Formation of the Distinct Redox‐Interrelated Forms of Nitric Oxide from Reaction of Dinitrosyl Iron Complexes (DNICs) and Substitution Ligands

Release of the distinct NO redox‐interrelated forms (NO⁺, ^.NO, and HNO/NO^?), derived from reaction of the dinitrosyl iron complex (DNIC) [(NO)₂Fe(C₁₂H₈N)₂]^? ( 1 ) (C₁₂H₈N=carbazolate) and the substitution ligands (S₂CNMe₂)₂, [SC₆H₄‐o‐NHC(O)(C₅H₄N)]₂ ((PyPepS)₂), and P(C₆H₃‐3‐SiMe₃‐2‐SH)₃ ([P(SH)₃]), respectively, was demonstrated. In contrast to the reaction of (PyPepS)₂ and DNIC 1 in a 1:1 stoichiometry that induces the release of an NO radical and the formation of complex [PPN][Fe(PyPepS)₂] ( 4 ), the incoming substitution ligand (S₂CNMe₂)₂ triggered the transformation of DNIC 1 into complex [(NO)Fe(S₂CNMe₂)₂] ( 2 ) along with N‐nitrosocarbazole ( 3 ). The subsequent nitrosation of N‐acetylpenicillamine (NAP) by N‐nitrosocarbazole ( 3 ) to produce S‐nitroso‐N‐acetylpenicillamine (SNAP) may signify the possible formation pathway of S‐nitrosothiols from DNICs by means of transnitrosation of N‐nitrosamines. Protonation of DNIC 1 by [P(SH)₃] triggers the release of HNO and the generation of complex [PPN][Fe(NO)P(C₆H₃‐3‐SiMe₃‐2‐S)₃] ( 5 ). In a similar fashion, the nucleophilic attack of the chelating ligand P(C₆H₃‐3‐SiMe₃‐2‐SNa)₃ ([P(SNa)₃]) on DNIC 1 resulted in the direct release of [NO]^? captured by [(¹⁵NO)Fe(SPh)₃]^?, thus leading to [(¹⁵NO)(¹⁴NO)Fe(SPh)₂]^?. These results illustrate one aspect of how the incoming substitution ligands ((S₂CNMe₂)₂ vs. (PyPepS)₂ vs. [P(SH)₃]/[P(SNa)₃]) in cooperation with the carbazolate‐coordinated ligands of DNIC 1 function to control the release of NO⁺, ^.NO, or [NO]^? from DNIC 1 upon reaction of complex 1 and the substitution ligands. Also, these results signify that DNICs may act as an intermediary of NO in the redox signaling processes by providing the distinct redox‐interrelated forms of NO to interact with different NO‐responsive targets in biological systems.     

Transformation of the {Fe(NO)2}9 dinitrosyl iron complexes (DNICs) into S-nitrosothiols (RSNOs) triggered by acid-base pairs

S‐Nitrosation of the coordinated thiolate of dinitrosyl iron complexes (DNICs) to generate S‐nitrosothiols (RSNOs) was demonstrated. Transformation of [{(NO)₂Fe(μ‐StBu)}₂] ( 1‐tBuS ) into the {Fe(NO)₂}⁹ DNIC [(NO)₂Fe(StBu)(MeIm)] ( 2‐MeIm ) occurs under addition of 20 equiv of 1‐methylimidazole (MeIm) into a solution of 1‐tBuS in THF. The dynamic interconversion between {Fe(NO)₂}⁹ [(NO)₂Fe(S‐NAP)(dmso)] ( 2‐dmso ) (NAP=N‐acetyl‐D ‐penicillamine) and [{(NO)₂Fe(μ‐S‐NAP)}₂] ( 1‐NAP ) was also observed in a solution of complex 1‐NAP in DMSO. In contrast to the reaction of complex 2‐MeIm and bis(dimethylthiocarbamoyl) disulfide ((DTC)₂) to yield {Fe(NO)}⁷ [(NO)Fe(DTC)₂] ( 3 ) (DTC=S₂CNMe₂) accompanied by (tBuS)₂ and NO_(g), transformation of {Fe(NO)₂}⁹ 2‐MeIm ( 2‐dmso ) into RSNOs (RS=tBuS, NAP‐S) along with complex 3 induced by the Brønsted acid solution of (DTC)₂ demonstrated that Brønsted acid may play a critical role in triggering S‐nitrosation of the coordinated thiolate of DNICs 2‐MeIm (or 2‐dmso ) to produce RSNOs. That is, DNIC‐mediated S‐nitrosation requires a Brønsted acid–Lewis base pair to produce RSNO. Transformation of DNICs into RSNOs may only occur on the one‐thiolate‐containing {Fe(NO)₂}⁹ DNICs, in contrast to protonation of the two‐thiolate‐containing DNICs [(NO)₂Fe(SR)₂]^? by Brønsted acid to yield [{(NO)₂Fe(μ‐SR)}₂]. These results might rationalize that the known protein‐Cys‐SNO sites derived from DNICs were located adjacent to acid and base motifs, and no protein‐bound SNO characterized to date has been directly derived from [protein–(cysteine)₂Fe(NO)₂] in biology.     

Mononuclear Nonheme Iron(III)‐Iodosylarene and High‐Valent Iron‐Oxo Complexes in Olefin Epoxidation Reactions

High‐spin iron(III)‐iodosylarene complexes are highly reactive in the epoxidation of olefins, in which epoxides are formed as the major products with high stereospecificity and enantioselectivity. The reactivity of the iron(III)‐iodosylarene intermediates is much greater than that of the corresponding iron(IV)‐oxo complex in these reactions. The iron(III)‐iodosylarene species—not high‐valent iron(IV)‐oxo and iron(V)‐oxo species—are also shown to be the active oxidants in catalytic olefin epoxidation reactions. The present results are discussed in light of the long‐standing controversy on the one oxidant versus multiple oxidants hypothesis in oxidation reactions.     

Contrasting Effects of Axial Ligands on Electron‐Transfer Versus Proton‐Coupled Electron‐Transfer Reactions of Nonheme Oxoiron(IV) Complexes

The effects of axial ligands on electron‐transfer and proton‐coupled electron‐transfer reactions of mononuclear nonheme oxoiron(IV) complexes were investigated by using [Fe^IV(O)(tmc)(X)]ⁿ⁺ ( 1 ‐X) with various axial ligands, in which tmc is 1,4,8,11‐tetramethyl‐1,4,8,11‐tetraazacyclotetradecane and X is CH₃CN ( 1 ‐NCCH₃), CF₃COO^? ( 1 ‐OOCCF₃), or N₃^? ( 1 ‐N₃), and ferrocene derivatives as electron donors. As the binding strength of the axial ligands increases, the one‐electron reduction potentials of 1 ‐X (E_red, V vs. saturated calomel electrode (SCE)) are more negatively shifted by the binding of the more electron‐donating axial ligands in the order of 1 ‐NCCH₃ (0.39) > 1 ‐OOCCF₃ (0.13) > 1 ‐N₃ (?0.05 V). Rate constants of electron transfer from ferrocene derivatives to 1 ‐X were analyzed in light of the Marcus theory of electron transfer to determine reorganization energies (λ) of electron transfer. The λ values decrease in the order of 1 ‐NCCH₃ (2.37) > 1 ‐OOCCF₃ (2.12) > 1 ‐N₃ (1.97 eV). Thus, the electron‐transfer reduction becomes less favorable thermodynamically but more favorable kinetically with increasing donor ability of the axial ligands. The net effect of the axial ligands is the deceleration of the electron‐transfer rate in the order of 1 ‐NCCH₃ > 1 ‐OOCCF₃ > 1 ‐N₃. In sharp contrast to this, the rates of the proton‐coupled electron‐transfer reactions of 1 ‐X are markedly accelerated in the presence of an acid in the opposite order: 1 ‐NCCH₃ < 1 ‐OOCCF₃ < 1 ‐N₃. Such contrasting effects of the axial ligands on the electron‐transfer and proton‐coupled electron‐transfer reactions of nonheme oxoiron(IV) complexes are discussed in light of the counterintuitive reactivity patterns observed in the oxo transfer and hydrogen‐atom abstraction reactions by nonheme oxoiron(IV) complexes (Sastri et al. Proc. Natl. Acad. Sci. U.S.A. 2007 , 104, 19 181–19 186).     

Structural and Spectroscopic Characterization of a High‐Spin {FeNO}6 Complex with an Iron(IV)−NO− Electronic Structure

Although the interaction of low‐spin ferric complexes with nitric oxide has been well studied, examples of stable high‐spin ferric nitrosyls (such as those that could be expected to form at typical non‐heme iron sites in biology) are extremely rare. Using the TMG₃tren co‐ligand, we have prepared a high‐spin ferric NO adduct ({FeNO}⁶ complex) via electrochemical or chemical oxidation of the corresponding high‐spin ferrous NO {FeNO}⁷ complex. The {FeNO}⁶ compound is characterized by UV/Visible and IR spectroelectrochemistry, Mössbauer and NMR spectroscopy, X‐ray crystallography, and DFT calculations. The data show that its electronic structure is best described as a high‐spin iron(IV) center bound to a triplet NO^? ligand with a very covalent iron?NO bond. This finding demonstrates that this high‐spin iron nitrosyl compound undergoes iron‐centered redox chemistry, leading to fundamentally different properties than corresponding low‐spin compounds, which undergo NO‐centered redox transformations.     

X‐Ray Emission Spectroscopy: A Spectroscopic Measure for the Determination of NO Oxidation States in Fe–NO Complexes

Extensive study of the electronic structure of Fe‐NO complexes using a variety of spectroscopic methods was attempted to understand how iron controls the binding and release of nitric oxide. The comparable energy levels of NO π* orbitals and Fe 3d orbitals complicate the bonding interaction within Fe? NO complexes and puzzle the quantitative assignment of NO oxidation state. Enemark–Feltham notation, {Fe(NO)_x}ⁿ, was devised to circumvent this puzzle. This 40‐year puzzle is revisited using valence‐to‐core X‐ray emission spectroscopy (V2C XES) in combination with computational study. DFT calculation establishes a linear relationship between ΔE_σ2s*‐σ2p of NO and its oxidation state. V2C Fe XES study of Fe? NO complexes reveals the ΔE_σ2s*‐σ2p of NO derived from NO σ_2s*/σ_2p→Fe_1s transitions and determines NO oxidation state in Fe? NO complexes. Quantitative assignment of NO oxidation state will correlate the feasible redox process of nitric oxide and Fe‐nitrosylation biology.     

Metal-ion-coordinating properties of the dinucleotide 2'-deoxyguanylyl(5'-->3')-2'-deoxy-5'-guanylate (d(pGpG)3-): isomeric equilibria including macrochelated complexes relevant for nucleic acids

The interaction between divalent metal ions and nucleic acids is well known, yet knowledge about the strength of binding of labile metal ions at the various sites is very scarce. We have therefore studied the stabilities of complexes formed between the nucleic acid model d(pGpG) and the essential metal ions Mg2+ and Zn2+ as well as with the generally toxic ions Cd2+ and Pb2+ by potentiometric pH titrations; all four ions are of relevance in ribozyme chemistry. A comparison of the present results with earlier data obtained for M(pUpU)- complexes allows the conclusion that phosphate-bound Mg2+ and Cd2+ form macrochelates by interaction with N7, whereas the also phosphate-coordinated Pb2+ forms a 10-membered chelate with the neighboring phosphate diester bridge. Zn2+ forms both types of chelates with formation degrees of about 91% and 2.4% for Zn[d(pGpG)]cl/N7 and Zn[d(pGpG)]-cl/PO, respectively; the open form with Zn2+ bound only to the terminal phosphate group, Zn[d(pGpG)]-op, amounts to about 6.8 %. The various intramolecular equilibria have also been quantified for the other metal ions. Zn2+, Cu2+, and Cd2+ also form macrochelates in the monoprotonated M[H;d(pGpG)] species (the proton being at the terminal phosphate group), that is, the metal ion at N7 interacts to some extent with the P(O)2(OH)- group. Thus, this study demonstrates that the coordinating properties of the various metal ions toward a pGpG unit in a nucleic acid differ: Mg2+, Zn2+, and Cd2+ have a significant tendency to bridge the distance between N7 and the phosphate group of a (d)GMP unit, although to various extents, whereas Pb2+ (and possibly Ca2+) prefer a pure phosphate coordination.     

Highly Reactive Nonheme Iron(III) Iodosylarene Complexes in Alkane Hydroxylation and Sulfoxidation Reactions

High‐spin iron(III) iodosylarene complexes bearing an N‐methylated cyclam ligand are synthesized and characterized using various spectroscopic methods. The nonheme high‐spin iron(III) iodosylarene intermediates are highly reactive oxidants capable of activating strong C? H bonds of alkanes; the reactivity of the iron(III) iodosylarene intermediates is much greater than that of the corresponding iron(IV) oxo complex. The electrophilic character of the iron(III) iodosylarene complexes is demonstrated in sulfoxidation reactions.     

Syntheses,Characterization, and DNA Binding Studies of a Series of Copper(II), Nickel(II), Platinum(II) and Zinc(II) Complexes Derived from Schiff Base Ligands

Three series of metal salophen complexes derived from Zn²⁺, Cu²⁺, Pt²⁺ and Ni²⁺ have been synthesized and their interaction with quadruplex DNA has been evaluated. The compounds differ on the number of ethyl piperidine substituents. They have been characterized by ¹H NMR, IR and UV-visible spectroscopies and by HR-mass spectrometry. Their luminescent properties have been also evaluated and we can observe that, as expected, Zn²⁺ and Pt²⁺ complexes are those displaying more interesting luminescence with an emission band red-shifted with respect to the corresponding uncoordinated ligand. DNA interactions with G4 and duplex DNA were evaluated by FRET melting assays (for the Zn²⁺, Cu²⁺ and Ni²⁺ complexes) and by emission titrations (for one Pt²⁺ complex) which indicated that the disubstituted compounds 2-Ni and 2-Pt are the only ones that display good affinity for G4 DNA structures.     

Synthesis,X‐ray Structure of Ferrocene Bearing Bis(Zn‐cyclen) Complexes and the Selective Electrochemical Sensing of TpT

The new ligand, [Fc(cyclen)₂] ( 5 ) (Fc=ferrocene, cyclen=1,4,7,10‐tetraazacyclododecane), and corresponding Zn^II complex receptor, [Fc{Zn(cyclen)(CH₃OH)}₂](ClO₄)₄ ( 1 ), consisting of a ferrocene moiety bearing one Zn^II‐cyclen complex on each cyclopentadienyl ring, have been designed and prepared through a multi‐step synthesis. Significant shifts in the ¹H NMR signals of the ferrocenyl group, cf. ferrocene and a previously reported [Fc{Zn(cyclen)}]²⁺ derivative, indicated that the two Zn^II‐cyclen units in 1 significantly affect the electronic properties of the cyclopentadienyl rings. The X‐ray crystal structure shows that the two positively charged Zn^II‐cyclen complexes are arranged in a trans like configuration, with respect to the ferrocene bridging unit, presumably to minimise electrostatic repulsion. Both 5 and 1 can be oxidized in 1:4 CH₂Cl₂/CH₃CN and Tris‐HCl aqueous buffer solution under conditions of cyclic voltammetry to give a well defined ferrocene‐centred (Fc^0/+) process. Importantly, 1 is a highly selective electrochemical sensor of thymidilyl(3′‐5′)thymidine (TpT) relative to other nucleobases and nucleotides in Tris‐HCl buffer solution (pH 7.4). The electrochemical selectivity, detected as a shift in reversible potential of the Fc^0/+ component, is postulated to result from a change in the configuration of bis(Zn^II‐cyclen) units from a trans to a cis state. This is caused by the strong 1:1 binding of the two deprotonated thymine groups in TpT to different Zn^II centres of receptor 1 . UV‐visible spectrophotometric titrations confirmed the 1:1 stoichiometry for the 1 :TpT adduct and allowed the determination of the apparent formation constant of 0.89±0.10×10⁶ M ^?1 at pH 7.4.     

A Synthetic High‐Spin Oxoiron(IV) Complex: Generation,Spectroscopic Characterization,and Reactivity

High versus low : The high‐yield generation of a synthetic high‐spin oxoiron(IV) complex, [Fe^IV(O)(TMG₃tren)]²⁺ (see picture, TMG₃tren = 1,1,1‐tris{2‐[N2‐(1,1,3,3‐tetramethylguanidino)]ethyl}amine), has been achieved by using the very bulky tetradentate TMG₃tren ligand, in order to both sterically protect the oxoiron(IV) moiety and enforce a trigonal bipyramidal geometry at the iron center, for which an S=2 ground state is favored.

     

Enhanced Electron Transfer Reactivity of a Nonheme Iron(IV)–Imido Complex as Compared to the Iron(IV)‐Oxo Analogue

Reactions of N,N‐dimethylaniline (DMA) with nonheme iron(IV)‐oxo and iron(IV)‐tosylimido complexes occur via different mechanisms, such as an N‐demethylation of DMA by a nonheme iron(IV)‐oxo complex or an electron transfer dimerization of DMA by a nonheme iron(IV)‐tosylimido complex. The change in the reaction mechanism results from the greatly enhanced electron transfer reactivity of the iron(IV)‐tosylimido complex, such as the much more positive one‐electron reduction potential and the smaller reorganization energy during electron transfer, as compared to the electron transfer properties of the corresponding iron(IV)‐oxo complex.     

Two‐Coordinate Fe0 and Co0 Complexes Supported by Cyclic (alkyl)(amino)carbenes

The CAAC [CAAC=cyclic (alkyl)(amino)carbene] family of carbene ligands have shown promise in stabilizing unusually low‐coordination number transition‐metal complexes in low formal oxidation states. Here we extend this narrative by demonstrating their utility in affording access to the first examples of two‐coordinate formal Fe⁰ and Co⁰ [(CAAC)₂M] complexes, prepared by reduction of their corresponding two‐coordinate cationic Fe^I and Co^I precursors. The stability of these species arises from the strong σ‐donating and π‐accepting properties of the supporting CAAC ligands, in addition to steric protection.     

Mononuclear Nonheme High‐Spin (S=2) versus Intermediate‐Spin (S=1) Iron(IV)–Oxo Complexes in Oxidation Reactions

Mononuclear nonheme high‐spin (S=2) iron(IV)–oxo species have been identified as the key intermediates responsible for the C?H bond activation of organic substrates in nonheme iron enzymatic reactions. Herein we report that the C?H bond activation of hydrocarbons by a synthetic mononuclear nonheme high‐spin (S=2) iron(IV)–oxo complex occurs through an oxygen non‐rebound mechanism, as previously demonstrated in the C?H bond activation by nonheme intermediate (S=1) iron(IV)–oxo complexes. We also report that C?H bond activation is preferred over C=C epoxidation in the oxidation of cyclohexene by the nonheme high‐spin (HS) and intermediate‐spin (IS) iron(IV)–oxo complexes, whereas the C=C double bond epoxidation becomes a preferred pathway in the oxidation of deuterated cyclohexene by the nonheme HS and IS iron(IV)–oxo complexes. In the epoxidation of styrene derivatives, the HS and IS iron(IV) oxo complexes are found to have similar electrophilic characters.     

Theranostic Iridium(III) Complexes as One‐ and Two‐Photon Phosphorescent Trackers to Monitor Autophagic Lysosomes

During autophagy, the intracellular components are captured in autophagosomes and delivered to lysosomes for degradation and recycling. Changes in lysosomal trafficking and contents are key events in the regulation of autophagy, which has been implicated in many physiological and pathological processes. In this work, two iridium(III) complexes ( LysoIr1 and LysoIr2 ) are developed as theranostic agents to monitor autophagic lysosomes. These complexes display lysosome‐activated phosphorescence and can specifically label lysosomes with high photostability. Simultaneously, they can induce autophagy potently without initiating an apoptosis response. We demonstrate that LysoIr2 can effectively implement two functions, namely autophagy induction and lysosomal tracking, in the visualization of autophagosomal–lysosomal fusion. More importantly, they display strong two‐photon excited fluorescence (TPEF), which is favorable for live cell imaging and in vivo applications.