Carboxylic Acid Moiety Research Articles

The Emergence of Carbon Isotope Exchange.

Significant progress in C-C bond activation with transition metals has recently enabled the development of several carbon isotope exchange reactions. These methods are based on C-C bond decarboxylative carboxylation reactions in the presence of selected transition metals and labelled carbon monoxide or carbon dioxide.

Adsorption mediated tandem acid catalyzed cellulose hydrolysis by ortho-substituted benzoic acids

Carboxylic acid and phenol moiety containing carbon materials are proven to catalyze cellulose hydrolysis. Experiments utilizing benzoic acid and substituted derivatives as model catalysts revealed that vicinal oxygenated group containing catalysts showed significantly higher activities regardless of acidity. However, the increase in catalytic activity was not well understood. Using density functional theory, the mechanism of catalysis was elucidated. Calculated binding energy followed the experimental turnover number suggesting that the formation and the stability of the adduct complex is imperative to catalysis. In addition to this, protonated system effectively modeled the experimental activation energy implying that a hydronium participates in the reaction. These calculations indicated that during the life time of the adduct complex, a dissolved proton assists in the overall catalytic mechanism.

Sulfur as a hydrogen bond donor in the gas phase: Rotational spectroscopic and computational study of 3-mercaptopropionic acid

Rotational spectra of 3-mercaptopropionic acid (3-mpa) were measured from 6 to 18 GHz using chirped pulse and cavity-based Fourier transform microwave (FTMW) spectroscopy. Theoretical calculations using the B3LYP-D3BJ and MP2 methods with the aug-cc-pVTZ basis set show the presence of seven energy minima of 3-mpa below 8.4 kJ mol−1. Comparison of calculated rotational and centrifugal distortion constants with experimental data led to the unequivocal assignment of the global energy minimum geometry. This conformer has the mercaptan hydrogen directly oriented towards the carbonyl oxygen of the carboxylic acid moiety suggesting the presence of a six–membered ring SH…OC intramolecular hydrogen bond. Quantum theory of atoms in molecules, noncovalent interactions, and natural bond orbital analyses confirm the stability of the sulfur hydrogen bond which plays a key role in the conformational preferences of 3-mpa.

Exploration of the Binding Properties of the Azo Dye Pollutants with Nitrogen‐Doped Graphene Oxide by Computational Modeling for Wastewater Treatment Improvement

AbstractSystematic studies were carried out to investigate the binding properties of ten selected azo dye pollutants with nitrogen‐doped graphene oxide. Acid Blue 29, Acid Orange 5, Acid Orange 7, Acid Orange 8, Acid Orange 52, Blue 113, Direct Blue 71, hydrolyzed Reactive Black 5H, hydrolyzed Reactive Orange 16H, and hydrolyzed Reactive Orange 107H were selected to be studied. At the first step, docking studies were done to provide the best binding modes between azo dye and nitrogen–doped graphene oxide. In continue, molecular dynamics simulation method, molecular mechanics/generalized Born and surface area (MM/GBSA) analysis, and energy decomposition analysis were carried out to examine the strength and nature of interactions between azo dye pollutants and nitrogen–doped graphene oxide. Analyzing of interaction during molecular dynamics simulation showed that van der Waals interaction has the most important role on the binding of the azo dyes to the surface of the nitrogen‐doped graphene oxide. Also, the contribution of electrostatic and hydrogen bonding interactions are not ignorable. The –SO3H, –OH, and –NH2 moieties on the azo dyes have a contribution in hydrogen bonding with the epoxide and –OH functional groups and pyridinium–like and pyrrole–like nitrogen‐containing functional groups on the nitrogen‐doped graphene oxide. No contributions from the carboxylic acid moieties and graphite‐like nitrogen‐containing functional groups in the hydrogen bonding were observed. The binding energies related to ADs/NGO systems during the MD simulation process, calculated by MM/GBSA approach. Entry Azo dye Binding energy (kcal mol–1) 1 Acid Blue 29 –42.7 2 Acid Orange 5 –32.6 3 Acid Orange 7 –30.1 4 Acid Orange 8 –32.2 5 Acid Orange 52 –28.3 6 Blue 113 –55.2 7 Direct Blue 71 –67.3 8 Hydrolyzed Reactive Black 5H –30.2 9 Hydrolyzed Reactive Orange 16H –32.6 10 Hydrolyzed Reactive Orange 107H –27.0

Photoelectrochemical Hydrogen Generation Using a Bis-Chelating Nickel PNP Catalyst Tethered to Band-Edge Modified Si(111)|TiO2

We report the generation of a novel “bis-bidentate” chelating nickel phosphine electrocatalyst functionalized with pendant amines. Two PNP appended donor moieties are tethered to a single surface-tethering anchor, with the intention of leveraging the chelate effect to increase the kinetic stability of the bound nickel ion upon surface immobilization. The carboxylic acid moiety of this bis-bidentate PNP catalyst allows for adsorption to band-edge modified p-silicon(111) photoelectrodes coated with amorphous TiO2 for photogeneration of dihydrogen under illumination and negative applied bias. The synthesis of this ligand also allows for variability in metal oxide binding groups and phosphine R-groups. The band-edge modification of p-silicon(111) is achieved with a mixed monolayer of phenyl-3,5-bismethoxytriethylene glycol and methyl units, which also enhances electron transport through the interface. An ultrathin film (20Å) of amorphous titania further passivates the semiconductor from the generation of surface defects, acts as an electron selective layer, and allows for adsorption of the metal complex to the electrode. Cyclic voltammetry and XPS were used in conjunction to estimate catalyst loading, evaluate photoelectrochemical performance of these devices, and investigate different mechanisms of activity loss such as via loss of the nickel or desorption of the ligand. Different modes of device construction, such as via adsorption of the PNP ligand to the TiO2-coated photoelectrodes followed by treatment with a solution of [Ni(MeCN)6]·2ClO4 and via deposition of the fully constructed, metalated complex were evaluated for differences in Ni loading and device performance. Both the adsorbed catalyst as well as non-specifically adsorbed Ni2+ on TiO2 were shown to be active for proton reduction, albeit at different potentials. Efforts were therefore made to isolate the activity of the nickel phosphine catalyst and prevent convolution of the electrochemical response.

Carboxylic‐Acid‐Activated Olefins in Decarboxylative Reactions

AbstractThis Minireview summarizes the application of carboxylic‐acid‐activated olefins in organic synthesis. The ability of carboxylic acid moiety to increase the electrophilic character of alkenes combined with the possibility to remove it under mild reaction conditions via decarboxylation process allows for the development of new reactivity patterns. These strategies involve mainly cascade reactions consisting of either Michael addition followed by decarboxylation or cycloaddition followed by decarboxylation. New synthetic possibilities provided by these approaches are summarized and discussed within this review article.

The First Vinylogous, Decarboxylative Michael Reaction with 3‐Cyano‐4‐methylcoumarins as Pronucleophiles

AbstractIn the manuscript the first vinylogous, decarboxylative Michael reaction is described. It utilizes 3‐cyano‐4‐methylcoumarins as pronucleophiles undergoing Michael reaction with Michael acceptors activated by the presence of carboxylic acid moiety. Subsequent decarboxylative protonation affords interesting heterocycles in high yields with the reaction realized in the presence of Brønsted base catalyst. Attempts to develop an enantioselective variant of the decarboxylative reaction cascade are also described.

Influence of Side‐Chain Composition on Polythiophene Properties and Supramolecular Assembly of Anionic Polythiophene Derivatives

ABSTRACTA series of 10 polythiophene derivatives is reported, in which each polymer has a different percentage of carboxylic acid‐bearing repeat units. The properties of these polymers are explored under acidic conditions, where the carboxylic acid moieties remain neutral, and under basic conditions, where the carboxylic acid units become anionic carboxylates. The properties that are examined for both solutions and films include UV–vis absorption spectroscopy, photoluminescence spectroscopy, and red‐edge optical band gaps. All the properties studied are strongly dependent both on protonation state and percentage of carboxylic acid/carboxylate side chains along the polymer backbone. The anionic form of each polythiophene derivative was also used in layer‐by‐layer film deposition with a cationic phosphonium polyelectrolyte. The film growth process was studied by spectroscopic techniques to assess the influence of side‐chain composition on the film growth and optical properties. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019

E- and Z-, di- and tri-substituted alkenyl nitriles through catalytic cross-metathesis.

Nitriles are found in many bioactive compounds, and are among the most versatile functional groups in organic chemistry. Despite many notable recent advances, however, there are no approaches that may be used for preparation of di- or trisubstituted alkenyl nitriles. Related approaches which are broad in scope and can deliver the desired products in high stereoisomeric purity are especially scarce. Here, we describe the development of several efficient catalytic cross-metathesis strategies, which provide direct access to a considerable range of Z- or E-disubstituted cyano-substituted alkenes or their corresponding trisubstituted variants. Depending on the reaction type, a molybdenum-based monoaryloxide pyrrolide (MAP) or chloride (MAC) complex may be the optimal choice. The utility of the approach, enhanced by an easy-to-apply protocol for utilization of substrates bearing an alcohol or a carboxylic acid moiety, is highlighted in the context of applications to synthesis of biologically active compounds.

Benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety

Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety. Our results show that single isomer 3A maintains in vitro and in vivo inhibition against DGAT1. In contrast to previous lead compounds, 3A does not undergo isomerization during in vitro hepatocyte incubation study or in vivo mouse study.

Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1

The long-chain fatty acid receptor FFAR1/GPR40 binds agonists in both an interhelical site between the extracellular segments of transmembrane helix (TM)-III and TM-IV and a lipid-exposed groove between the intracellular segments of these helices. Molecular dynamics simulations of FFAR1 with agonist removed demonstrated a major rearrangement of the polar and charged anchor point residues for the carboxylic acid moiety of the agonist in the interhelical site, which was associated with closure of a neighboring, solvent-exposed pocket between the extracellular poles of TM-I, TM-II, and TM-VII. A synthetic compound designed to bind in this pocket, and thereby prevent its closure, was identified through structure-based virtual screening and shown to function both as an agonist and as an allosteric modulator of receptor activation. This discovery of an allosteric agonist for a previously unexploited, dynamic pocket in FFAR1 demonstrates both the power of including molecular dynamics in the drug discovery process and that this specific, clinically proven, but difficult, antidiabetes target can be addressed by chemotypes different from existing ligands.

Design, synthesis and biological evaluation of 2,5-dimethylfuran-3-carboxylic acid derivatives as potential IDO1 inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in tumor immune escape and has emerged as a promising target for cancer immunotherapy. In this study, a novel series of 2,5-dimethylfuran-3-carboxylic acid derivatives were designed, synthesized and evaluated for inhibitory activities against IDO1, and their structure-activity relationship was investigated. Among these, compound 19a exhibited excellent IDO1 inhibitory activity (HeLa cellular IC50 = 4.0 nM, THP-1 cellular IC50 = 4.6 nM). Further molecular docking studies revealed that the compound 19a formed a coordinate bond with the heme iron through the carboxylic acid moiety. These results indicate that compound 19a is a potential IDO1 inhibitor for further investigation.

Luminescent dinuclear rhenium(I)[sbnd]PNA conjugates for microRNA-21 targeting: Synthesis, chemico-physical and biological characterization

Two different luminescent rhenium complexes, having the general formula [Re2(μ-Cl)2(CO)6(μ-1,2-diazine)] and containing two different diazine ligands, namely 4-(pyridazin-4-yl)-butanoic acid (Re-1) and 8-(5-methylpyridazin-4-yl)-octanoic acid (Re-2), were prepared. Exploiting the presence of the carboxylic acid moieties, both complexes were further covalently linked to a 20-mer oligomer (PNA1), bearing a nucleobase sequence complementary to that of mature miR-21–5p (5′-TCAACATCAGTCTGATAAGCTA-3′), as well as to a 20-mer oligomer (PNA2) used as a negative control bearing the sequence 5′-GTGTAACACGTCCTATACGCC-3’. The resulting four Re-PNA conjugates were characterized and used to target miR-21 in the DU145 prostate cancer cell line. The conjugation with PNA did not perturb the photoluminescence behavior of the organometallic fragments: emission from 3MLCT excited states, centered in a range between 580 and 610 nm, was observed, with satisfactory photoluminescence quantum yields (Φ = ca. 0.03–0.01, in aerated water/acetonitrile solution 1/1). Experiments of cell uptake, performed with living prostate cancer cells showed that the length of the aliphatic linker between the rhenium complex and the PNA sequence, strongly affects the cellular localization.

Buffer solutions in drug formulation and processing: How pKa values depend on temperature, pressure and ionic strength

Solution pH is an important factor during drug formulation and processing. Changes in pH present challenges. Regulation of pH is typically managed by using a buffer system, which must have a suitable pKa. The pKa of buffers depends on temperature, pressure and ionic strength. In addition, the pKa can also be affected by the polarity of the solvent, e.g., by the addition of a co-solvent. Theoretical considerations and accessible experimental data were used to understand how the pKa values of pharmaceutically relevant buffers depend on these factors. Changes in temperature also affect the buffer pKa. Carboxylic acid moieties were least affected by changes in temperature. Buffers containing amino groups were most affected by changes in temperature, and the pKa decreased as temperature was increased. It was possible to predict accurately how buffer pKa varies with temperature, based on changes in enthalpy and heat capacity for the ionization reactions. Changes in pressure had a limited effect on buffer pKa for pressures <100 MPa. At higher pressures, buffer pKa varied by up to 0.5 pH units. Altering the ionic strength or polarity of the solvent influenced buffer pKa slightly. However, it is possible to keep both the ionic strength and the polarity of the solvent constant during drug formulation and processing.

Synthesis and Biological Evaluation of Novel Thiazolyl-Coumarin Derivatives as Potent Histone Deacetylase Inhibitors with Antifibrotic Activity.

New histone deacetylases (HDAC) inhibitors with low toxicity to non-cancerous cells, are a prevalent issue at present because these enzymes are actively involved in fibrotic diseases. We designed and synthesized a novel series of thiazolyl-coumarins, substituted at position 6 (R = H, Br, OCH3), linked to classic zinc binding groups, such as hydroxamic and carboxylic acid moieties and alternative zinc binding groups such as disulfide and catechol. Their in vitro inhibitory activities against HDACs were evaluated. Disulfide and hydroxamic acid derivatives were the most potent ones. Assays with neonatal rat cardiac fibroblasts demonstrated low cytotoxic effects for all compounds. Regarding the parameters associated to cardiac fibrosis development, the compounds showed antiproliferative effects, and triggered a strong decrease on the expression levels of both α-SMA and procollagen I. In conclusion, the new thiazolyl-coumarin derivatives inhibit HDAC activity and decrease profibrotic effects on cardiac fibroblasts.

Tetrazoles via Multicomponent Reactions.

Tetrazole derivatives are a prime class of heterocycles, very important to medicinal chemistry and drug design due to not only their bioisosterism to carboxylic acid and amide moieties but also to their metabolic stability and other beneficial physicochemical properties. Although more than 20 FDA-approved drugs contain 1H- or 2H-tetrazole substituents, their exact binding mode, structural biology, 3D conformations, and in general their chemical behavior is not fully understood. Importantly, multicomponent reaction (MCR) chemistry offers convergent access to multiple tetrazole scaffolds providing the three important elements of novelty, diversity, and complexity, yet MCR pathways to tetrazoles are far from completely explored. Here, we review the use of multicomponent reactions for the preparation of substituted tetrazole derivatives. We highlight specific applications and general trends holding therein and discuss synthetic approaches and their value by analyzing scope and limitations, and also enlighten their receptor binding mode. Finally, we estimated the prospects of further research in this field.

Mucoadhesive approach for buccal application: Preactivated chitosan

Buccal adhesive drug delivery has gained pharmaceutical interest in the past decades. This study aimed to establish an efficient mucoadhesive dosage form based on chitosan for the potential use in buccal application. Mercaptonicotinic acid (MNA) was covalently linked to chitosan via amide bond formation between the primary amino groups of chitosan and the carboxylic acid moieties of mercaptonicotinic acid. In a second step, obtained sulfhydryl linked chitosan was preactivated with the formation of disulfide bonds between chitosan-MNA and mercaptonicotinic acid (MNA). Preactivated chitosan-MNA-MNA conjugates were characterized in terms of degree of substitution and stability. Furthermore, whirling medium assay was performed on mucosal tissue. Chitosan-MNA-MNA convinced with its 18.8-fold enhanced stability of the polymeric matrix compared to unmodified chitosan. Moreover, adhesive properties were 12.56-fold improved in presence of chitosan-MNA-MNA in comparison to respective chitosan. All conjugates showed no toxicity to the cells. Taken together, synthesis of chitosan-MNA-MNA established a promising mucoadhesive dosage form for buccal application.

Association of Halogen Bonding and Hydrogen Bonding in Metal Acetate-Catalyzed Asymmetric Halolactonization

SummaryCooperative activation using halogen bonding and hydrogen bonding works in metal-catalyzed asymmetric halolactonization. The Zn3(OAc)4-3,3′-bis(aminoimino)binaphthoxide (tri-Zn) complex catalyzes both asymmetric iodolactonization and bromolactonization. Carboxylic acid substrates are converted to zinc carboxylates on the tri-Zn complex, and the N-halosuccinimide (N-bromosuccinimide [NBS] or N-iodosuccinimide [NIS]) is activated by hydrogen bonding with the diamine unit of chiral ligand. Halolactonization is significantly enhanced by the addition of catalytic I2. Density functional theory calculations revealed that a catalytic amount of I2 mediates the alkene portion of the substrates and NIS to realize highly enantioselective iodolactonization. The tri-Zn catalyst activates both sides of the carboxylic acid and alkene moiety, so that asymmetric five-membered iodolactonization of prochiral diallyl acetic acids proceeded to afford the chiral γ-butyrolactones. In the total description of the catalytic cycle, iodolactonization using the NIS-I2 complex proceeds with the regeneration of I2, which enables the catalytic use of I2. The actual iodination reagent is I2 and not NIS.

5-Norbornene-2-carboxylic acid: Another catalytic mediator for Catellani-type reactions

Mediators play a central role in Catellani-type reactions. Herein we reported the discovery of inexpensive 5-norbornene-2-carboxylic acid (N4) as a general catalytic mediator (20 mol%) to facilitate ortho C–H activation and the following C–C bond formation of aryl iodides. Firstly, a cooperative catalytic system comprising N4 and a palladium/XPhos complex was developed for the novel Catellani/redox-relay Heck cascade to construct tetrahydronaphthalenes and indanes that contain a quaternary carbon stereogenic center. The striking feature of this work was the avoidance of stoichiometric NBE mediator that are usually required for Catellani-type reactions. Then, preliminary results demonstrated that N4 could act as a general catalytic mediator to replace NBE for other Catellani-type reactions, which will undoubtedly inspire future developments in the field of cooperative catalysis. Finally, control experiments indicated that the carboxylic acid moiety of N4 plays an essential role in its ability to serve as a superior mediator.

Fluorescent Superparamagnetic Core-Shell Nanostructures: Facile Synthesis of Fe@C-CN&amp;lt;sub&amp;gt;x&amp;lt;/sub&amp;gt; Particles for Reusable Photocatalysts

Synthesis and characterization of hybrid fluorescent superparamagnetic core-shell particles of Fe@C-CNx composition are presented for the first time. The prepared Fe@C-CNx hybrid nanoparticles were found to possess multifunctionality by exhibiting strong superparamagnetic properties and bright fluorescence emissions at 500 nm after the excitation with light in the UV-visible range. Fe@C-CNx also exhibits photocatalytic activities for organic dye degradation comparable to pure amorphous CNx with reusability through magnetic separation. The combination of magnetic and fluorescent properties of core-shell Fe@C-CNx nanoparticles opens opportunities for their application as sensors and magnet manipulated reusable photocatalysts. Superparamagnetic Fe@C core-shell nanoparticles were used as the template material in the synthesis, where the carbon shell was functionalized through one-step free-radical addition of alkyl groups terminated with carboxylic acid moieties. The method utilizes the organic acyl peroxide of dicarboxylic acid (succinic acid peroxide) as a non-oxidant functional free radical precursor for functionalization. Further, covalently functionalized succinyl-Fe@C core-shell nanoparticles were coated with the amorphous carbon nitride (CNx) generated by an in-situ solution-based chemical reaction of cyanuric chloride with lithium nitride. A detailed physicochemical characterization of the microstructure, magnetic and fluorescence properties of the synthesized hybrid nanoparticles is provided.