Synthesis and characterization of oxorhenium(v) diamido pyridine complexes that catalyze oxygen atom transfer reactions

The detailed syntheses of complexes 1-4, Re(O)(X)(DAP) (X = Me, 1; Cl, 2; I, 3; OTf (triflate), 4) incorporating the diamido pyridine (DAP) ancillary ligand (2,6-bis((mesitylamino)methyl)pyridine) are described and shown to be effective catalysts for oxygen atom transfer (OAT) reactions of PyO to PPh(3). The catalytic activities are as follows: 4≈3 > 2 > 1. The observed electronic trend is consistent with the turnover limiting reduction of the proposed Re(VII) dioxo intermediate, Re(O)(2)(X)(DAP), during the catalytic cycle. The catalytic activity of complexes 1-3 was compared to previously published diamido amine (DAAm) oxorhenium complexes of the type Re(O)(X)(DAAm) (X = Me, 5; Cl, 6; I, 7 and DAAm = N,N-bis(2-arylaminoethyl)methylamine) which exhibit hydrolytic degradation during the catalytic reaction. Complexes 1-3 displayed higher turnover frequencies compared to 5-7. This higher catalytic activity was attributed to the more rigid DAP ligand backbone, which makes the complexes less susceptible to decomposition. However, another decomposition pathway was proposed for this catalytic system due to the observation of Re(O)(3)((MesNCH(2))(MesNCH)NC(5)H(3)) 8 in which one arm of the DAP ligand is oxidized.     

Label-free molecular beacon system based on DNAs containing abasic sites and fluorescent ligands that bind abasic sites

A new class of label-free molecular beacon (MB) system based on DNA strands that contain abasic (AP) sites (AP-DNA) and adopt stem-loop structures, in combination with fluorescent ligands that bind these AP sites, has been developed. Unlike a conventional MB, which requires covalent labeling of the MB with a fluorophore and a quencher, the developed system (APMB) does not require covalent attachment of signal transduction units. Detailed sensing functions of a series of APMB systems were examined with the aid of the fluorescent ligand named ATMND to provide insight into the design strategy for APMB systems. The effects of the stem length and the position of the AP site in the stem moiety on the fluorescence response of the APMB system were examined. Genotyping of a G/C SNP of PCR amplification products was successfully demonstrated with the APMB system and blue-fluorescent ATMND as a ligand. The APMB system was further extended to a system that utilized green-fluorescent lumiflavin.     

Recent advances in vanadium catalyzed oxygen transfer reactions

Vanadium complexes have proven to be effective catalysts for the activation of peroxides and the selective oxidation of substrates like bromides, sulfides and alkenes. Besides their capability to form metalloperoxo species, which effectively transfer oxygen atoms to the substrate, these systems are synthetically useful for obtaining valuable oxidized molecules on a preparative scale, with a high degree of selectivity and TONs. Furthermore, the use of environmentally friendly oxidants like hydrogen and alkyl hydroperoxides increases significantly their potential application at an industrial level.Here we report a critical survey on the most effective homogeneous vanadium catalysts reported in the last decade concerning their synthetic application in oxygen transfer reactions (sulfoxidation, epoxidation, haloperoxidation) using hydrogen peroxide or alkyl hydroperoxides, demonstrating the different classes of ligands and complexes, their catalytic performances, their reactivity, chemo, stereo and substrate selectivity. Some examples of the use of non conventional reaction media or techniques and catalyst recycling studies will be also discussed.     

Anti-idiotype RNAs that mimic the leucine-rich nuclear export signal and specifically bind to CRM1/exportin 1

BACKGROUND: Anti-idiotype approaches are based on the assumption that an antibody recognising a ligand can be structurally related to the receptor. Recently we have generated anti-idiotype RNA aptamers designed to mimic the human immunodeficiency virus-1 (HIV-1) Rev nuclear export signal (NES). Nuclear injection of either NES-peptide conjugates or aptamer causes the inhibition of Rev-mediated export. This implied that NES mimics and export substrate might compete for binding to the NES receptor. The mechanism of inhibition, however, is unknown. RESULTS: The interaction between the export aptamer and CRM1 was characterised in vitro. The aptamer binds specifically to CRM1 and this interaction is sensitive to competition by Rev NES-peptide conjugates. The recognition domain of CRM1 has been mapped and includes residues found previously to affect binding of leptomycin B, a fungicide interfering with nuclear export. CONCLUSIONS: Inhibition of Rev-mediated export in vivo by export aptamers appears to result from the binding of the aptamers to the NES-recognition domain of CRM1. This observation demonstrates that anti-idiotype RNA can mimic faithfully structural and functional properties of a protein and can be used to map ligand-binding domains of receptors.     

Hydrogen atom transfer reactions of iron-porphyrin-imidazole complexes as models for histidine-ligated heme reactivity

Hydrogen atom transfer (HAT) reactions of the bis(histidine) cytochrome active site models (TPP)FeII(ImH)2 (FeIIImH) and (TPP)Fe(Im)(ImH) (FeIIIIm) have been examined in acetonitrile solvent (TPP = tetraphenylporphyrin, ImH = 4-methylimidazole). The ascorbate derivative 5,6-isopropylidine ascorbate, hydroquinone, and the hydroxylamine TEMPOH all rapidly add H* to FeIIIIm to give FeIIImH. Similarly, the phenoxyl radical 2,4,6-tBu3C6H2O* and excess TEMPO* each oxidize FeIIImH to give FeIIIIm. On the basis of redox potential, pKa, and equilibrium measurements, the N-H bond in FeIIImH was found to have a bond dissociation free energy (BDFE) of 70 +/- 2 kcal mol(-1). A hydrogen atom transfer mechanism (concerted transfer of e- and H+) is indicated based on data for the ascorbate and TEMPO* reactions.     

Ultrafast and ultraslow oxygen atom transfer reactions between late metal centers

Oxotrimesityliridium(V), (mes)3Ir=O (mes = 2,4,6-trimethylphenyl), and trimesityliridium(III), (mes)3Ir, undergo extremely rapid degenerate intermetal oxygen atom transfer at room temperature. At low temperatures, the two complexes conproportionate to form (mes)3Ir-O-Ir(mes)3, the 2,6-dimethylphenyl analogue of which has been characterized crystallographically. Variable-temperature NMR measurements of the rate of dissociation of the mu-oxo dimer combined with measurements of the conproportionation equilibrium by low-temperature optical spectroscopy indicate that oxygen atom exchange between iridium(V) and iridium(III) occurs with a rate constant, extrapolated to 20 degrees C, of 5 x 107 M-1 s-1. The oxotris(imido)osmium(VIII) complex (ArN)3Os=O (Ar = 2,6-diisopropylphenyl) also undergoes degenerate intermetal atom transfer to its deoxy partner, (ArN)3Os. However, despite the fact that its metal-oxygen bond strength and reactivity toward triphenylphosphine are nearly identical to those of (mes)3Ir=O, the osmium complex (ArN)3Os=O transfers its oxygen atom 12 orders of magnitude more slowly to (ArN)3Os than (mes)3Ir=O does to (mes)3Ir (kOsOs = 1.8 x 10-5 M-1 s-1 at 20 degrees C). Iridium-osmium cross-exchange takes place at an intermediate rate, in quantitative agreement with a Marcus-type cross relation. The enormous difference between the iridium-iridium and osmium-osmium exchange rates can be rationalized by an analogue of the inner-sphere reorganization energy. Both Ir(III) and Ir(V) are pyramidal and can form pyramidal iridium(IV) with little energetic cost in an orbitally allowed linear approach. Conversely, pyramidalization of the planar tris(imido)osmium(VI) fragment requires placing a pair of electrons in an antibonding orbital. The unique propensity of (mes)3Ir=O to undergo intermetal oxygen atom transfer allows it to serve as an activator of dioxygen in cocatalyzed oxidations, for example, acting with osmium tetroxide to catalyze the aerobic dihydroxylation of monosubstituted olefins and selective oxidation of allyl and benzyl alcohols.     

Density functional methods in the study of oxygen transfer reactions

The oxygen transfer reactions from heterocyclic compounds such as oxaziridine, methyldioxirane and ethylene oxide to ethylene and phosphine have been studied using different computational methods, and the results have been compared to those obtained with CASPT2 and CBS-QB3 methods. The results show that the generalized gradient approximation (GGA) functionals BLYP and PBEPBE, highly underestimate the barriers. On the other hand, the hybrid meta-GGA functionals (BB1K, M05 and M05-2X) and BHandHLYP tend to overestimate the barriers. Finally, the B3LYP and OPBE functionals provide reasonable barriers. Nevertheless, none of the tested functionals describes all the studied reactions with the same accuracy.     

A study of the electron transfer and oxygen binding reactions of myoglobin

Quasi-reversible electron transfer kinetics are reported for sperm whale myoglobin reacting at tin-doped indium oxide electrodes. This reaction was studied by three different electrochemical methods; cyclic voltammetry (CV), single potential step chronoabsorptometry (SPS/CA) and derivative cyclic voltabsorptometry (DCVA). Kinetic parameters were determined from experiments which followed the purification of the protein, the pretreatment of the electrode surface and the removal of dioxygen from the sample solution. A formal heterogeneous electron transfer rate constant, k^0'. of 2.6 (±0.5) × 10⁻⁵ cm s⁻¹ and a transfer coefficient, α, of 0.48 (±0.05) were obtained using SPS/CA. These results are shown to correlate well with those obtained using a second spectroelectrochemical method, DCVA. Anodic and cathodic responses for the heterogeneous electron transfer of myoglobin can be observed using cyclic voltammetry, but these responses are not as reproducible as those that are obtained using the optical methods described here. The advantages of these optical methods over those of cyclic voltammetry are clear from this study.     

Theoretical studies of electron and hydrogen transfer reactions between semiquinone radicals and oxygen

 To explore the interactions between ubiquinones and oxygen in living organisms, the thermodynamics of a series of electron and hydrogen transfer reactions between semiquinone radicals, as well as their corresponding protonated forms, and oxygen, singlet or triplet, were studied using the hybrid Hartree–Fock–density functional theory method Becke's three parameter hybrid method with the Lee, Yang, and Parr correlation functional. Effects of the solvent and of the isoprenyl tail on the electron and hydrogen transfer reactions were also investigated. It is found that semiquinone radicals (semiquinone anion radicals or protonated semiquinone radicals) cannot react with triplet oxygen to form the superoxide anion radical O₂ ⁻. In contrast, neutral quinones can scavenge O₂ ⁻ efficiently. In the gas phase, only protonated semiquinone radicals can react spontaneously with singlet oxygen to produce peroxyl radical (HO₂). However, both semiquinone anion radicals and protonated semiquinone radicals can react with singlet oxygen to produce harmful oxygen radicals (O₂ ^{− a l l b u l l} and HO₂, respectively) in aqueous and protein environments. The free-energy changes of the corresponding reactions obtained for different ubiquinone systems are very similar. It clearly shows that the isoprenyl tail does not influence the electron and hydrogen transfer reactions between semiquinone radicals and oxygen significantly. Results of electron affinities, vertical ionization potentials, and proton affinities also show that the isoprenyl tail has no substantial effect on the electronic properties of ubiquinones. Received: 3 July 2000 / Accepted: 6 September 2000 / Published online: 21 December 2000     

Ab initio and post-ab initio quantum chemical study of the heme spin states in electron transfer reactions

Quantum-chemical calculations of neutral and charged ironporphyrin (FeP, FeP⁺¹ and FeP⁻) systems were performed using B3LYP and MP2 methods. It was shown that all ground states of FeP (S = 1), FeP⁺¹ (S = 3/2) and FeP⁻ (S = 1/2) systems have C_2v symmetry. During the first step of electron transfer process an electron goes to β-LUMO − 1 Fe d_yz-orbital of FeP⁺¹. The second electron goes to β-LUMO of FeP which is attributed to π-system of porphyrin ring. The 3s- and 3p-orbitals do not play a significant role in the electron transfer process. The ability of FeP⁻¹ system to form π-dative chemical bond is low. The formation of π–π-complexes is preferable.     

Ultrasound-responsive polymer-coated microbubbles that bind and protect DNA

Ultrasound in combination with microbubbles has recently been considered by gene delivery scientists to be an interesting approach to enhance gene transfer into cells. Its low toxicity and simplicity to apply in vivo without major complications make this technology (sonoporation) especially attractive. Sonoporation of DNA has been evaluated in vivo by the injection of free plasmid DNA (pDNA) together with microbubbles (as used in diagnostic imaging) in the bloodstream. However, the in vivo gene-transfer efficiency in these experiments remained rather low. Both the enzymatic degradation of the injected pDNA as well as the low pDNA concentration in the neighborhood of sonoporated cell membranes may explain this low efficiency. Therefore, we developed polymer-coated microbubbles that can bind and protect the pDNA. Coating albumin-shelled microbubbles with poly(allylamine hydrochloride) (PAH) makes the surface charge of the microbubbles positive without drastically affecting the size distribution of the microbubbles, thereby not affecting the ultrasound responsiveness and injectability. The cationic coating allowed both to bind up to 0.1 pg of DNA per microbubble as well as to protect the bound DNA against nucleases. Finally, the PAH coating significantly increased the lifetime of the microbubbles (half-life approximately 7 h), making them more convenient for in vivo applications because more microbubbles are expected to reach the target organ. Binding and nuclease protection of DNA by polymer-coated diagnostic microbubbles has, to our knowledge, never been demonstrated. We conclude that these LbL-coated microbubbles might be significant in the further development of ultrasound-mediated gene delivery.     

l-Proline amides catalyze direct asymmetric aldol reactions of aldehydes with methylthioacetone and fluoroacetone

Direct aldol reactions of aldehydes with methylthio- and fluoroacetone catalyzed by proline amides have been investigated. l-Prolinamide 5e was found to be the best catalyst. Under the optimized reaction conditions, a series of aromatic and aliphatic aldehydes reacted smoothly with methylthioacetone, to generate 1-methylthio-4-hydroxyketones 3 in good yields and with high regio- and enantioselectivities. Excellent enantioselectivities of up to 98% ee were observed for aromatic aldehydes and even higher enantioselectivities of >99% ee were observed for aliphatic aldehydes. Asymmetric direct aldol reactions of fluoroacetone with aldehydes in the presence of 20 mol % of 5e preferentially occurred at the fluoromethyl group, yielding products with high enantioselectivities (up to 98% ee).     

The preparation and X-ray structural study of complexes that catalyze isocyanate cyclotrimerization

A 11-complex of trinitrophenol with benzyldimethylamine (1) and a 111-complex, the product of the interaction of benzyldimethylamine, glycidyl phenyl ether, and phenol (2), have been synthesized and characterized by means of X-ray analysis. Complex1 is a precursor for the catalysts of selective isocyanate cyclotrimerization, while complex2 is one of those catalysts. In the crystal structure complex1 forms H-bonded cationic-anionic aggregates with proton transfer from phenol to the N-atom of the tertiary amine. Complex2 crystallizes as a monohydrate (2a) with a strong H-bond between the quaternary ammonium and phenolic components, and exists in crystals in the form of globular H-bonded dimeric hydrates. Possible pathways of dissociation of complex2a are discussed. The data obtained may be used as a basis for further interpretation of the regularities of cyclotrimerization of isocyanates catalyzed by complexes of this type.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No 1, pp. 92–97, January, 1993.     

RNA aptamers that bind flavin and nicotinamide redox cofactors

RNA molecules that specifically bind riboflavin (Rb) and beta-nicotinamide mononucleotide (NMN) have been isolated by in vitro selection. A simple structural motif containing intramolecular G-quartets was found to bind tightly to oxidized riboflavin (Kd = 1-5 micromolar). DNA versions of the consensus sequence also bind, but with weaker affinity. DMS protection experiments show that the quartet structure of these aptamers is stabilized by interaction with the flavin. As a measure of their redox specificity, the aptamers do not show significant differential binding between oxidized and reduced forms of a 5-deazariboflavin derivative that is a close structural analog of riboflavin. In contrast to the lack of redox specificity of the riboflavin aptamers, RNAs selected for binding to the nicotinamide portion of NAD discriminate between NAD and NADH in solution by over an order of magnitude. A mutagenized pool based on one of the NMN aptamer sequences was used to reselect for NMN binding. Comparison of the reselected sequences led to the identification of the binding region of the aptamer. A complex secondary structure containing two interacting stem-loops is proposed for the minimal NMN-binding RNA. The same mutagenized pool was used to select for increased discrimination between NMN and NMNH. From these reselected sequences, a mutation within the binding region was identified that increases specificity for NMN. These experiments show that RNA can bind these cofactors with low micromolar affinity and, in the case of nicotinamide cofactors, can discriminate between the two redox states. These cofactor binding motifs may provide a framework for generating new ribozymes that catalyze redox reactions similar to those found in basic metabolic pathways.     

Studies on the oxygen atom transfer reactions of peroxomonosulfate: Oxidation of glycolic acid

The kinetics of oxidation of glycolic acid, an α‐hydroxy acid, by peroxomonosulfate (PMS) was studied in the presence of Ni(II) and Cu(II) ions and in acidic pH range 4.05–5.89. The metal glycolate, not the glycolic acid (GLYCA), is oxidized by PMS. The rate is first order in [PMS] and metal ion concentrations. The oxidation of nickel glycolate is zero‐order in [GLYCA] and inverse first order in [H⁺]. The increase of [GLYCA] decreases the rate in copper glycolate, and the rate constants initially increase and then remain constant with pH. The results suggest that the metal glycolate ML⁺ reacts with PMS through a metal‐peroxide intermediate, which transforms slowly into a hydroperoxide intermediate by the oxygen atom transfer to hydroxyl group of the chelated GLYCA. The effect of hydrogen ion concentrations on k_obs suggests that the structure of the metal‐peroxide intermediates may be different in Ni(II) and Cu(II) glycolates. © 2008 Wiley Periodicals, Inc. Int J Chem Kinet 41: 160–167, 2009     

Studies on the oxygen atom transfer reactions of peroxomonosulfate: Oxidation of lactic acid

Kinetics of oxidation of lactic acid by peroxomonosulfate (PMS) catalyzed by Ni(II) ions has been studied in aqueous buffered (sodium acetate‐acetic acid) medium. The reaction follows first order in [PMS] and [Ni(II)] and inverse first order in [H⁺]. The effect of pH on the rate suggests that both HSO and SO are the active forms of the oxidant. The intermolecular reaction between HSO and nickel lactate results in hydroperoxide intermediate in the rate‐limiting step. The deprotonated form of PMS, SO, gives a lactate‐nickel‐peroxomonosulfate intermediate, which then undergoes intramolecular oxidation–reduction reaction. The thermodynamic parameters also support the kinetic scheme. Comparison with (nickel) glycolate shows that the electron‐donating methyl group in lactic acid enhances the nucleophilic interaction of the α‐hydroxyl group. A suitable mechanistic scheme is also proposed. © 2009 Wiley Periodicals, Inc. Int J Chem Kinet 41: 449–454, 2009     

Studies on the oxygen atom transfer reactions of peroxomonosulfate: Catalytic effect of hemiacetal

The reaction of peroxomonosulfate (PMS) with glycolic acid (GLYCA), an alpha hydroxy acid, in the presence of Ni(II) ions and formaldehyde was studied in the pH range 4.05–5.89 and at 31°C and 38°C. When formaldehyde and Ni(II) ions concentrations are ～5.0 × 10^?4 M to 10.0 × 10^?4 M, the reaction is second order in PMS concentration. The rate is catalyzed by formaldehyde, and the observed rate equation is (?d[PMS])/dt = (k′₂[HCHO][Ni(II)][PMS]²)/{[H⁺](1+K₂[GLYCA])}. The number of PMS decomposed for each mole of formaldehyde (turnover number) is 5–10, and the major reaction product is oxygen gas. The first step of the reaction mechanism is the formation of hemiacetal by the interaction of HCHO with the hydroxyl group of nickel glycolate. The peroxomonosulfate intermediate of the Ni‐hemiacetal reacts with another molecule of PMS in the rate‐limiting step to give the product. This reaction is similar to the thermal decomposition of PMS catalyzed by Ni(II) ions. © 2009 Wiley Periodicals, Inc. Int J Chem Kinet 41: 642–649, 2009     

Nonclassical oxygen atom transfer reactions of oxomolybdenum(VI) bis(catecholate)

Mechanistic studies indicate that the oxomolybdenum(vi) bis(3,5-di-tert-butylcatecholate) fragment deoxygenates pyridine-N-oxides in a reaction where the oxygen is delivered to molybdenum but the electrons for substrate reduction are drawn from the bound catecholate ligands, forming 3,5-di-tert-butyl-1,2-benzoquinone.