Anion Pathway Research Articles

Mechanism of Cu/Pd-catalyzed decarboxylative cross-couplings: a DFT investigation.

The reaction mechanism of decarboxylative cross-couplings of benzoates with aryl halides to give biaryls, which is cooperatively catalyzed by copper/palladium systems, was investigated with DFT methods. The geometries and energies of all starting materials, products, intermediates, and transition states of the catalytic cycle were calculated for the two model reactions of potassium 2- and 4-fluorobenzoate with bromobenzene in the presence of a catalyst system consisting of copper(I)/1,10-phenanthroline and the anionic monophosphine palladium complex [Pd(PMe3)Br](-). Several neutral and anionic pathways were compared, and a reasonable catalytic cycle was identified. The key finding is that the transmetalation has a comparably high barrier as the decarboxylation, which was previously believed to be solely rate-determining. The electronic activation energy of the transmetalation is rather reasonable, but the free energy loss in the initial Cu/Pd adduct formation is high. These results suggested that research aimed at further improving the catalyst should target potentially bridging bidentate ligands likely to assist in the formation of bimetallic intermediates. Experimental studies confirm this somewhat counterintuitive prediction. With a bidentate, potentially bridging ligand, designed to support the formation of bimetallic adducts, the reaction temperature for decarboxylative couplings was reduced by 70 °C to only 100 °C.

ChemInform Abstract: Base‐Catalyzed Tandem Michael/Dehydro‐Diels—Alder Reaction of α,α‐Dicyanoolefins with Electron‐Deficient 1,3‐Conjugated Enynes: A Facile Entry to Angularly Fused Polycycles.

Angularly fused carbocyclic frameworks and their heteroatom-substituted analogues exist in many natural products that display a broad and interesting range of biological activities. Preparation of polycyclic products by cycloaddition reactions have been the long-standing hot topic in the synthetic community. Dehydro-Diels-Alder (DDA) reactions are one class of dehydropericyclic reactions that are derived conceptually by systematic removal of hydrogen atom pairs. A base-promoted tandem Michael addition and DDA reaction of α,α-dicyanoolefins with electron-deficient 1,3-conjugated enynes was realized in which a DDA reaction takes place between the arylalkynes and electron-deficient tetrasubstituted olefin. The control experiments support the stepwise anionic reaction pathway rather than the concerted reaction pathway.

Slc26a7 Chloride Channel Activity and Localization in Mouse Reissner’s Membrane Epithelium

Several members of the SLC26 gene family have highly-restricted expression patterns in the auditory and vestibular periphery and mutations in mice of at least two of these (SLC26A4 and SLC26A5) lead to deficits in hearing and/or balance. A previous report pointed to SLC26A7 as a candidate gene important for cochlear function. In the present study, inner ears were assayed by immunostaining for Slc26a7 in neonatal and adult mice. Slc26a7 was detected in the basolateral membrane of Reissner’s membrane epithelial cells but not neighboring cells, with an onset of expression at P5; gene knockout resulted in the absence of protein expression in Reissner’s membrane. Whole-cell patch clamp recordings revealed anion currents and conductances that were elevated for NO3 − over Cl− and inhibited by I− and NPPB. Elevated NO3 − currents were absent in Slc26a7 knockout mice. There were, however, no major changes to hearing (auditory brainstem response) of knockout mice during early adult life under constitutive and noise exposure conditions. The lack of Slc26a7 protein expression found in the wild-type vestibular labyrinth was consistent with the observation of normal balance. We conclude that SLC26A7 participates in Cl− transport in Reissner’s membrane epithelial cells, but that either other anion pathways, such as ClC-2, possibly substitute satisfactorily under the conditions tested or that Cl− conductance in these cells is not critical to cochlear function. The involvement of SLC26A7 in cellular pH regulation in other epithelial cells leaves open the possibility that SLC26A7 is needed in Reissner’s membrane cells during local perturbations of pH.

The Thermal Stability of Tris(methimazolyl)borates and Their Germanium Complexes

AbstractA series of methimazole‐based soft scorpionate anions ([RTmMe]–, R = H, Ph, Me, nBu) bearing substitution at the bridgehead boron have been used to produce a series of germanium complexes of general formulae [Ge(RTmMe)2]I2. Structural analyses of the germanium complexes by X‐ray crystallography reveal that they all contain an octahedral S6 coordination sphere. The scorpionate anions (as their Li or Na salts) and their germanium complexes have been studied by thermogravimetric analysis. This analysis suggests that the degradation pathway for the free scorpionate anions differs from that of the complexes. Both pathways involve the loss of a methimazole ring thereby supporting the view that cleavage of the boron–nitrogen bonds can occur under thermally aggressive conditions. As expected, the presence of the germanium alters the degradation profile of the anion. In contrast to the free anions, the four complexes all display a similar mechanism for degradation. Although the presence of the germanium enforces a conformational change in the anions, its presence does not significantly increase the stability of the boron–nitrogen bonds.

Computational Study on the Mechanism of the Electron-Transfer-Induced Repair of the (6–4) T–T Photoproduct of DNA by Photolyase: Possibility of a Radical Cation Pathway

Abstract The oxetane and the non-oxetane mechanisms of the electron-transfer-driven repair of the (6–4) T–T photolesion of DNA by photolyase are examined by density functional theory (B3LYP). We calculated the radical cation pathway in addition to the radical anion and the neutral pathways for both mechanisms in order to assess the possibility of the radical cation pathway, because relatively large energy barriers have been found for the radical anion pathway. As a result, the radical anion pathway showed a large energy barrier in both the oxetane and the non-oxetane mechanisms in agreement with previous calculations. However, it was found that the radical cation pathway of the oxetane mechanism has a realistic low energy barrier. This advantage of the radical cation pathway was ascribed to the position of the radical before the formation of the oxetane and the stability of the oxetane in energy.

Base‐Catalyzed Tandem Michael/Dehydro‐Diels–Alder Reaction of α,α‐Dicyanoolefins with Electron‐Deficient 1,3‐Conjugated Enynes: A Facile Entry to Angularly Fused Polycycles

Angularly fused carbocyclic frameworks and their heteroatom-substituted analogues exist in many natural products that display a broad and interesting range of biological activities. Preparation of polycyclic products by cycloaddition reactions have been the long-standing hot topic in the synthetic community. Dehydro-Diels-Alder (DDA) reactions are one class of dehydropericyclic reactions that are derived conceptually by systematic removal of hydrogen atom pairs. A base-promoted tandem Michael addition and DDA reaction of α,α-dicyanoolefins with electron-deficient 1,3-conjugated enynes was realized in which a DDA reaction takes place between the arylalkynes and electron-deficient tetrasubstituted olefin. The control experiments support the stepwise anionic reaction pathway rather than the concerted reaction pathway.

ChemInform Abstract: N‐Heterocyclic Carbene Catalyzed Addition of Aldehydes to Diazo Compounds: Stereoselective Synthesis of N‐Acylhydrazones.

An innovative stereoselective synthesis of N-acylhydrazones via an unprecedented N-heterocyclic carbene catalyzed addition of aldehydes to diazo compounds is presented. Enals exclusively afforded N-acylhydrazones, in yields up to 91%. The observed regioselectivity was traced back to the reaction of the vinylogous Breslow intermediate via the acyl anion pathway over competing homoenolate, enol, and acyl azolium pathways. This unusual reaction profile was studied based on DFT calculations, which revealed that the reaction is under orbital control, rather than being ruled by charge.

ChemInform Abstract: Facile Synthesis of 2‐Substituted Benzo[b]thiophen‐3‐ols in Water.

Abstract A facile synthesis of 2-substituted benzo[b]thiophen-3-ols in a simple reaction system is reported with water as the only media. Density functional theory (DFT) investigations suggest two pathways comparable in energetics: A neutral pathway with concerted C-C bond formation and hydrogen transfer and an anionic pathway with anion attack to the carbonyl group. Studies indicate that water plays crucial mechanistic roles in both cases. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.

N-Heterocyclic Carbene Catalyzed Addition of Aldehydes to Diazo Compounds: Stereoselective Synthesis of N-Acylhydrazones

An innovative stereoselective synthesis of N-acylhydrazones via an unprecedented N-heterocyclic carbene catalyzed addition of aldehydes to diazo compounds is presented. Enals exclusively afforded N-acylhydrazones, in yields up to 91%. The observed regioselectivity was traced back to the reaction of the vinylogous Breslow intermediate via the acyl anion pathway over competing homoenolate, enol, and acyl azolium pathways. This unusual reaction profile was studied based on DFT calculations, which revealed that the reaction is under orbital control, rather than being ruled by charge.

Facile Synthesis of 2-Substituted Benzo[b]thiophen-3-ols in Water

A facile synthesis of 2-substituted benzo[b]thiophen-3-ols in a simple reaction system is reported with water as the only media. Density functional theory (DFT) investigations suggest two pathways comparable in energetics: A neutral pathway with concerted C-C bond formation and hydrogen transfer and an anionic pathway with anion attack to the carbonyl group. Studies indicate that water plays crucial mechanistic roles in both cases. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.

DFT Investigation of the Mechanism and Chemical Kinetics for the Gelation of Colloidal Silica

ABSTRACTThe mechanism for the gelation reaction of colloidal silica, Si(OH)4 +Si(OH)3 (O)- ----> Si2O8H5- + H2O, by an anionic pathway was investigated using density functional theory(DFT). Using transition state theory, the rate constants were obtained by analyzing the potential energy surface at the reactants, saddle point, and the products. In addition, reaction rate constants were investigated in the presence of ammonium chloride (NH4Cl) and sodium chloride (NaCl). These salts act as catalysts to induce gelation by destabilizing the double layer of colloidal silica to allow for Van der Waal interactions. Furthermore, it was observed that ammonium chloride plays an important role by initiating a hydride transfer allowing the reaction to proceed from the second transition state to the final product.

Molecular mechanism of proton transport in CLC Cl-/H+ exchange transporters.

CLC proteins underlie muscle, kidney, bone, and other organ system function by catalyzing the transport of Cl(-) ions across cell and organellar membranes. Some CLC proteins are ion channels while others are pumps that exchange Cl(-) for H(+). The pathway through which Cl(-) ions cross the membrane has been characterized, but the transport of H(+) and the principle by which their movement is coupled to Cl(-) movement is not well understood. Here we show that H(+) transport depends not only on the presence of a specific glutamate residue but also the presence of Cl(-) ions. H(+) transport, however, can be isolated and analyzed in the absence of Cl(-) by mutating the glutamate to alanine and adding carboxylate-containing molecules to solution, consistent with the notion that H(+) transfer is mediated through the entry of a carboxylate group into the anion pathway. Cl(-) ions and carboxylate interact with each other strongly. These data support a mechanism in which the glutamate carboxylate functions as a surrogate Cl(-) ion, but it can accept a H(+) and transfer it between the external solution and the central Cl(-) binding site, coupled to the movement of 2 Cl(-) ions.

Room Temperature Electrochemical Synthesis of Oxygenates through a Carbonate Anion Pathway

not Available.

Differential Modulation of ATP-Induced P2X7-Associated Permeabilities to Cations and Anions of Macrophages by Infection with Leishmania amazonensis

Leishmania and other parasites display several mechanisms to subvert host immune cell function in order to achieve successful infection. The ATP receptor P2X7, an agonist-gated cation channel widely expressed in macrophages and other cells of the immune system, is also coupled to inflammasome activation, IL-1 beta secretion, production of reactive oxygen species, cell death and the induction of the permeabilization of the plasma membrane to molecules of up to 900 Da. P2X7 receptors can function as an effective microbicidal triggering receptor in macrophages infected with several microorganisms including Mycobacteria tuberculosis, Chlamydia and Leishmania. We have previously shown that its expression is up-regulated in macrophages infected with L.amazonensis and that infected cells also display an increase in P2X7-induced apoptosis and membrane permeabilization to some anionic fluorescent dyes. In an independent study we recently showed that the phenomenon of macrophage membrane permeabilization can involve at least two distinct pathways for cations and anions respectively. Here, we re-addressed the effects of ATP-induced P2X7-associated phenomena in macrophages infected with L.amazonensis and demonstrated that the P2X7-associated dye uptake mechanisms are differentially modulated. While the membrane permeabilization for anionic dyes is up-modulated, as previously described, the uptake of cationic dyes is strongly down-modulated. These results unveil new characteristics of two distinct permeabilization mechanisms associated with P2X7 receptors in macrophages and provide the first evidence indicating that these pathways can be differentially modulated in an immunologically relevant situation. The possible importance of these results to the L.amazonensis escape mechanism is discussed.

Electrochemical Conversion of CO2 and CH4 to CH3OH at Room Temperature through a Carbonate Anion Pathway

not Available.

Radiation Induced Redox Reactions and Fragmentation of Constituent Ions in Ionic Liquids. 1. Anions

Room temperature ionic liquids (IL) find increasing use for the replacement of organic solvents in practical applications, including their use in solar cells and electrolytes for metal deposition, and as extraction solvents for the reprocessing of spent nuclear fuel. The radiation stability of ILs is an important concern for some of these applications, as previous studies suggested extensive fragmentation of the constituent ions upon irradiation. In the present study, electron paramagnetic resonance (EPR) spectroscopy has been used to identify fragmentation pathways for constituent anions in ammonium, phosphonium, and imidazolium ILs. Many of these detrimental reactions are initiated by radiation-induced redox processes involving these anions. Scission of the oxidized anions is the main fragmentation pathway for the majority of the practically important anions; (internal) proton transfer involving the aliphatic arms of these anions is a competing reaction. For perfluorinated anions, fluoride loss following dissociative electron attachment to the anion can be even more prominent than this oxidative fragmentation. Bond scission in the anion was also observed for NO(3)(-) and B(CN)(4)(-) anions and indirectly implicated for BF(4)(-) and PF(6)(-) anions. Among small anions, CF(3)SO(3)(-) and N(CN)(2)(-) are the most stable. Among larger anions, the derivatives of benzoate and imide anions were found to be relatively stable. This stability is due to suppression of the oxidative fragmentation. For benzoates, this is a consequence of the extensive sharing of unpaired electron density by the π-system in the corresponding neutral radical; for the imides, this stability could be the consequence of N-N σ(2)σ(*1) bond formation involving the parent anion. While fragmentation does not occur for these "exceptional" anions, H atom addition and electron attachment are prominent. Among the typically used constituent anions, aliphatic carboxylates were found to be the least resistant to oxidative fragmentation, followed by (di)alkyl phosphates and alkanesulfonates. The discussion of the radiation stability of ILs is continued in the second part of this study, which examines the fate of organic cations in such liquids.

Anionic Production Pathways Involved in the Reaction between OH<sup>-</sup> and CH<sub>2</sub>ClF

The anionic production pathways involved in the reaction between hydroxide anion (OH) and chlorofluoromethane (CH2ClF) were theoretically investigated. The optimized geometries of all the important species on the reaction potential energy surface were obtained at the B3LYP/6-31+G(d,p) and B3LYP/6-311 ++ G(2d,p) levels. Consequently, harmonic vibrational frequencies and zero point energies (ZPEs) were calculated. Based on the relative energies of all the species that were calculated at the CCSD(T)/6-311+G(3df,3dp) level, the anionic production channels for the H-abstraction and the bimolecular nucleophilic substitution (SN2) reaction processes are elaborated upon. According to the calculated barrier heights for the production pathways, the H-abstraction channel is dominant, which agrees very well with previous experimental conclusions. In addition, non-typical anionic products are suggested to form during the SN2 reaction processes where the serious dynamic effect probably causes the SN2 reaction process to produce F.

Permeant anions contribute to voltage dependence of ClC‐2 chloride channel by interacting with the protopore gate

It has been shown that the voltage (V(m)) dependence of ClC Cl(-) channels is conferred by interaction of the protopore gate with H(+) ions. However, in this paper we present evidence which indicates that permeant Cl(-) ions contribute to V(m)-dependent gating of the broadly distributed ClC-2 Cl() channel. The apparent open probability (P(A)) of ClC-2 was enhanced either by changing the [Cl(-)](i) from 10 to 200 mM or by keeping the [Cl(-)](i) low (10 mM) and then raising [Cl(-)](o) from 10 to 140 mM. Additionally, these changes in [Cl(-)] slowed down channel closing at positive V(m) suggesting that high [Cl(-)] increased pore occupancy thus hindering closing of the protopore gate. The identity of the permeant anion was also important since the P(A)(V(m)) curves were nearly identical with Cl(-) or Br(-) but shifted to negative voltages in the presence of SCN() ions. In addition, gating, closing rate and reversal potential displayed anomalous mole fraction behaviour in a SCN(-)/Cl() mixture in agreement with the idea that pore occupancy by different permeant anions modifies the V(m) dependence ClC-2 gating. Based on the ec1-ClC anion pathway, we hypothesized that opening of the protopore gate is facilitated when Cl(-) ions dwell in the central binding site. In contrast, when Cl(-) ions dwell in the external binding site they prevent the gate from closing. Finally, this Cl(-)-dependent gating in ClC-2 channels is of physiological relevance since an increase in [Cl(-)](o) enhances channel opening when the [Cl(-)](i) is in the physiological range.

Acute cholesterol depletion leads to net loss of the organic osmolyte taurine in Ehrlich Lettré tumor cells

In mammalian cells, the organic osmolyte taurine is accumulated by the Na-dependent taurine transporter TauT and released though the volume- and DIDS-sensitive organic anion channel. Incubating Ehrlich Lettré tumor cells with methyl-β-cyclodextrin (5 mM, 1 h) reduces the total cholesterol pool to 60±5% of the control value. Electron spin resonance data indicate a concomitant disruption of cholesterol-rich micro-domains. Active taurine uptake, cellular taurine content, and cell volume are reduced by 50, 20 and 20% compared to control values, respectively, whereas the passive taurine release is increased 4.5-fold under isotonic conditions following cholesterol depletion. However, taurine release under isotonic conditions is insensitive to DIDS and inhibitors of the volume-regulated anion channel. Uptake and release of meAIB are similarly affected following cholesterol depletion. Kinetic analysis reveals that cholesterol depletion increases TauT's affinity toward taurine but reduces its maximal transport capacity. Cholesterol depletion has no impact on TauT regulation by protein kinases A and C. Phospholipase A2 activity, which is required for the activation of volume-sensitive organic anion channel (VSOAC), is increased under isotonic and hypotonic conditions following cholesterol depletion, whereas taurine release under hypotonic conditions is reduced following cholesterol depletion. Hence, acute cholesterol depletion of Ehrlich Lettré cells leads to reduced TauT and VSOAC activities and at the same time increases the release of organic osmolytes via a leak pathway different from the volume-sensitive pathways for amino acids and anions.

Cation-selective Pathway of OmpF Porin Revealed by Anomalous X-ray Diffraction

The OmpF porin from the Escherichia coli outer membrane folds into a trimer of β-barrels, each forming a wide aqueous pore allowing the passage of ions and small solutes. A long loop (L3) carrying multiple acidic residues folds into the β-barrel pore to form a narrow “constriction zone”. A strong and highly conserved charge asymmetry is observed at the constriction zone, with multiple basic residues attached to the wall of the β-barrel (Lys16, Arg42, Arg82 and Arg132) on one side, and multiple acidic residues of L3 (Asp107, Asp113, Glu117, Asp121, Asp126, Asp127) on the other side. Several computational studies have suggested that a strong transverse electric field could exist at the constriction zone as a result of such charge asymmetry, giving rise to separate permeation pathways for cations and anions. To examine this question, OmpF was expressed, purified and crystallized in the P6 3 space group and two different data sets were obtained at 2.6 Å and 3.0 Å resolution with K + and Rb +, respectively. The Rb +-soaked crystals were collected at the rubidium anomalous wavelength of 0.8149 Å and cation positions were determined. A PEG molecule was observed in the pore region for both the K + and Rb +-soaked crystals, where it interacts with loop L3. The results reveal the separate pathways of anions and cations across the constriction zone of the OmpF pore.