Carboxylic Acid Moiety Research Articles

Molecular insight into carboxylic acid-alkali metal cations interactions: reversed affinities and ion-pair formation revealed by non-linear optics and simulations.

Specific interactions between the carboxylic acid moiety and the monovalent salts CsCl, NaCl, and LiCl, have been investigated in Langmuir monolayers using vibrational sum frequency spectroscopy (VSFS) and complemented with coarse grained and all-atom molecular dynamics simulations. By exploiting VSFS's intrinsic surface specificity, an emphasis was made on targeting headgroup vibrations of both its charged and uncharged forms as well as water molecules in the interfacial layer. The degree of deprotonation of the monolayer as a function of cation concentration and pH was experimentally determined and theoretically rationalized. Starting from 100 mM, the surface charge was overestimated by the Gouy-Chapman model and varied depending on the identity of the cation, highlighting the appearance of ion specific effects. Agreement could be found using a modified Poisson-Boltzmann model that takes into account steric effects, with a fitted effective ion-size compatible with the hydrated ion diameters. The relative affinity of the cations to the carboxylic acid moiety was pH dependent: at pH 4.5 they arranged in the order Cs+ > Na+ > Li+, but fully reversed (Li+ > Na+ > Cs+) at pH 9. Simulations yielded microscopic insight into the origin of this behavior, with the cations showing contrasting interaction preferences for either the uncharged carboxylic acid or the charged carboxylate. Sum frequency spectra also provided evidence that all cations remained hydrated when interacting with the charged headgroup, forming solvent-separated or solvent-shared ion pairs. However, for the specific case of 1 M Li+ at pH 9, contact ion pairs were formed. Finally, the remarkable effect of trace metal multivalent cations in the interpretation of experiments is briefly discussed. The results provide exciting new insights into the complex interactions of alkali metal cations with the biophysically relevant carboxylic acid moiety.

Site-selective C-H activation and regiospecific annulation using propargylic carbonates.

Herein we describe an unprecedented RuII-catalyzed site-selective and regiospecific annulation of benzoic acids with propargylic carbonates. The weakly coordinating carboxylic acid moiety outperformed other typically used directing groups in C-H activation, including ketone, nitrile, sulfonamide, amide and strongly coordinating nitrogen heterocycles. This is an important step towards the application of C-H activation reactions in complex (functional) real-world molecules.

Amino‐TEMPO Grafted on Magnetic Multi‐Walled Nanotubes: An Efficient and Recyclable Heterogeneous Oxidation Catalyst

An efficient and easy recyclable heterogeneous oxidation catalyst was prepared by grafting TEMPO–NH2 moieties on the surface of magnetic multi‐walled carbon nanotubes (MWCNT), first by a radical reaction introducing butyric acid moieties on carbon nanotube surface. Subsequently, carboxylic acid moieties were submitted for amidation using TEMPO–NH2. The functionalized nanotubes [MWCNT‐{(CH2)3‐CO‐NH‐TEMPO}n] were investigated as a (pre‐)catalyst for the oxidation of primary and secondary alcohols for the production of aldehydes and ketones in a Montanari‐type catalytic oxidation using the cheap and readily available 1,3‐dichloro‐5,5‐dimethylhydantoin as the terminal oxidant.

Exploring the Selective Demethylation of Aryl Methyl Ethers with a Pseudomonas Rieske Monooxygenase.

Biocatalytic dealkylation of aryl methyl ethers is an attractive reaction for valorization of lignin components, as well as for deprotection of hydroxy functionalities in synthetic chemistry. We explored the demethylation of various aryl methyl ethers by using an oxidative demethylase from Pseudomonas sp. HR199. The Rieske monooxygenase VanA and its partner electron transfer protein VanB were recombinantly coexpressed in Escherichia coli and they constituted at least 25 % of the total protein content. Enzymatic transformations showed that VanB accepts NADH and NADPH as electron donors. The VanA-VanB system demethylates a number of aromatic substrates, the presence of a carboxylic acid moiety is essential, and the catalysis occurs selectively at the meta position to this carboxylic acid in the aromatic ring. The reaction is inhibited by the by-product formaldehyde. Therefore, we tested three different cascade/tandem reactions for cofactor regeneration and formaldehyde elimination; in particular, conversion was improved by addition of formaldehyde dehydrogenase and formate dehydrogenase. Finally, the biocatalyst was applied for the preparation of protocatechuic acid from vanillic acid, giving a 77 % yield of the desired product. The described reaction may find application in the conversion of lignin components into diverse hydroxyaromatic building blocks and generally offers potential for new, mild methods for efficient unmasking of phenols.

Coupling layer-by-layer assembly and multilayer transfer to fabricate flexible transparent film heater

Flexible transparent film heaters (f-TFH) were prepared on a polysulfone (PSU) film with a multilayer transfer of silver nanowires (AgNWs) coated on glass substrates via layer-by-layer (LBL) deposition. First, as-received AgNWs were functionalized with carboxylic acid (AgNW-COOH) and amine (AgNW-NH2) moieties to obtain negatively and positively charged nanowires, respectively. Second, functionalized AgNWs were sequentially coated on a glass substrate via the LBL deposition, which was followed by subjecting the multilayer film to annealing at 125 °C for 30 min to improve the electrical conductivity. Third, the multilayer was transferred from the glass substrate to the polymer film by coating and detaching the PSU. The multilayer film provided optical transmission of 84% and sheet resistance of 12 Ω/□ with 5 bilayer sample, which is comparable to indium tin oxide (ITO) film. The f-TFH reached maximum temperature of 128 °C at 7 V with a response time of 45 s. Moreover, it exhibited good defrosting capability by applying 7 V for 20 s. Cyclic bending test results indicated that the sheet resistance of the flexible multilayer film does not demonstrate any change until 300 cycles, while adhesion test 3-M tapes exhibited no sheet resistance change even after 20 peel cycles showing the superior performance of the multilayer film. In addition, the film showed stable heating performance at 128 °C for 5 h.

Charging of Carboxylic Acid Monolayers with Monovalent Ions at Low Ionic Strengths: Molecular Insight Revealed by Vibrational Sum Frequency Spectroscopy

The charging of arachidic acid Langmuir monolayers as a function of subphase pH and monovalent ion concentration below 100 mM was investigated using vibrational sum frequency spectroscopy. Molecular information was obtained by targeting the vibrational modes of the carboxylic acid headgroups, alkyl chains, and water molecules in the immediate surface and diffuse double layers. The surface charge in the monolayer was experimentally determined by monitoring the hydrated carboxylate stretching modes. The charging behavior was found to be in excellent agreement with that predicted by Gouy–Chapman theory using a thermodynamic pKa of 5.1 ± 0.2. This resulted in an apparent pKa of ∼10.8 when the only ions present in solution were those associated with adjusting the pH. Water molecules with a preferred orientation in the immediate surface region were found to primarily interact with the uncharged carboxylic acid moiety, decreasing in number as the monolayer further deprotonated. Contributions from water molecules...

Towards the enzymatic formation of artificial metal base pairs with a carboxy-imidazole-modified nucleotide

The identification of synthetic nucleotides that sustain the formation of orthogonal, unnatural base pairs is an important goal in synthetic biology. Such artificial synthons have been used for the generation of semi-synthetic organisms as well as functional nucleic acids with enhanced binding properties. The enzymatic formation of artificial metal-base pairs is a vastly underexplored and alluring alternative to existing systems. Here, we report the synthesis and biochemical characterization of 1‑(2-deoxy‑β‑d‑ribofuranosyl) imidazole‑4‑carboxylate nucleoside triphosphate (dImCTP) which is equipped with a carboxylic acid moiety on the imidazole moiety in order to increase the coordination environment to [2 + 2] and [2 + 1]. A clear metal dependence was observed for the single incorporation of the modified nucleotide into DNA by the DNA polymerase from Thermus aquaticus (Taq). The presence of AgI in primer extension reactions conducted with combinations of 1‑(2‑deoxy‑β‑d‑ribofuranosyl) imidazole nucleoside triphosphate (dImTP) and dImCTP supported the unusual [2 + 1] coordination pattern. The efficiency of the tailing reactions mediated by the terminal deoxynucleotidyl transferase (TdT) was markedly improved when using dImCTP instead of dImTP. Even though products with multiple modified nucleotides were not observed, the appendage of additional metal binding ligands on the imidazole nucleobase appears to be a valid approach to improve the biochemical properties of modified triphosphates in the context of an expansion of the genetic alphabet with metal base pairs.

Trans-Bis(2,2′-bipyridine-4,4′-dicarboxylic acid-κ2 N,N′)dichloridoruthenium(III) perchlorate

In the crystal structure of the ruthenium(III) complex, trans-[RuIII(dcbpy)2Cl2]ClO4 (dcbpy = 2,2′-bipyridine-4,4′-dicarboxylic acid, C12H8N2O4), the RuIII atom lies on an inversion centre, showing a small distortion in its octahedral environment. The Ru—Cl bond lengths are shorter than those present in the analogous trans-ruthenium(II) compound containing the bipyridine ligand. The C—O distances in the two symmetry-independent carboxylic acid moieties of the ligand are similar in one group, but different in the other. This is probably due to the different intermolecular interactions they experience with neighbouring cationic complexes. The hydrogen-bonding interactions in which they are involved form a three-dimensional structure, similar to those found in coordination polymers.

Synthesis and biological evaluation of thielocin B1 analogues as protein-protein interaction inhibitors of PAC3 homodimer

The synthesis and biological evaluation of thielocin B1 analogues have been demonstrated. Fourteen analogues modified in the central core and terminal carboxylic acid moiety were concisely synthesized by simple esterification or etherification reaction. The evaluation of synthetic analogues as inhibitors of proteasome assembling chaperone (PAC) complexes (the PAC3 homodimer and PAC1/PAC2) revealed that the natural product-like bending structure and terminal carboxylic acid groups were crucial for its biological activity. Moreover, SAR and in silico docking studies indicated that all methyl groups on the diphenyl ether moiety of thielocin B1 contribute to the potent and selective inhibition of the PAC3 homodimer via hydrophobic interactions.

CO2-Catalyzed Efficient Dehydrogenation of Amines with Detailed Mechanistic and Kinetic Studies

CO2-catalyzed dehydrogenation of amines has been achieved under photocatalytic conditions. With this concept, various amines have been selectively dehydrogenated to the corresponding imines in the presence of different functional groups such as nitrile, nitro, ester, halogen, ether, thioether, and carbonyl or carboxylic acid moieties. At the end, the CO2-catalyzed synthesis of pharmaceutical drugs has been achieved. The CO2 radical has been detected by EPR spectroscopy using DMPO, and the mechanism of this reaction is proposed on the basis of DFT calculations and experimental evidence.

Co-crystal screening of disubstituted adamantane molecules with N-heterocyclic moieties for hydrogen-bonded arrays

Four disubstituted adamantane-based molecules containing N-heterocyclic moieties were designed and synthesized as hydrogen bond acceptors for the preparation of co-crystals with hydrogen bond donors. Co-crystal screening of the four adamantane-based molecules with terephthalic acid was firstly attempted in mixed solvents. Only the compound with methylimidazole moieties (1) afforded the co-crystals in 1:1 ratio, whereas the others gave individual crystals. X-ray crystallographic analysis demonstrated that the hydrogen bonds between the imidazole and the carboxylic acid moieties of both components provided infinite one-dimensional chains that were assembled into network structures through CH···O interactions. When isophthalic acid or resorcinol was employed as the partner, the co-crystals were similarly generated by intermolecular non-covalent interactions. The selective co-crystal formation of 1 is mainly attributed to the increase of strength of the hydrogen-bonding acceptor on the nitrogen atoms of the N-heterocyclic moieties and the stabilization of the hydrogen-bonded complexes due to the electron-donating ability and the steric effect of the methyl groups.

Pyrazole-3-carboxylic acid as a new anchoring group for phthalocyanine-sensitized solar cells

We have designed and synthesized an unsymmetrical zinc phthalocyanine (PCA-ZnPc-1) bearing an electron-withdrawing pyrazole-3-carboxylic acid anchoring group and three electron-donating tert-butyl groups as a sensitizer for dye-sensitized solar cells (DSSCs). PCA-ZnPc-1 sensitized solar cell showed a modest power conversion efficiency (1.74%), which may suffer from the flexible and non-conjugated oxygen linker on the sensitizer. However, the obtained efficiency is found to be three to four times higher than that of the unsymmetrical ones bearing only carboxylic acid due to the combination of pyrazole and carboxylic acid moieties within the same anchoring group, which enhances the binding of the dye on the TiO2 surface and results in an increase of electron injection efficiency. Therefore, the pyrazole-3-carboxylic acid is a promising anchoring group for developing new phthalocyanines to build efficient DSSCs.

Mechanistic Insights on Orthogonal Selectivity in Heterocycle Synthesis

Recently, we have developed a method for catalytic regioselective synthesis of 2-substituted and 3-substituted benzofurans starting from phenols. The choice of reacting partner, olefin versus α,β-unsaturated acid, is critical to dictate the isomeric product formation. Instances are known where these olefinic partners did not complement each other and yield a similar outcome. In the current work, we have addressed this paradox with emphasis on (a) the origin of orthogonal selectivity and (b) the key requirements to expect complementary behavior. Experimental and computational studies provided important mechanistic insights. Electrostatic compatibility during migratory insertion and the positioning of the carboxylic acid moiety in catalytic steps are found to exert a paramount impact in determining the regioselectivity. The study offers a predictable single component tuning tool to control the regioselectivity.

Palladium-Catalyzed Direct Synthesis of Various Branched, Carboxylic Acid-Functionalized Polyolefins: Characterization, Derivatization, and Properties

Ethylene-co-acrylic acid (E–AA) copolymers are typically produced via high-pressure free radical copolymerization and have great industrial importance because of their many applications. The radical polymerization mechanism usually leads to highly branched products with poor mechanical properties. Transition-metal-catalyzed E–AA copolymerization represents a direct and economical route to access these copolymers with potentially better control over their microstructures and material properties. However, this is highly challenging due to catalyst poisoning from both the oxygen and carboxylic acid moieties in the monomers. In this contribution, we demonstrate that a series of α-diimine-based palladium catalysts can mediate efficient copolymerizations of ethylene with AA, allylacetic acid, and 10-undecenoic acid, leading to the formation of various branched, carboxylic acid-functionalized polyolefin materials. These comonomers exist as carboxylic acid-based dimeric species at ambient temperatures, which is p...

Distinct substrate specificity and physicochemical characterization of native human hepatic thymidine phosphorylase.

Thymidine phosphorylase (TP; EC 2.4.2.4) is involved regulation of intra- or extracellular thymidine concentration, angiogenesis, cancer chemotherapy, radiotherapy, as well as tumor imaging. Although the liver is main site of pyrimidine metabolism and contains high levels of TP, nonetheless, purification and characterization of human hepatic TP has not been accomplished. We here report the purification and characterization of native human hepatic TP. The enzyme was purified to apparent homogeneity by a procedure shorter and more efficient than previously reported methods. Human hepatic TP has an apparent Kthymidine of 285 ± 55 μM. Like the enzyme from other tissues, it is highly specific to 2'-deoxyribosides. However, in contrast to TP from other normal tissues, the hepatic enzyme is active in the phosphorolysis of 5'-deoxy-5-fluorouridine, and the riboside 5-fluorouridine. Furthermore, native hepatic TP exists in different aggregates of 50 kDa subunits, with unknown aggregation factor(s) while TP from extra tissues exists as a homodimer. Isoelectric point was determined as 4.3. A total of 65 residues in the N-terminal were sequenced. The sequence of these 65 amino acids in hepatic TP has 100% sequence and location homology to the deduced amino acid sequence of the platelet derived-endothelial cell growth factor (PD-ECGF) cDNA. However, and contrary to PD-ECGF, the N-terminal of hepatic TP is blocked. The block was neither N-formyl nor pyrrolidone carboxylic acid moieties. The differences in substrate specificities, existence in multimers, and weak interaction with hydroxyapatite resin strongly suggest that hepatic TP is distinct from the enzyme in normal extrahepatic tissues. These results may have important clinical implications when TP is involved in activation or deactivation of chemotherapeutic agents in different tissues.

Oil Sands Derived Naphthenic Acids Are Oxidative Uncouplers and Impair Electron Transport in Isolated Mitochondria.

Naphthenic acids (NAs) are predominant compounds in oil sands influenced waters. These acids cause numerous acute and chronic effects in fishes. However, the mechanism of toxicity underlying these effects has not been fully elucidated. Due to their carboxylic acid moiety and the reported disruption of cellular bioenergetics by similar structures, we hypothesized that NAs would uncouple mitochondrial respiration with the resultant production of reactive oxygen species (ROS). Naphthenic acids were extracted and purified from 17-year-old oil sands tailings waters yielding an extract of 99% carboxylic acids with 90% fitting the classical O2-NA definition. Mitochondria were isolated from rainbow trout liver and exposed to different concentrations of NAs. Mitochondrial respiration, membrane potential, and ROS emission were measured using the Oroboros fluorespirometry system. Additionally, mitochondrial ROS emission and membrane potential were evaluated with real-time flow cytometry. Results showed NAs uncoupled oxidative phosphorylation, inhibited respiration, and increased ROS emission. The effective concentration (EC50) and inhibition concentration (IC50) values for the end points measured ranged from 21.0 to 157.8 mg/L, concentrations similar to tailings waters. For the same end points, EC10/IC10 values ranged from 11.8 to 66.7 mg/L, approaching concentrations found in the environment. These data unveil mechanisms underlying effects of NAs that may contribute to adverse effects on organisms in the environment.

Carboxylic Acid Derivatives of Amlexanox Display Enhanced Potency toward TBK1 and IKKε and Reveal Mechanisms for Selective Inhibition.

Chronic low-grade inflammation is a hallmark of obesity, which is a risk factor for the development of type 2 diabetes. The drug amlexanox inhibits IκB kinase ε (IKKε) and TANK binding kinase 1 (TBK1) to promote energy expenditure and improve insulin sensitivity. Clinical studies have demonstrated efficacy in a subset of diabetic patients with underlying adipose tissue inflammation, albeit with moderate potency, necessitating the need for improved analogs. Herein we report crystal structures of TBK1 in complex with amlexanox and a series of analogs that modify its carboxylic acid moiety. Removal of the carboxylic acid or mutation of the adjacent Thr156 residue significantly reduces potency toward TBK1, whereas conversion to a short amide or ester nearly abolishes the inhibitory effects. IKKε is less affected by these modifications, possibly due to variation in its hinge that allows for increased conformational plasticity. Installation of a tetrazole carboxylic acid bioisostere improved potency to 200 and 400 nM toward IKKε and TBK1, respectively. Despite improvements in the in vitro potency, no analog produced a greater response in adipocytes than amlexanox, perhaps because of altered absorption and distribution. The structure-activity relationships and cocrystal structures described herein will aid in future structure-guided inhibitor development using the amlexanox pharmacophore for the treatment of obesity and type 2 diabetes.

Enantiomeric Identification of Pregabalin by GC-MS via Methylation and S-TPC Chiral Derivatization.

Pregabalin is a Schedule V controlled substance which is defined as the (S) enantiomer of 3-(aminomethyl)-5-methylhexanoic acid. It is used legitimately to treat neuropathy in patients with diabetes as well as for epilepsy and fibromyalgia. Pregabalin is an amino acid and an amphoteric compound, which makes it difficult to analyze using the conventional GC-MS instrumentation found in most forensic drug analysis laboratories. Problems associated with the traditional GC-MS analysis of pregabalin include selective solubility, ring closure to the corresponding lactam in the GC injection port and/or the MS transfer line and difficulty with chiral derivatization due to the presence of a carboxylic acid moiety. Here, we show that these challenges can be overcome by methylating (capping) the carboxylic acid portion of the pregabalin molecule and converting to the corresponding methyl ester. Once the methyl ester is synthesized, chiral derivatization at the amine can be achieved to identify the controlled (S) enantiomer of pregabalin via GC-MS.

Waterborne Polyurethane Colloids with Sensitive CO2‐Switchable Hydrophilic/Hydrophobic Properties

AbstractA novel conceptual approach to gas‐responsive functionality, with the capability to tune the amphiphilic characteristics of existing waterborne polyurethanes (WPUs), via CO2/N2 bubbling in aqueous solution, is exploited. In this study, a series of functional WPUs are successfully prepared. These colloids exhibit high aqueous stability, excellent capability for emulsification/demulsification as a surfactant, and reversible hydrophilic/hydrophobic phase transition owing to reversible formation of carboxylic acid moieties induced by bubbling CO2 gas. More interestingly, when carboxylated multiwalled carbon nanotubes (CNTs) are covalently incorporated into these WPUs, the CNT exhibits CO2‐switchable amphiphilic behavior in a two‐phase mixture of n‐butanol (BuOH)/deionized water, forming a stable hydrophobic CNT dispersion in BuOH upon CO2 bubbling, and reversibly reverting to the previous hydrophilic CNT dispersion in water upon N2 bubbling. With simple preparation and switchable amphiphilic properties, these CO2‐responsive WPUs offer a paradigm for the development of multifunctional gas‐responsive polymers.

A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution

The title compounds were synthesized from the selectively protected N-acylated d-glucosamine derivatives, containing α-halo carboxylic acid moieties, via intramolecular 3-O-alkylation. It was found that if the starting compound contains asymmetric electrophilic center, isomuramic acid derivatives were mainly formed, regardless of the configuration of the electrophilic carbon atom. An explanation for the observed stereochemical results was proposed on the basis of the analysis of steric interactions in the molecules of the starting compounds, as well as using the concept of anchimeric assistance. It was shown that N-acetylation of the obtained lactam derivatives and subsequent methanolysis under mild conditions led to the selective cleavage of δ-lactam ring resulting in the formation of the corresponding ester derivatives of N-acetylmuramic acid or its analogues in high yields.