From Simple Palladium(II) Monomers to 2D Heterometallic Sodium-Palladium(II) Coordination Networks with 2-Halonicotinates.

The 2D heterometallic sodium-palladium(II) coordination polymers with 2-halonicotinates [2-chloropyridine-3-carboxylate (2-chloronicotinate), 2-Clnic- and 2-bromopyridine-3-carboxylate (2-bromonicotinate), 2-Brnic-], {[Na2(H2O)2(µ-H2O)4PdCl2(µ-2-Clnic-N:O')2]}n (1), and {[Na2(H2O)2(µ-H2O)4PdBr2(µ-2-Brnic-N:O')2]·2H2O}n (2) were prepared in aqueous solutions under the presence of NaHCO3, while palladium(II) monomers with the neutral 2-chloronicotinic and 2-bromonicotinic acid ligands, [PdCl2(2-ClnicH-N)2]·2DMF (3) and [PdCl2(2-BrnicH-N)2]·2DMF (4), were prepared in DMF/water mixtures (DMF = N,N'-dimethylformamide). The zigzag chains of water-bridged sodium ions are in turn bridged by [PdCl2(2-Clnic)2]2- moieties in 1 or by [PdBr2(2-Brnic)2]2- moieties in 2, leading to the formation of the infinite 2D coordination networks of 1 or 2. The DFT calculations showed the halosubstituents type (Cl vs Br) does not have an influence on the formation of either trans or cis isomers. The trans isomers were found in all reported compounds; being more stable for about 10 to 15 kJ mol-1. The 2D coordination networks 1 and 2 are more stabilized by the formation of Na-Ocarboxylate bonds, comparing to the stabilization of palladium(II) monomers 3 and 4 by hydrogen-bonding with DMF molecules. The difference in DFT calculated energy stabilization for 1 and 2 is ascribed to the type of halosubstituents and to the presence/absence of lattice water molecules in 1 and 2. The compounds show no antibacterial activity toward reference strains of Escherichia coli and Staphylococcus aureus bacteria and no antiproliferative activity toward bladder (T24) and lung (A549) cancer cell lines.

Structural insight into halide-coordinated [Fe4S4XnY4-n]2- clusters (X, Y = Cl, Br, I) by XRD and Mössbauer spectroscopy.

Iron sulphur halide clusters [Fe4S4Br4]2- and [Fe4S4X2Y2]2- (X, Y = Cl, Br, I) were obtained in excellent yields (77 to 78%) and purity from [Fe(CO)5], elemental sulphur, I2 and benzyltrimethylammonium (BTMA+) iodide, bromide and chloride. Single crystals of (BTMA)2[Fe4S4Br4] (1), (BTMA)2[Fe4S4Br2Cl2] (2), (BTMA)2[Fe4S4Cl2I2] (3), and (BTMA)2[Fe4S4Br2I2] (4) were isostructural to the previously reported (BTMA)2[Fe4S4I4] (5) (monoclinic, Cc). Instead of the chloride cubane cluster [Fe4S4Cl4]2-, we found the prismane-shaped cluster (BTMA)3[Fe6S6Cl6] (6) (P1̄). 57Fe Mössbauer spectroscopy indicates complete delocalisation with Fe2.5+ oxidation states for all iron atoms. Magnetic measurements showed small χMT values at 298 K ranging from 1.12 to 1.54 cm3 K mol-1, indicating the dominant antiferromagnetic exchange interactions. With decreasing temperature, the χMT values decreased to reach a plateau at around 100 K. From about 20 K, the values drop significantly. Fitting the data in the Heisenberg-Dirac-van Vleck (HDvV) as well as the Heisenberg Double Exchange (HDE) formalism confirmed the delocalisation and antiferromagnetic coupling assumed from Mössbauer spectroscopy.

Structural characterization of the water-soluble porphyrin complexes [FeII(TPPS) (NO•)]4─ and [µ-O-([FeIII(TPPS)])2]8─.

Iron water-soluble porphyrins have been long used as biomimetic compounds for modelling the active sites found in heme-enzymes. In this regard, the anionic porphyrin [FeIII(TPPS)]3─ and its coordination complexes have been repeatedly chosen as suitable water-soluble platforms for bioinorganic chemistry studies. In this work we report for the first time the crystal structure of the water-soluble nitrosyl complex [FeII(TPPS) (NO•)]4─ along with that of oxodimeric ferric species [µ-O-([FeIII(TPPS)])2]8─.

H2S/Thiols, NO•, and NO-/HNO: Interactions with Iron Porphyrins.

In the past decade, gasotransmitters NO• and H2S have been thoroughly studied in biological contexts, as their biosynthesis and physiological effects became known. Moreover, an additional intricate crosstalk reaction scheme between these compounds and related species is thought to exist as part of the cascade signaling processes in physiological conditions. In this context, heme enzymes, as modeled by iron porphyrins, play a central role in catalyzing the key interconversions involved. In this work, iron porphyrin interactions with sulfide and nitric-oxide-related species are described. The stability and reactivity of mixed ternary systems are also described, and future perspectives are discussed.

Azanone (HNO): generation, stabilization and detection.

HNO (nitroxyl, azanone), joined the 'biologically relevant reactive nitrogen species' family in the 2000s. Azanone is impossible to store due to its high reactivity and inherent low stability. Consequently, its chemistry and effects are studied using donor compounds, which release this molecule in solution and in the gas phase upon stimulation. Researchers have also tried to stabilize this elusive species and its conjugate base by coordination to metal centers using several ligands, like metalloporphyrins and pincer ligands. Given HNO's high reactivity and short lifetime, several different strategies have been proposed for its detection in chemical and biological systems, such as colorimetric methods, EPR, HPLC, mass spectrometry, fluorescent probes, and electrochemical analysis. These approaches are described and critically compared. Finally, in the last ten years, several advances regarding the possibility of endogenous HNO generation were made; some of them are also revised in the present work.

Nitric Oxide Reacts Very Fast with Hydrogen Sulfide, Alcohols, and Thiols to Produce HNO: Revised Rate Constants.

The chemical reactivity of NO and its role in several biological processes seem well established. Despite this, the chemical reduction of •NO toward HNO has been historically discarded, mainly because of the negative reduction potential of NO. However, this value and its implications are nowadays under revision. The last reported redox potential, E'(NO,H+/HNO), at micromolar and picomolar concentrations of •NO and HNO, respectively, is between -0.3 and 0 V at pH 7.4. This potential implies that the one-electron-reduction process for NO is feasible under biological conditions and could be promoted by well-known biological reductants with reduction potentials of around -0.3 to -0.5 V. Moreover, the biologically compatible chemical reduction of •NO (nonenzymatic), like direct routes to HNO by alkylamines, aromatic and pseudoaromatic alcohols, thiols, and hydrogen sulfide, has been extensively explored by our group during the past decade. The aim of this work is to use a kinetic modeling approach to analyze electrochemical HNO measurements and to report for the first-time direct reaction rate constants between •NO and moderate reducing agents, producing HNO. These values are between 5 and 30 times higher than the previously reported keff values. On the other hand, we also showed that reaction through successive attack by two NO molecules to biologically compatible compounds could produce HNO. After over 3 decades of intense research, the •NO chemistry is still there, ready to be discovered.

Solid-gas reactions for nitroxyl (HNO) generation in the gas phase.

We present a novel nitroxyl (HNO) generation method, which avoids the need of using a liquid system or extreme experimental conditions. This method consists of the reaction between a gaseous base and an HNO donor (Piloty's acid) in the solid phase, allowing the formation of gaseous HNO in a fast and economical way. Detection of HNO was carried out indirectly, measuring the nitrous oxide (N2O) byproduct of HNO dimerization using infrared spectroscopy, and directly, using mass spectrometry techniques and an electrochemical HNO sensor.

Redox and Antioxidant Modulation of Circadian Rhythms: Effects of Nitroxyl, N-Acetylcysteine and Glutathione.

The circadian clock at the hypothalamic suprachiasmatic nucleus (SCN) entrains output rhythms to 24-h light cycles. To entrain by phase-advances, light signaling at the end of subjective night (circadian time 18, CT18) requires free radical nitric oxide (NO•) binding to soluble guanylate cyclase (sGC) heme group, activating the cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG). Phase-delays at CT14 seem to be independent of NO•, whose redox-related species were yet to be investigated. Here, the one-electron reduction of NO• nitroxyl was pharmacologically delivered by Angeli's salt (AS) donor to assess its modulation on phase-resetting of locomotor rhythms in hamsters. Intracerebroventricular AS generated nitroxyl at the SCN, promoting phase-delays at CT14, but potentiated light-induced phase-advances at CT18. Glutathione/glutathione disulfide (GSH/GSSG) couple measured in SCN homogenates showed higher values at CT14 (i.e., more reduced) than at CT18 (oxidized). In addition, administration of antioxidants N-acetylcysteine (NAC) and GSH induced delays per se at CT14 but did not affect light-induced advances at CT18. Thus, the relative of NO• nitroxyl generates phase-delays in a reductive SCN environment, while an oxidative favors photic-advances. These data suggest that circadian phase-locking mechanisms should include redox SCN environment, generating relatives of NO•, as well as coupling with the molecular oscillator.

Updating NO•/HNO interconversion under physiological conditions: A biological implication overview.

Azanone (HNO/NO-), also called nitroxyl, is a highly reactive compound whose biological role is still a matter of debate. A key issue that remains to be clarified regarding HNO and its biological activity is that of its endogenous formation. Given the overlap of the molecular targets and reactivity of nitric oxide (NO•) and HNO, its chemical biology was perceived to be similar to that of NO• as a biological signaling agent. However, despite their closely related reactivity, NO• and HNO's biochemical pathways are quite different. Moreover, the reduction of nitric oxide to azanone is possible but necessarily coupled to other reactions, which drive the reaction forward, overcoming the unfavorable thermodynamic barrier. The mechanism of this NO•/HNO interplay and its downstream effects in different contexts were studied recently, showing that more than fifteen moderate reducing agents react with NO• producing HNO. Particularly, it is known that the reaction between nitric oxide and hydrogen sulfide (H2S) produces HNO. However, this rate constant was not reported yet. In this work, firstly the NO•/H2S effective rate constant was measured as a function of the pH. Then, the implications of these chemical (non-enzymatic), biologically compatible, routes to endogenous HNO formation was discussed. There is no doubt that HNO could be (is?) a new endogenously produced messenger that mediates specific physiological responses, many of which were attributed yet to direct NO• effects.

Cobalt Corroles as Electrocatalysts for Water Oxidation: Strong Effect of Substituents on Catalytic Activity.

Two Co(III) complexes (1Py2 and 2Py2) of new corrole ligands H3L1 (5,15-bis(p-methylcarboxyphenyl)-10-(o-methylcarboxyphenyl)corrole) and H3L2 (5,15-bis(p-nitrophenyl)-10-(o-methylcarboxyphenyl)corrole) with two apical pyridine ligands have been synthesized and thoroughly characterized by cyclic voltammetry, UV-vis-NIR, and EPR spectroscopy, spectroelectrochemistry, single-crystal X-ray diffraction studies, and DFT methods. Complexes 1Py2 and 2Py2 possess much lower oxidation potentials than cobalt(III)-tris-pentafluorophenylcorrole (Co(tpfc)) and similar corroles containing pentafluorophenyl (C6F5) substituents, thus allowing access to high oxidation states of the former metallocorroles using mild chemical oxidants. The spectroscopic (UV-vis-NIR and EPR) and electronic properties of several oxidation states of these complexes have been determined by a combination of the mentioned methods. Complexes 1Py2 and 2Py2 undergo three oxidations within 1.3 V vs FcH+/FcH in MeCN, and we show that both complexes catalyze water oxidation in an MeCN/H2O mixture upon the third oxidation, with kobs (TOF) values of 1.86 s-1 at 1.29 V (1Py2) and 1.67 s-1 at 1.37 V (2Py2). These values are five times higher than previously reported TOF values for C6F5-substituted cobalt(III) corroles, a finding we ascribe to the additional charge in the corrole macrocycle due to the increased oxidation state. This work opens up new possibilities in the study of metallocorrole water oxidation catalysts, particularly by allowing spectroscopic probing of high-oxidation states and showing strong substituent-effects on catalytic activity of the corrole complexes.

Synthesis, structure and reactivity of NO+, NO˙ and NO- pincer PCN-Rh complexes.

Synthesis of a pincer-type linear nitrosyl complex [Rh(PtBu2CNEt2)(NO)]+ (3+) is described. The product and all intermediates involved were fully characterized by FTIR, NMR, cyclic voltammetry and X-ray crystallography. Attempts at obtaining (3+) from its chlorinated precursor Rh(PCN)(NO)Cl (2) revealed that a relative stabilization of this complex ion is introduced by the BArF- counteranion, as other counteranions-PF6-, BF4- and triflate-proved to coordinate to the metal center. Redox reactivity both of (3+) and of that of its five-coordinate derivatives (2) and [Rh(PCN)(NO)(CH3CN)]+ (4+) was found to distinguish itself from analogous PCP complexes due to a relative stabilization of higher oxidation states. Oxidation of these three complexes was studied by FTIR spectroelectrochemistry. Reduction of complex (3+) to yield a short-lived {RhNO}9 species [Rh(PCN)(NO)]˙ (3˙) was also carried out. Complex (3˙) was proved able to activate carbon-halogen bonds in aryl halides, in much a similar way as that of its PCP analogue. Complex (3+) was also seen to establish a linear ↔ bent nitrosyl equilibrium upon addition of CO which could not be fully displaced with excess CO.

The Underlying Mechanism of HNO Production by the Myoglobin-Mediated Oxidation of Hydroxylamine.

Azanone (HNO, nitroxyl) is a highly reactive molecule that, in the past few years, has drawn significant interest because of its pharmacological properties. However, the understanding of how, when, and where endogenous HNO is produced remains a matter of discussion. In this study, we examined the ability of myoglobin to produce HNO via the peroxidation of hydroxylamine with H2O2 using both experimental and computational approaches. The production of HNO was confirmed using an azanone selective electrochemical method and by the detection of N2O using FTIR. The catalytic capacity of myoglobin was characterized by the determination of the turnover number. The reaction kinetics of the hydroxylamine peroxidation were studied by both electrochemical and UV-vis methods. Further evidence about the reaction mechanism was obtained by EPR spectroscopy. Additionally, quantum mechanical/molecular mechanics experiments were performed to calculate the energy barrier for HNO production and to gain insight into the reaction mechanism. Our results confirm that myoglobin produces HNO via the peroxidation of hydroxylamine with a great catalytic capacity. In addition, our mechanistic study allows us to state that the Mb ferryl state is the most likely intermediate that reacts with hydroxylamine, yielding important evidence for endogenous HNO generation.

NO/H2S "Crosstalk" Reactions. The Role of Thionitrites (SNO-) and Perthionitrites (SSNO-).

The redox chemistry of H2S with NO and other oxidants containing the NO group is discussed on a mechanistic basis because of the expanding interest in their biological relevance, with an eye open to the chemical differences of H2S and thiols RSH. We focus on the properties of two "crosstalk" intermediates, SNO- (thionitrite) and SSNO- (perthionitrite, nitrosodisulfide) based in the largely controversial status on their identity and chemistry in aqueous/nonaqueous media, en route to the final products N2O, NO2-, NH2OH/NH3, and S8. Thionitrous acid, generated either in the direct reaction of NO + H2S or through the transnitrosation of RSNO's (nitrosothiols) with H2S at pH 7.4, is best described as a mixture of rapidly interconverting isomers, {(H)SNO}. It is reactive in different competitive modes, with a half-life of a few seconds at pH 7.4 for homolytic cleavage of the N-S bond, and could be deprotonated at pH values of up to ca. 10, giving SNO-, a less reactive species than {(H)SNO}. The latter mixture can also react with HS-, giving HNO and HS2- (hydrogen disulfide), a S0(sulfane)-transfer reagent toward {(H)SNO}, leading to SSNO-, a moderately stable species that slowly decomposes in aqueous sulfide-containing solutions in the minute-hour time scale, depending on [O2]. The previous characterization of HSNO/SNO- and SSNO- is critically discussed based on the available chemical and spectroscopic evidence (mass spectrometry, UV-vis, 15N NMR, Fourier transform infrared), together with computational studies including quantum mechanics/molecular mechanics molecular dynamics simulations that provide a structural and UV-vis description of the solvatochromic properties of cis-SSNO- acting as an electron donor in water, alcohols, and aprotic acceptor solvents. In this way, SSNO- is confirmed as the elusive "yellow intermediate" (I412) emerging in the aqueous crosstalk reactions, in contrast with its assignment to polysulfides, HSn-. The analysis extends to the coordination abilities of {(H)SNO}, SNO-, and SSNO- into heme and nonheme iron centers, providing a basis for best unraveling their putative specific signaling roles.

Water-Soluble Nitroxyl Porphyrin Complexes FeIITPPSHNO and FeIITPPSNO- Obtained from Isolated FeIITPPSNO•.

The first biomimetic water-soluble FeII-porphyrin nitroxyl complexes were obtained and characterized by UV-vis in protonated and deprotonated forms by reduction of previously isolated and characterized FeIITPPSNO•. The pKa involved in the FeII-HNO ⇄ FeII-NO- + H+ equilibrium was estimated to be around 9.7. The FeIITPPSHNO complex spontaneously reoxidizes to the nitrosyl form following a first-order kinetic decay with a measured kinetic constant of k = 0.017 s-1. Experiments show that the HNO adduct undergoes unimolecular homolytic cleavage of the H-NO bond. DFT calculations suggest a phlorin radical intermediate for this reaction. The deprotonated NO- complex resulted to be more stable, with a half-life of about 10 min.

Insights into Second-Sphere Effects on Redox Potentials, Spectroscopic Properties, and Superoxide Dismutase Activity of Manganese Complexes with Schiff-Base Ligands.

Six Mn-Schiff base complexes, [Mn(X-salpn)]0/+ (salpn = 1,3-bis(sal-ic-ylidenamino)propane, X = H [1], 5-Cl [2], 2,5-F2 [3], 3,5-Cl2 [4], 5-NO2 [5], 3,5-(NO2)2 [6]), were synthesized and characterized in solution, and second-sphere effects on their electrochemical and spectroscopic properties were analyzed. The six complexes catalyze the dismutation of superoxide with catalytic rate constants in the range 0.65 to 1.54 × 106 M-1 s-1 obtained through the nitro blue tetrazolium photoreduction inhibition superoxide dismutases assay, in aqueous medium of pH 7.8. In solution, these compounds possess two labile solvent molecules in the axial positions favoring coordination of the highly nucleophilic O2 •- to the metal center. Even complex 5, [Mn(5-(NO2)salpn) (OAc) (H2O)], with an axial acetate in the solid state, behaves as a 1:1 electrolyte in methanolic solution. Electron paramagnetic resonance and UV-vis monitoring of the reaction of [Mn(X-salpn)]0/+ with KO2 demonstrates that in diluted solutions these complexes behave as catalysts supporting several additions of excess O2 •-, but at high complex concentrations (≥0.75 mM) catalyst self-inhibition occurs by the formation of a catalytically inactive dimer. The correlation of spectroscopic, electrochemical, and kinetics data suggest that second-sphere effects control the oxidation states of Mn involved in the O2 •- dismutation cycle catalyzed by complexes 1-6 and modulate the strength of the Mn-substrate adduct for electron-transfer through an inner-sphere mechanism.

Synthesis, structural elucidation and antiradical activity of a copper (II) naringenin complex.

Coupling the extraction and derivatization of flavonoids to the Citrus processing industry is attractive from both the environmental and economic points of view. In the present work, the flavonoid naringin, obtained by "green" extraction with a water:ethanol mixture from waste grapefruit industry, was hydrolyzed to obtain naringenin. This flavonoid was used to synthesize the complex trans-di(aqua) bis(7-hydroxy-2-(4-hydroxyphenyl)-4-oxo-5-chromanolato) copper (II). This compound was characterized by spectroscopic techniques (UV/Vis, IR, Raman, NMR and EPR), and by thermal analysis (TG and DSC). Then, a monocrystal of the complex obtained by dissolution and recrystallization in DMF was analyzed by single crystal X-ray diffraction. This is the first report of the crystal structure of a Citrus flavonoid complex. Additionally, its antiradical activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) was determined and compared with that for naringenin, demonstrating that coordination to copper enhances the antiradicalar activity of naringenin. According to the Mulliken population analysis conducted, by copper favors the delocalization and stabilization of the produced radical, since it acts as an electronic density acceptor.

Synthesis and structural characterisation of unprecedented primary N-nitrosamines coordinated to iridium(iv).

The redox chemistry of the N-nitrosamine complexes [IrCl5(RN(H)N[double bond, length as m-dash]O)]2- (R = benzyl or n-butyl) was studied in detail. One-electron oxidations at around 200 mV vs. ferrocene/ferrocenium were reversible in cyclic voltammograms. UV-vis spectroelectrochemistry reveals spectra characteristic of IrIV species but also partial decomposition of the oxidised species [IrIVCl5(RN(H)N[double bond, length as m-dash]O)]˙- on this timescale (minutes). Detailed studies on chemically oxidised solutions of the parent IrIII complexes gave evidence for paramagnetic IrIV from NMR spectra. Final products of the decomposition were the corresponding alcohols and presumably [IrIIICl5(L)]2- (L = N2, solvent, amine) complexes. Similar decomposition reactions of acidic DMSO solutions of [IrCl5(RN(H)N[double bond, length as m-dash]O)]2-revealed that this combination produces the so-called "activated" DMSO (Me2S+-O- or Me2S+-OE, with "E" being an electrophile) which oxidises the parent IrIII complexes. Finally, with the very reactive purple IrIV compound (PPh4)[IrCl5(BnN(H)N[double bond, length as m-dash]O)], the first primary N-nitrosamine coordinated to [IrIVCl5]- was isolated and characterised by UV-vis absorption, FTIR, NMR spectroscopy, ultra-high resolution electrospray mass spectrometry (UHR-ESI-MS) and iridium L3 X-ray absorption near-edge spectroscopy (XANES).

NO˙ disproportionation by a {RhNO}9 pincer-type complex.

The reactivity of the {RhNO}9 complex [Rh(PCPtBu)(NO)]˙ (1˙) with NO˙ was studied. A disproportionation reaction takes place in which N2O is released quantitatively, while the complex Rh(PCPtBu)(NO)(NO2) (2), with coordinated nitrite, is formed. The new complex 2 was fully characterized by multinuclear NMR techniques, IR and X-ray diffraction. The X-ray structure reveals a square pyramidal geometry with an N-bound nitro ligand trans to the Cipso of the PCP ligand and a bent nitrosyl ligand in the apical position. IR measurement of released N2O confirms that one equivalent forms for each molecule of 1˙. Infrared spectroscopic experiments with 1˙-15NO and 14NO˙ suggest that the reaction occurs through the intermediacy of a dinitrosyl complex. In addition, DFT calculations were performed to provide more evidence on the structure of the intermediates and to support the observed reactivity.

HNO Is Produced by the Reaction of NO with Thiols.

Azanone (nitroxyl, HNO) is a highly reactive compound whose biological role is still a matter of debate. One possible route for its formation is NO reduction by biological reductants. These reactions have been historically discarded due to the negative redox potential for the NO,H+/HNO couple. However, the NO to HNO conversion mediated by vitamins C, E, and aromatic alcohols has been recently shown to be feasible from a chemical standpoint. Based on these precedents, we decided to study the reaction of NO with thiols as potential sources of HNO. Using two complementary approaches, trapping by a Mn porphyrin and an HNO electrochemical sensor, we found that under anaerobic conditions aliphatic and aromatic thiols (as well as selenols) are able to convert NO to HNO, albeit at different rates. Further mechanistic analysis using ab initio methods shows that the reaction between NO and the thiol produces a free radical adduct RSNOH•, which reacts with a second NO molecule to produce HNO and a nitrosothiol. The nitrosothiol intermediate reacts further with RSH to produce a second molecule of HNO and RSSR, as previously reported.