This study deals with the unprecedented reactivity of a [(cyclam)MnII(OTf)2] (3-cis; OTf = CF3SO3-) with O2, which, depending on the presence or absence of a hydrogen atom donor like 1-hydroxy-2,2,6,6-tetramethyl-piperidine (TEMPO-H), selectively generates di-μ-oxo Mn(III)Mn(IV) (1) or MnIV2 (2) complexes, respectively. Both dimers have been characterized by different techniques including single-crystal X-ray diffraction, X-ray absorption spectroscopy, and electron paramagnetic resonance. Oxygenation reactions carried out with labeled 18O2 and Resonance Raman spectroscopy unambiguously show that the oxygen atoms present in the MnIVMnIII dimer originate from O2. Experimental evidences are provided for a novel method of dioxygen activation involving three Mn ions or two Mn ions and TEMPO-H to generate the bis(μ-oxo)dimanganese(IV) or bis(μ-oxo) dimanganese(III, IV) cores, respectively.

Nitrite reductase (NiR) catalyzes nitrite (NO2 -) to nitric oxide (NO) transformation in the presence of an acid (H+ ions/pH) and serves as a critical step in NO biosynthesis. In addition to the NiR enzyme, NO synthases (NOSs) participate in NO production. The chemistry involved in the catalytic reduction of NO2 -, in the presence of H+, generates NO with a H2O molecule utilizing two H+ + one electron from cytochromes and is believed to be affected by the pH. Here, to understand the effect of H+ ions on NO2 - reduction, we report the acid-induced NO2 - reduction chemistry of a nonheme FeII-nitrito complex, [(12TMC)FeII(NO2 -)]+ (FeII-NO2 -, 2), with variable amounts of H+. FeII-NO2 - upon reaction with one-equiv. of acid (H+) generates [(12TMC)Fe(NO)]2+, {FeNO}7 (3) with H2O2 rather than H2O. However, the amount of H2O2 decreases with increasing equivalents of H+ and entirely disappears when H+ reaches ≅ two-equiv. and shows H2O formation. Furthermore, we have spectroscopically characterized and followed the formation of H2O2 (H+ = one-equiv.) and H2O (H+ ≅ two-equiv.) and explained why bio-driven NiR reactions end with NO and H2O. Mechanistic investigations, using 15N-labeled-15NO2 - and 2H-labeled-CF3SO3D (D+ source), revealed that the N atom in the {Fe14/15NO}7 is derived from the NO2 - ligand and the H atom in H2O or H2O2 is derived from the H+ source, respectively.

Cis-anionic ligands stabilize high-spin Fe(iii)–alkylperoxo complexes against homolytic O–O bond cleavage to form an iron(iv)–oxo moiety. The study provides some basis to speculate the structure of peroxy intermediates in superoxide reductase.

Acid-catalyzed conversion of nitrite to nitric oxide at the copper( ii ) center: a new catalytic pathway.

Small molecule activation and their transfer reactions in biological or catalytic reactions are greatly influenced by the metal-centers and the ligand frameworks. Here, we report the metal-directed nitric oxide (NO) transfer chemistry in low-spin mononuclear {Co(NO)}8, [(12-TMC)CoIII(NO−)]2+ (1-CoNO, S = 0), and {Cr(NO)}5, ([(BPMEN)Cr(NO)(Cl)]+) (4-CrNO, S = 1/2) complexes. 1-CoNO transfers its bound NO moiety to a high-spin [(BPMEN)CrII(Cl2)] (2-Cr, S = 2) and generates 4-CrNOvia an associative pathway; however, we did not observe the reverse reaction, i.e., NO transfer from 4-CrNO to low-spin [(12-TMC)CoII]2+ (3-Co, S = 1/2). Spectral titration for NO transfer reaction between 1-CoNO and 2-Cr confirmed 1 : 1 reaction stoichiometry. The NO transfer rate was found to be independent of 2-Cr, suggesting the presence of an intermediate species, which was further supported experimentally and theoretically. The experimental and theoretical observations support the formation of μ-NO bridged intermediate species ({Cr–NO–Co}4+). Mechanistic investigations using 15N-labeled-15NO and tracking the 15N-atom established that the NO moiety in 4-CrNO is derived from 1-CoNO. Further, to investigate the factors deciding the NO transfer reactivity, we explored the NO transfer reaction between another high-spin CrII-complex, [(12-TMC)CrII(Cl)]+ (5-Cr, S = 2), and 1-CoNO, showing the generation of the low-spin [(12-TMC)Cr(NO)(Cl)]+ (6-CrNO, S = 1/2); however, again there was no opposite reaction, i.e., from Cr-center to Co-center. The above results advocate clearly that the NO transfer from Co-center generates thermally stable and low-spin and inert {Cr(NO)}5 complexes (4-CrNO & 6-CrNO) from high-spin and labile Cr-complexes (2-Cr & 5-Cr), suggesting a metal-directed NO transfer (cobalt to chromium, not chromium to cobalt). These results explicitly highlight that the NO transfer is strongly influenced by the labile/inert behavior of the metal-centers and/or thermal stability rather than the ligand architecture.

Acid-promoted hydride transfer from an NADH analogue to a Cr(iii)–superoxo complex in the presence of acid proceeds via the full formation of the NADH analogue radical cation, followed by the decay of the radical, and accompanied then by the formation of NAD+.

Nitrate reductases (NRs) are molybdoenzymes that reduce nitrate (NO3 -) to nitrite (NO2 -) in both mammals and plants. In mammals, the salival microbes take part in the generation of the NO2 - from NO3 -, which further produces nitric oxide (NO) either in acid-induced NO2 - reduction or in the presence of nitrite reductases (NiRs). Here, we report a new approach of VCl3 (V3+ ion source) induced step-wise reduction of NO3 - in a CoII-nitrato complex, [(12-TMC)CoII(NO3 -)]+ (2,{CoII-NO3 -}), to a CoIII-nitrosyl complex, [(12-TMC)CoIII(NO)]2+ (4,{CoNO}8), bearing an N-tetramethylated cyclam (TMC) ligand. The VCl3 inspired reduction of NO3 - to NO is believed to occur in two consecutive oxygen atom transfer (OAT) reactions, i.e., OAT-1 = NO3 - → NO2 - (r1) and OAT-2 = NO2 - → NO (r2). In these OAT reactions, VCl3 functions as an O-atom abstracting species, and the reaction of 2 with VCl3 produces a CoIII-nitrosyl ({CoNO}8) with VV-Oxo ({VV[double bond, length as m-dash]O}3+) species, via a proposed CoII-nitrito (3, {CoII-NO2 -}) intermediate species. Further, in a separate experiment, we explored the reaction of isolated complex 3 with VCl3, which showed the generation of 4 with VV-Oxo, validating our proposed reaction sequences of OAT reactions. We ensured and characterized 3 using VCl3 as a limiting reagent, as the second-order rate constant of OAT-2 (k 2 /) is found to be ∼1420 times faster than that of the OAT-1 (k 2) reaction. Binding constant (K b) calculations also support our proposition of NO3 - to NO transformation in two successive OAT reactions, as K b(CoII-NO2 -) is higher than K b(CoII-NO3 -), hence the reaction moves in the forward direction (OAT-1). However, K b(CoII-NO2 -) is comparable to K b{CoNO}8 , and therefore sequenced the second OAT reaction (OAT-2). Mechanistic investigations of these reactions using 15N-labeled-15NO3 - and 15NO2 - revealed that the N-atom in the {CoNO}8 is derived from NO3 - ligand. This work highlights the first-ever report of VCl3 induced step-wise NO3 - reduction (NRs activity) followed by the OAT induced NO2 - reduction and then the generation of Co-nitrosyl species {CoNO}8.

Redox-inactive and -active metal ions that act as Lewis acids are essential cofactors in modulating the redox reactivity of metal-oxygen complexes and metalloenzymes, such as the manganese(V)-oxo intermediate in the oxygen-evolving complex, where Ca2+ in the Mn4CaO5 cluster is indispensable for the catalytic water oxidation in Photosystem II. Zinc ion is also an essential cofactor in Cu-Zn superoxide dismutases (Cu,Zn-SOD), in which binding of O-2(-) to Zn2+ facilitates the electron-transfer reduction of O-2(-), whereas Zn2+ ion that is bridged with Cu2+ by imidazolate accelerates the electron-transfer oxidation of O-2(-). This review focuses on the effects of redox-inactive and -active metal ions that act as Lewis acids on the electron-transfer and redox reactivity of metal-oxygen intermediates such as metal-oxo, metalperoxo and metal-superoxo complexes. Such electron-transfer reactions from electron donors to acceptors enhanced by binding of metal ions to electron acceptors is referred as metal ion-coupled electron transfer (MCET). Lewis acid metal ions can bind to metal-oxo, metal-peroxo and metal-superoxo complexes to enhance the MCET reactivity of these metal-oxygen species. A quantitative measure of Lewis acidity of redox-inactive diamagnetic metal ions is obtained from the g(zz) values of EPR spectra of O-2(-)-metal ion complexes, whereas a quantitative measure of Lewis acidity of paramagnetic redox-active metal ions such as Fe3+ and Co2+ is provided from the emission maxima of 10-methylacridone-metal ion complexes. The MCET reactivity of Fe-IV-oxo, Mn-IV-oxo, Fe-III-peroxo, and Cr-III-superoxo complexes is enhanced by Lewis acids and the logarithm of the enhancement of the rate constant by metal ions is correlated linearly with the quantitative measure of Lewis acidity of metal ions obtained from the g zz values of EPR spectra of O-2(-)-metal ion complexes and the emission maxima of metal ion-10-methylacridone complexes. (C) 2020 Elsevier B.V. All rights reserved.

Calcium ion plays an indispensable role for water oxidation by oxygen-evolving complex (OEC) composed of a manganese-oxo cluster (Mn4CaO5) in Photosystem II. In this context, the effects of Ca2+ ion and other redox-inactive metal ions on the redox reactivity of high-valent metal-oxo and metal-peroxo complexes have been studied extensively. Among metal-oxygen intermediates involved in interconversion between H2O and O-2, however, the effects of Ca2+ ion and other redox-inactive metal ions (Mn+) on the redox reactivity of metal-superoxo complexes have yet to be reported. Herein, we report that electron transfer (ET) from octamethylferrocene (Me(8)Fc) to a mononuclear nonheme Cr(III)-superoxo complex, [(Cl)(TMC)Cr-III(O-2)]+ (1), occurs in the presence of redox-inactive metal ions (Mn+ = Ca2+, Mg2+, Y3+, Al3+, and Sc3+); in the absence of the redox-inactive metal ions, ET from Me(8)Fc to 1 does not occur. The secondorder rate constants (k(et)) of ET from Me(8)Fc to 1 in the presence of a redox-inactive metal ion increased with increasing concentration of Mn+ ([Mn+]), exhibiting a second-order dependence on [Mn+]: k(et) = k(MCET)[Mn+2](2), where k(MCET) is the fourthorder rate constant of metal ion-coupled electron transfer (MCET). This means that two Mn+ ions are bound to the oneelectron reduced species of 1. Such a binding of two Mn+ ons associated with the ET reduction of! resulted in a 92 mV positive shift of the one-electron reduction potential of 1 (E-red) with increasing log( [Mn+]). The log kmcET values increased linearly with the increasing Lewis acidity of Mn+ (Delta E), which was determined from the g values of O-2(center dot-)-Mn+ complexes. The driving force dependence of log k(et) of MCET from ferrocene derivatives to 1 in the presence of Mn+ has been well-evaluated in light of the Marcus theory of electron transfer.

The chemistry of metal-superoxo intermediates started being unveiled in oxidation reactions by enzymes and their synthetic model compounds. However, aromatic hydroxylation reactions by the metal-superoxo species are yet to be demonstrated. In this study, we report for the first time that the hydroxylation of aromatic compounds such as anthracene and its derivatives by a mononuclear nonheme Cr(iii)-superoxo complex, [(Cl)(TMC)CrIII(O2)]+ (1), occurs in the presence of triflic acid (HOTf) via the rate-determining proton-coupled electron transfer (PCET) from anthracene to 1, followed by a fast further oxidation to give anthraquinone. The rate constants of electron transfer from anthracene derivatives to 1 in the presence of HOTf are well analyzed in light of the Marcus theory of electron transfer.

Much enhanced acid catalysis was observed in oxygen atom transfer (OAT) reactions by a mononuclear nonheme Cr(III)-superoxo complex, [(Cl)(TMC)CrIII(O2)]+ (1), in the presence of triflic acid. In the acid-catalyzed reactions, the reactivity of 1 in OAT of thioanisole was enhanced significantly, showing more than 104-fold acceleration in rate. Electron transfer (ET) from electron donors to 1 also occurred only in the presence of HOTf. The enhanced reactivity of 1 by HOTf was explained by proton-coupled electron transfer from electron donors, such as ferrocene, to 1 in light of the Marcus theory of ET. The present study reports for the first time the dramatic proton effect on the chemical properties of metal-superoxo species.

Metal-superoxo species are involved in a variety of enzymatic oxidation reactions, and multi-electron oxidation of substrates is frequently observed in those enzymatic reactions. A CrIII -superoxo complex, [CrIII (O2 )(TMC)(Cl)]+ (1; TMC=1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane), is described that acts as a novel three-electron oxidant in the oxidation of dihydronicotinamide adenine dinucleotide (NADH) analogues. In the reactions of 1 with NADH analogues, a CrIV -oxo complex, [CrIV (O)(TMC)(Cl)]+ (2), is formed by a heterolytic O-O bond cleavage of a putative CrII -hydroperoxo complex, [CrII (OOH)(TMC)(Cl)], which is generated by hydride transfer from NADH analogues to 1. The comparison of the reactivity of NADH analogues with 1 and p-chloranil (Cl4 Q) indicates that oxidation of NADH analogues by 1 proceeds by proton-coupled electron transfer with a very large tunneling effect (for example, with a kinetic isotope effect of 470 at 233 K), followed by rapid electron transfer.

The main objective of the present study is to enhance the dissolution of clopidogrel bisulphate in intestinal fluids by formulating into mini-tablets with in-situ acidifying agent mini-tablets. The solubility data reveals, Clopidogrel bisulphate is freely soluble in pH 2.0 and the solubility decreases with increase in pH. Whereas, with weak acid, the solubility of clopidogrel is increased at pH 5.0 blank fed state simulated intestinal fluid and & pH 6.5 blank fasted state simulated intestinal fluid. Hence, tartaric acid is selected in the core tablet to enhance the dissolution of clopidogrel tablets at intestinal fluid pH 5.0 & pH 6.5. Formulation was evaluated with different levels of tartaric acid in core tablet. Formulation with 50mg/unit of tartaric acid showed the extent of dissolution of 100% in pH 5.0 blank fed state simulated intestinal fluid and 96% in pH 6.5 blank fasted state simulated intestinal fluid. To control the impact of humidity on degradation, a moisture protective layer is coated on core tablet with non-aqueous solvent, using conventional coating pan. The coated mini tablets are encapsulated in a hard gelatin capsule shell. The filled capsules are evaluated for description, assay, dissolution, water by KF.

A reverse phase high performance liquid chromatographic method was developed for the simultaneous estimation of levofloxacin hemihydrate and ornidazole in tablet formulation. The mobile phase was triethylamine (0.5%v/v adjusted to pH 3 using orthophosphoric acid), Acetonitrile and Methanol (40:30:30) at a flow rate of 0.5 ml/min. Detection was carried out at 310nm. The stationary phase was Phenomenex Luna C18 column (5μ, 150x4.6mm I.D).Retention time was 3.42 and 5.65 min for levofloxacin hemihydrate and ornidazole, respectively. Linearity was established in the range of 10-50 μg/ml and 20-80 μg/ml for the assay of levofloxacin hemihydrate and ornidazole.Mean recovery obtained for levofloxacin hemihaydrate and ornidazole were 100.58% and 99.68%, respectively.Developed method was found to be accurate, precise, selective and rapid for simultaneous estimation of levofloxacin hemihydrate and ornidazole in tablets.