Synthetic Analogues of Dinitrosyl Iron Complexes: Reactivity Studies and Improvements towards Therapeutic Applications

Dinitrosyl iron complexes (DNICs) are organometallic-like compounds formed endogenously as products of degradation of iron-sulfur clusters by NO or its interaction with the cellular chelatable iron pool. Substantial evidence has accrued on the role of DNICs as endogenous transport and storage agents for the highly reactive NO radical. Such biological significance has led to biomimetic work on such entities in synthetic inorganic chemistry. Recently, such synthetic models have emerged as a new class of potential NO releasing agents. A series of N-heterocyclic carbene (NHC)-stabilized oxidized and reduced DNICs ({Fe(NO)2}^9 /{Fe(NO)2}^10: Enemark-Feltham notation) appeared promising candidates for further investigations on the reactivity of DNICs and on synthetic improvements for possible therapeutic applications. Planar NHC ligands mimic ligands such as imidazole, itself a surrogate for histidine. A base-promoted conversion was observed of an N-alkyl imidazole bearing, neutral {Fe(NO)2}^10 DNIC to the NHC-DNIC, while maintaining the Fe(NO)2 unit intact. Subsequent alkylation led to the isolation of the NHC-DNIC product; signifying the integrity of the Fe(NO)^2 unit and further establishing that NHCs are ‘better’ ligands to Fe(NO)2 than imidazoles. Making use of an NHC-stabilized DNIC [(NHC)(RS)Fe(NO)2], a RS^−/RS• oxidation process in the presence of added CO was discovered, wherein the oxidized {Fe(NO)2}^9 is reduced to {Fe(NO)2}^10 through carbon monoxide (CO)/RS• ligand substitution. Kinetic studies established a bimolecular rate law and activation parameters suggested an associative mechanism. Computational results indicated a unique role for the delocalized frontier molecular orbitals of the Fe(NO)2 unit, involving an initial side-on approach of CO to the electron-rich N-Fe-N site. Attempts to further test the aforementioned computational proposal employed classical Hammett correlations for the elucidation of structure-activity relationships. Hammett correlations were used to monitor the changes in electron density at the {Fe(NO)2} unit and effects on the rate of reaction with CO of a series of (NHC)(SPhX)Fe(NO)2 derivatives with varying para substituents at the aryl thiolate. In accordance with the computational mechanistic proposal, rate enhancement was observed with increasing electron donating ability of the substituents. Although DNICs appear to be promising candidates in the context of nitric oxide releasing therapeutics, their lack of biocompatibility has hindered the progress of such applicability. The first examples of ‘sugar appended’ monomeric and dimeric DNICs were synthesized, making use of the tuning sites provided by the NHC-DNIC architecture. Such efforts are among the few examples for the synthesis of bio-functionalized DNICs

In Situ Spectroscopic Investigation of the Rhenium-Catalyzed Deoxydehydration of Vicinal Diols

The mechanism of the CH3ReO3-catalyzed deoxydehydration of a vicinal diol to an alkene driven by oxidation of a secondary alcohol was investigated by time-resolved, in situ IR spectroscopy and was found to occur in three steps: 1) reduction of the catalytically active methyltrioxorhenium(VII) to a rhenium(V) complex (the rate-limiting step), 2) condensation of the diol and the rhenium(V) complex to a rhenium(V) diolate, and 3) extrusion of the alkene accompanied by oxidation of the Re center and thus regeneration of CH3ReO3. The reaction follows zero-order kinetics initially but, unexpectedly, accelerates towards the end, which is explained in terms of a deactivating pre-equilibrium, in which the catalytically active CH3ReO3 condenses reversibly with the diol to form an inactive rhenium(VII) diolate. This conclusion is supported by the direct observation of a catalytically inactive species as well as DFT calculations of the IR spectra of the relevant compounds

Carbon monoxide induced elimination of disulfide from dinitrosyl iron complexes: Hammett correlations of para-substituted [(NHC)Fe(NO)2S(p-PhX)] compounds

[[conferencetype]]國際[[conferencedate]]20140810~20140814[[booktype]]紙本[[iscallforpapers]]Y[[conferencelocation]]San Francisco, CA, United State

Metabolic Pathways of Pathogenic Planktonic & Biofilm Bacterial Communities: A Bottom-up Proteomic Study

The cause for persistence of chronic wounds is identified as antibiotic resistance which is caused by the mixed species of microbes that live together in synergy. The basic design of these consortia biofilms is poorly understood, and in-depth characterization of these complex systems is necessary. This dissertation presents the application of tandem mass spectrometric methodology to determine proteins that predict the phenotypic changes in pathogenic bacterial monocultures, cocultures and biofilm aggregates. These complex systems undergo adaptation to perturbations in their environment and they are observed to be resistive in the presence of other species that aid survival of these multiple species. A detailed description of the current understanding of their survival and threat is highlighted along with improvements in sample preparation, availability of high-resolution commercial instruments and their capability to help determine hundreds of protein identities. Data manipulation and interpretation methods with statistical software availability are elaborated in detail. The next part of this work presents proteomic data to validate the existence of pathogenic bacteria in oxygen deprived or excessive lactate supplemented diverse environments. These are simulations of natural environments in which these organisms thrive including the lungs of cystic fibrosis patients or the wound surfaces of diabetes mellitus patients. The highlight of this work is presented in the latter half of the thesis, where an application and development of a method of sampling was tested to remove biofilm material from surfaces using laser irradiation. This method enabled determination of the variations in cells that grow as layers within a biofilm to distinguish differences as they experience an oxygen and nutrient gradient. Finally, it was deemed necessary to determine methods to elucidate the presence or absence of contaminants (especially viral) in bacterial cultures to maintain reproducibility of results interpreted through the protein data obtained. Current practices were tested on already available data as a proof of concept of the work presented. Overall, these experiments were conducted to examine the growth phenotype of planktonic cultures and biofilms of disease-causing pathogenic bacteria Pseudomonas aeruginosa and Staphylococcus aureus. The data obtained in the thesis is to cater a larger goal of supporting computational models that is preliminarily dedicated to a three species model of a chronic wound biofilm which includes Pseudomonas aeruginosa (an aerobe), Staphylococcus aureus (a facultative anaerobe) and Clostridium perfringens (an anaerobe) pathogenic bacterial species. The refinement of these models and the applicability is enhanced by the data provided based on spatially resolved analytical methods developed and implemented

Routes to complexes of open chain polyethers

The open chain polyethers, 1-(o-carboxymethoxyphenoxy)-2-(ohydroxyphenoxy) ethane HL(A), HL(B), and the diol were prepared and characterised by m.pt. and IR and 1H NMR spectroscopies. In order to determine whether the ions other than Co(II) or Zn(ll) can form complexes of type [M(M'L2)2 (M = Transition element, M' = monovalent ion), the extraction of the metal ions Co(II), Ni(II), Cu(ll), Fe(ffl), Cr(ffl), and Pr(Ill) in the presence of K, Rb, Cs, and NH4 in an aqueous solution into the solutions of HL or HL(B) in methylene chloride was studied over a pH range. In contrast to conclusions reached previous, it was found that the Cu(ll) was extracted as [CuL2] and not as [Cu(KL2)2]. The structure of the blue crystals grown from the organic solution was determined using DTG (1-120), AAS (Cu), UV, IX, EXAFS and microanalysis (C, H) and the crystal structure was determined by X-ray crystallography. Attempts were made to substitute protonated amnes for the group 1 metals or NH4 ions in compounds of type [M(M'L2)2], (using HL and HL(B)) both in direct addition reactions and in solvent extraction studies. Extraction studies with some protonated amino esters, amino acids and alkyl ammOnium chlorides showed that Co(II), Ni(II), or Zn(ll) could not be extracted effectively from aqueous solution. The work has shown that only a very few systems analogous to [Co(KL2)2] appear sufficiently stable for isolation and extraction studies; protonated organic amines seem relatively ineffectual. Accordingly, it was decided to explore the possibility of inserting phosphonate residues into polyether ligands to develop a new class of ligands. Although the presence of phosphorus containing crown ether systems is known, it was found that the direct insertion of the phosphonate residues on to polyether ligands is not possible. As an another route to complexes of open chain polyethers, it was decided to introduce the open chain polyethers on to the phosphonateplatinum(II) complexes. Due to the requirement for a labile alkyl group on the phosphonate, it was decided to study the co-ordination chemistry of t-butyl phosphonate with platinum(ll). In reactions between (RO)2PHO and [PtC12(COD)], (COD = cyclo-octa- 1,5-diene) greater steric hindrance when R = t-Bu inhibits formation of the normal product [Pt((RO)2POH)2{(RO)2P0)2] (R = Me, Et and Ph) and results in formation of the symmetrical chlorine bridged complex [Pt2C12RRO)2POH}2{(RO)2PO}2]. The bridge is readily cleaved by neutral donors (L) to give cis-[PtC1(L){(RO)2POH}{(RO)2P0}] (L = amines, R3P, R3As, Ph3Sb, Ph3PSe, MeCN, DMSO), and trans-[PtC1(L){(RO)2POH}- ((RO)2P0)] where L = t-BuNC and Cl - to give [PtC12((RO)2POH)2]. In cis-[PtC1(L){(RO)2POH}{(RO)2P0}] the chloride ligand has been replaced by anionic ligands X, where X = Br, I, N3, NCO, NCS, NO2, 0NO2, 02CMe, 02CCF3, CN, CL!3, and H). The POH proton participates in an intramolecular hydrogen bond to the P0 group and may be replaced by Li or Na+. The complexes provide a general route to complexes of primary phosphites (HO)2POR and of phosphorus(uI) acid; the t-butyl groups of cis- [PtC1(Ph3P) ((t-BuO)2POH) {(t-BuO)2P0}] are cleaved sequentially by CF3COOH, eventually forming cis-EPtC1(Ph3P){(H0)3P)RHO)2P0)], the crystal structure of which shows an approximately planar ring formed by Pt, two P0 groups and a connecting hydrogen bond. All complexes have been characterised by 31P NMR specroscopy

Carbon Monoxide Induced Reductive Elimination of Disulfide in an N-Heterocyclic Carbene (NHC)/ Thiolate Dinitrosyl Iron Complex (DNIC)

[[abstract]]Dinitrosyliron complexes (DNICs) are organometallic-like compounds of biological significance in that they appear in vivo as products of NO degradation of iron–sulfur clusters; synthetic analogues have potential as NO storage and releasing agents. Their reactivity is expected to depend on ancillary ligands and the redox level of the distinctive Fe(NO)2 unit: paramagnetic {Fe(NO)2}9, diamagnetic dimerized forms of {Fe(NO)2}9 and diamagnetic {Fe(NO)2}10 DNICs (Enemark–Feltham notation). The typical biological ligands cysteine and glutathione themselves are subject to thiolate-disulfide redox processes, which when coupled to DNICs may lead to intricate redox processes involving iron, NO, and RS–/RS•. Making use of an N-heterocyclic carbene-stabilized DNIC, (NHC)(RS)Fe(NO)2, we have explored the DNIC-promoted RS–/RS• oxidation in the presence of added CO wherein oxidized {Fe(NO)2}9 is reduced to {Fe(NO)2}10 through carbon monoxide (CO)/RS• ligand substitution. Kinetic studies indicate a bimolecular process, rate = k [Fe(NO)2]1[CO]1, and activation parameters derived from kobs dependence on temperature similarly indicate an associative mechanism. This mechanism is further defined by density functional theory computations. Computational results indicate a unique role for the delocalized frontier molecular orbitals of the Fe(NO)2 unit, permitting ligand exchange of RS• and CO through an initial side-on approach of CO to the electron-rich N–Fe–N site, ultimately resulting in a 5-coordinate, 19-electron intermediate with elongated Fe–SR bond and with the NO ligands accommodating the excess charge.[[notice]]補正完畢[[journaltype]]國外[[ispeerreviewed]]Y[[booktype]]紙本[[booktype]]電子版[[countrycodes]]US

Mesomorphism of imidazolium-based fluorinated ionic liquids

Ionic liquid crystals have received increasing interest due to their positional and/or orientational order as well as the freedom in molecular motions that arise from the formation of mesophases between solid and liquid. While phase changes of non-fluorinated ionic liquids have been widely reported, there have been few reports on the temperature-dependent phase behavior of fluorinated ionic liquids. Here, we present a series of fluorinated ionic liquids with methylimidazolium cations bearing 1H, 1H, 2H, 2H-perfluoroalkyl chains (butyl, hexyl, and octyl) and halide counterions, and demonstrate their thermotropic mesomorphism. These cations were synthesized under solvent-free conditions, and anion exchange was used to vary the halide counterion. The thermal behavior of the compounds was studied using thermogravimetric analysis and differential scanning calorimetry, revealing both liquid crystalline phases and solid-solid phase transitions. We discovered that the mesomorphic properties of the ionic liquids depend strongly on the length of the perfluoroalkyl pendants. Specifically, ionic liquids with a fluorinated butyl chain showed no mesophase behavior while those with hexyl and octyl fluorinated chains displayed liquid crystalline phases at temperatures above 100 °C. The mesophases were further characterized by polarized optical microscopy and powder X-ray diffraction, highlighting the impact of the fluorinated alkyl chain length

Spatially resolved analysis of Pseudomonas aeruginosa biofilm proteomes measured by laser ablation sample transfer

Heterogeneity in the distribution of nutrients and oxygen gradients during biofilm growth gives rise to changes in phenotype. There has been long term interest in identifying spatial differences during biofilm development including clues that identify chemical heterogeneity. Laser ablation sample transfer (LAST) allows site-specific sampling combined with label free proteomics to distinguish radially and axially resolved proteomes for Pseudomonas aeruginosa biofilms. Specifically, differential protein abundances on oxic vs. anoxic regions of a biofilm were observed by combining LAST with bottom up proteomics. This study reveals a more active metabolism in the anoxic region of the biofilm with respect to the oxic region for this clinical strain of P. aeruginosa, despite this organism being considered an aerobe by nature. Protein abundance data related to cellular acclimations to chemical gradients include identification of glucose catabolizing proteins, high abundance of proteins from arginine and polyamine metabolism, and proteins that could also support virulence and environmental stress mediation in the anoxic region. Finally, the LAST methodology requires only a few mm2 of biofilm area to identify hundreds of proteins

Hammett correlations as test of mechanism of CO-induced disulfide elimination from dinitrosyl iron complexes

[[abstract]]The displacement of RS˙ from [(NHC)(SPh)Fe(NO)2] (NHC = N-heterocyclic carbene) by carbon monoxide follows associative kinetics, rate = k [CO]1 [(NHC)(SPh)Fe(NO)2]1, resulting in reduction of the oxidized form of the dinitrosyliron unit, {Fe(NO)2}9 (Enemark–Feltham notation) to {Fe(NO)2}10. Thermodynamically driven by the release of PhS–SPh concomitant with formation of [(NHC)(CO)Fe(NO)2], computational studies suggested the reactant dinitrosyliron unit serves as a nucleophile in the initial slanted interaction of the π* orbital of CO, shifting into normal linear Fe–CO with weakening of the Fe–SPh bond. The current study seeks to experimentally test this proposal. A series of analogous {Fe(NO)2}9 [(NHC)(p-S–C6H4X)Fe(NO)2] complexes, with systematic variation of the para-substituents X from electron donor to electron withdrawing groups was used to monitor variation in electron density at the Fe(NO)2 unit via Hammett analyses. Despite the presence of non-innocent NO ligands, data from ν(NO) IR spectroscopy and cyclic voltammetry showed consistent tracking of the electron density at the {Fe(NO)2} unit in response to the aryl substituent. The electronic modifications resulted in systematic changes in reaction rates when each derivative was exposed to CO. A plot of the rate constants and the Hammett parameter σp is linear with a negative slope and a ρ value of −0.831; such correlation is indicative of rate retardation by electron-withdrawing substituents, and provides experimental support for the unique role of the delocalized frontier molecular orbitals of the Fe(NO)2 unit.[[incitationindex]]SCI[[booktype]]紙

Synthesis and Characterization of Fluorinated Ionic Liquids and Their Application in Hydrofluorocarbon Gas Uptake

This study reports the synthesis and comprehensive characterization of five fluorinated ionic liquids (FILs), each composed of an imidazolium cation of varied fluoroalkyl chain lengths paired with a fluorinated anion: a newly developed aromatic sulfonamide, bistriflimide (Tf2N), or iodide. The relationship between molecular structure and physical properties, including thermal behavior, density, and viscosity, is reported. The identity of the anion has the strongest effect on both thermal stability and thermal behavior, whereas elongation of the fluorinated alkyl chain of the cation more strongly influences density and viscosity. These observations suggest nanosegregation within the liquid and the formation of three microphases (polar, nonpolar, and fluorous). We then evaluate the solubilities of commonly used hydrofluorocarbon refrigerant gases, HFC-32 (difluoromethane) and HFC-125 (pentafluoroethane), in the neat and encapsulated FILs, comparing their performance against commercially available ionic liquids (ILs). We find higher solubilities of HFC-32 in the FILs relative to nonfluorinated commercial ILs that exhibited greater solubility of HFC-125, highlighting selective gas absorption. Additionally, we observe that encapsulated FILs exhibit trends in gas uptake analogous to those of neat FILs. This work not only contributes to a deeper understanding of the structure–property relationships in FILs but also presents promising avenues for their utilization in HFC gas uptake and separation processes, emphasizing the potential of encapsulated FILs as a viable technology to overcome challenges associated with high viscosities of ILs in bulk processing