-bound DNICs and rationalize that most DNICs characterized/proposed nowadays are bound to the proteins almost through the thiolate groups of cysteinate/glutathione side chains in biological systems.

Roles of the Distinct Electronic Structures of the {Fe(NO)2}9 and {Fe(NO)2}10 Dinitrosyliron Complexes in Modulating Nitrite Binding Modes and Nitrite Activation Pathways

Nitrosylation of [PPN](2)[(ONO)(2)Fe(eta(2)-ONO)(2)] [1; PPN = bis(triphenylphosphoranylidene)ammonium] yields the nitrite-containing {Fe(NO)}(7) mononitrosyliron complex (MNIC) [PPN](2)[(NO)Fe(ONO)(3)(eta(2)-ONO)] (2). At 4 K, complex 2 exhibits an S = (3)/(2) axial EPR spectrum with principal g values of g( perpendicular) = 3.971 and g( parallel) = 2.000, suggestive of the {Fe(III)(NO(-))}(7) electronic structure. Addition of 1 equiv of PPh(3) to complex 2 triggers O-atom transfer of the chelating nitrito ligand under mild conditions to yield the {Fe(NO)(2)}(9) dinitrosyliron complex (DNIC) [PPN][(ONO)(2)Fe(NO)(2)] (3). These results demonstrate that both electronic structure [{Fe(III)(NO(-))}(7), S = (3)/(2)] and redox-active ligands ([RS](-) for [(RS)(3)Fe(NO)](-) and [NO(-)] for complex 2) are required for the transformation of {Fe(NO)}(7) MNICs into {Fe(NO)(2)}(9) DNICs. In comparison with the PPh(3)-triggered O-atom abstraction of the chelating nitrito ligand of the {Fe(NO)(2)}(9) DNIC [(1-MeIm)(2)(eta(2)-ONO)Fe(NO)(2)] (5; 1-MeIm = 1-methylimidazole) to generate the {Fe(NO)(2)}(10) DNIC [(1-MeIm)(PPh(3))Fe(NO)(2)] (6), glacial acetic acid protonation of the N-bound nitro ligand in the {Fe(NO)(2)}(10) DNIC [PPN][(eta(1)-NO(2))(PPh(3))Fe(NO)(2)] (7) produced the {Fe(NO)(2)}(9) DNIC [PPN][(OAc)(2)Fe(NO)(2)] (8), nitric oxide, and H(2)O. These results demonstrate that the distinct electronic structures of {Fe(NO)(2)}(9/10) motifs [{Fe(NO)(2)}(9) vs {Fe(NO)(2)}(10)] play crucial roles in modulating nitrite binding modes (O-bound chelating/monodentate nitrito for {Fe(NO)(2)}(9) DNICs vs N-bound nitro as a pi acceptor for {Fe(NO)(2)}(10) DNICs) and regulating nitrite activation pathways (O-atom abstraction by PPh(3) leading to the intermediate with a nitroxyl-coordinated ligand vs protonation accompanied by dehydration leading to the intermediate with a nitrosonium-coordinated ligand). That is, the redox shuttling between the {Fe(NO)(2)}(9) and {Fe(NO)(2)}(10) DNICs modulates the nitrite binding modes and then triggers nitrite activation to generate nitric oxide.

Dinitrosyl Iron Complexes (DNICs) Bearing O-Bound Nitrito Ligand: Reversible Transformation between the Six-Coordinate {Fe(NO)2}9 [(1-MeIm)2(η2-ONO)Fe(NO)2] (g = 2.013) and Four-Coordinate {Fe(NO)2}9 [(1-MeIm)(ONO)Fe(NO)2] (g = 2.03)

In contrast to the four-coordinate tetrahedral {Fe(NO)2}9 DNICs with an EPR g value of 2.03, the newly synthesized nonclassical six-coordinate {Fe(NO)2}9 DNIC [(1-MeIm)2(eta(2)-ONO)Fe(NO)2] (1-MeIm = 1-methylimidazole) (1) displays an EPR signal g = 2.013. The temperature-dependent reversible transformation occurs between the six-coordinate chelating nitrito {Fe(NO)2}9 DNIC 1 and the four-coordinate monodentate nitrito {Fe(NO)2}9 DNIC [(1-MeIm)(ONO)Fe(NO)2] (2-MeIm). The chelating nitrito of DNIC 1, triggered by PPh3, undergoes O-atom transfer to yield O=PPh3, accompanied by reductive elimination of NO and the generation of {Fe(NO)2}10 DNIC [(1-MeIm)(PPh3)Fe(NO)2] (3), in contrast to the inertness of the nitrite-containing {Fe(NO)2}9 DNIC [(HIm)(ONO)Fe(NO)2] (HIm = imidazole) (2-HIm) toward PPh3. The findings, EPR signals of g = 2.013 for complex 1 and g = 2.03 for complexes 2-MeIm/2-HIm, imply that characterization of DNICs may be possible via their distinctive EPR signal g = 2.03 for the tetrahedral DNICs and EPR signal g = 2.01 for the six-coordinate DNICs. This study also implicates that the six-coordinate nitrite-containing {Fe(NO)2}9 DNICs may act as a transient intermediate (or an active center) to trigger the transformation of nitrite into nitric oxide.

Nitrate-to-Nitrite-to-Nitric Oxide Conversion Modulated by Nitrate-Containing {Fe(NO)2}9 Dinitrosyl Iron Complex (DNIC)

Nitrosylation of high-spin [Fe(κ(2)-O(2)NO)(4)](2-) (1) yields {Fe(NO)}(7) mononitrosyl iron complex (MNIC) [(κ(2)-O(2)NO)(κ(1)-ONO(2))(3)Fe(NO)](2-) (2) displaying an S = 3/2 axial electron paramagnetic resonance (EPR) spectrum (g(⊥) = 3.988 and g(∥) = 2.000). The thermally unstable nitrate-containing {Fe(NO)(2)}(9) dinitrosyl iron complex (DNIC) [(κ(1)-ONO(2))(2)Fe(NO)(2)](-) (3) was exclusively obtained from reaction of HNO(3) and [(OAc)(2)Fe(NO)(2)](-) and was characterized by IR, UV-vis, EPR, superconducting quantum interference device (SQUID), X-ray absorption spectroscopy (XAS), and single-crystal X-ray diffraction (XRD). In contrast to {Fe(NO)(2)}(9) DNIC [(ONO)(2)Fe(NO)(2)](-) constructed by two monodentate O-bound nitrito ligands, the weak interaction between Fe(1) and the distal oxygens O(5)/O(7) of nitrato-coordinated ligands (Fe(1)···O(5) and Fe(1)···O(7) distances of 2.582(2) and 2.583(2) Å, respectively) may play important roles in stabilizing DNIC 3. Transformation of nitrate-containing DNIC 3 into N-bound nitro {Fe(NO)}(6) [(NO)(κ(1)-NO(2))Fe(S(2)CNEt(2))(2)] (7) triggered by bis(diethylthiocarbamoyl) disulfide ((S(2)CNEt(2))(2)) implicates that nitrate-to-nitrite conversion may occur via the intramolecular association of the coordinated nitrate and the adjacent polarized NO-coordinate ligand (nitrosonium) of the proposed {Fe(NO)(2)}(7) intermediate [(NO)(2)(κ(1)-ONO(2))Fe(S(2)CNEt(2))(2)] (A) yielding {Fe(NO)}(7) [(NO)Fe(S(2)CNEt(2))(2)] (6) along with the release of N(2)O(4) (·NO(2)) and the subsequent binding of ·NO(2) to complex 6. The N-bound nitro {Fe(NO)}(6) complex 7 undergoes Me(2)S-promoted O-atom transfer facilitated by imidazole to give {Fe(NO)}(7) complex 6 accompanied by release of nitric oxide. This result demonstrates that nitrate-containing DNIC 3 acts as an active center to modulate nitrate-to-nitrite-to-nitric oxide conversion.

New members of a class of dinitrosyliron complexes (DNICs): the characteristic EPR signal of the six-coordinate and five-coordinate {Fe(NO)2}9 DNICs.

Compared to the tetrahedral {Fe(NO)(2)}(9) dinitrosyliron complexes (DNICs) [(L)(2)Fe(NO)(2)](-) (L=SR, imidazolate) displaying EPR signal g=2.03, the newly synthesized six-/five-coordinate {Fe(NO)(2)}(9) DNICs [(TPA)Fe(NO)(2)][BF(4)] (1-TPA) (TPA=2-[CH(2)-C(5)H(4)N](3)N), [((iPr)PDI)Fe(NO)(2)][BF(4)] (2-(iPr)PDI) ((iPr)PDI=2,6-[2,6-(i)Pr(2)-C(6)H(3)N=CMe](2)C(5)H(3)N) and [(PyImiS)Fe(NO)(2)] (4-PyImiS) (PyImiS=2-[2-(C(5)H(4)N)CMe=N]C(6)H(4)S) exhibit the distinct EPR signal g=2.015-2.018. The Fe K-edge pre-edge energy (7113.4-7113.6eV) derived from the 1s→3d transition in the octahedral and square-pyramidal environment of the Fe center, falling within the range of 7113.4-7113.8eV for the tetrahedral {Fe(NO)(2)}(9) DNICs, implicates that the iron cores of DNICs 1-TPA, 2-(iPr)PDI and 4-PyImiS are tailored to minimize the electronic changes accompanying changes in coordination geometry. In contrast to the thermally stable 1-TPA, 2-(iPr)PDI and 4-PyImiS, the spontaneous transformation of the proposed thermally unstable five-coordinate {Fe(NO)(2)}(9) DNIC [(PyPepS-H)Fe(NO)(2)](-) (6-PyPepS) (PyPepS-H=[SC(6)H(4)-o-NC(O)(C(5)H(4)N)]) into the {Fe(NO)}(7)-{Fe(NO)}(7) [(μ-PyPepS-H)Fe(NO)](2) (7) along with release of nitroxyl demonstrates that the distinct electron-donating ability of the coordinated ligands ([PyPepS-H]>[PyImiS]~[TPA]>[(iPr)PDI]) regulates the stability and geometric structure of {Fe(NO)(2)}(9) DNICs. This study also shows the aspect of how the geometric structure of {Fe(NO)(2)}(9) DNICs imposed by the electron-donating ability and conformation of the coordinated ligands (tridentate [(iPr)PDI] vs tridentate [PyImiS] vs tetradentate [TPA] vs tridentate [PyPepS-H] vs bidentate [SC(6)H(4)-o-NC(O)Ph](2-)) regulates the Fe-NO bonding of {Fe(NO)(2)}(9) DNICs and presumably the release of nitroxyl from DNICs.

Insight into one-electron oxidation of the {Fe(NO)2}9 dinitrosyl iron complex (DNIC): aminyl radical stabilized by [Fe(NO)2] motif.

A reversible redox reaction ({Fe(NO)(2)}(9) DNIC [(NO)(2)Fe(N(Mes)(TMS))(2)](-) (4) ⇄ oxidized-form DNIC [(NO)(2)Fe(N(Mes)(TMS))(2)] (5) (Mes = mesityl, TMS = trimethylsilane)), characterized by IR, UV-vis, (1)H/(15)N NMR, SQUID, XAS, single-crystal X-ray structure, and DFT calculation, was demonstrated. The electronic structure of the oxidized-form DNIC 5 (S(total) = 0) may be best described as the delocalized aminyl radical [(N(Mes)(TMS))(2)](2)(-•) stabilized by the electron-deficient {Fe(III)(NO(-))(2)}(9) motif, that is, substantial spin is delocalized onto the [(N(Mes)(TMS))(2)](2)(-•) such that the highly covalent dinitrosyl iron core (DNIC) is preserved. In addition to IR, EPR (g ≈ 2.03 for {Fe(NO)(2)}(9)), single-crystal X-ray structure (Fe-N(O) and N-O bond distances), and Fe K-edge pre-edge energy (7113.1-7113.3 eV for {Fe(NO)(2)}(10) vs 7113.4-7113.9 eV for {Fe(NO)(2)}(9)), the (15)N NMR spectrum of [Fe((15)NO)(2)] was also explored to serve as an efficient tool to characterize and discriminate {Fe(NO)(2)}(9) (δ 23.1-76.1 ppm) and {Fe(NO)(2)}(10) (δ -7.8-25.0 ppm) DNICs. To the best of our knowledge, DNIC 5 is the first structurally characterized tetrahedral DNIC formulated as covalent-delocalized [{Fe(III)(NO(-))(2)}(9)-[N(Mes)(TMS)](2)(-•)]. This result may explain why all tetrahedral DNICs containing monodentate-coordinate ligands isolated and characterized nowadays are confined in the {Fe(NO)(2)}(9) and {Fe(NO)(2)}(10) DNICs in chemistry and biology.

In Vitro and in Vivo Imaging of Nitroxyl with Copper Fluorescent Probe in Living Cells and Zebrafish

Nitroxyl (HNO) plays a critical role in many physiological processes which includes vasorelaxation in heart failure, neuroregulation, and myocardial contractility. Powerful imaging tools are required to obtain information for understanding the mechanisms involved in these in vivo processes. In order to develop a rapid and high sensitive probe for HNO detection in living cells and the zebrafish model organism, 2-((2-(benzothiazole-2yl)benzylidene) amino)benzoic acid (AbTCA) as a ligand, and its corresponding copper(II) complex Cu(II)-AbTCA were synthesized. The reaction results of Cu(II)-AbTCA with Angeli’s salt showed that Cu(II)-AbTCA could detect HNO quantitatively in a range of 40–360 µM with a detection limit of 9.05 µM. Furthermore, Cu(II)-AbTCA is more selective towards HNO over other biological species including thiols, reactive nitrogen, and reactive oxygen species. Importantly, Cu(II)-AbTCA was successfully applied to detect HNO in living cells and zebrafish. The collective data reveals that Cu(II)-AbTCA could be used as a potential probe for HNO detection in living systems.