Carboxylic Acid Functionality Research Articles

Nickel-Catalyzed Highly Selective Radical C-C Coupling from Carboxylic Acids with Photoredox Catalysis.

The selective coupling of two different radicals is a long-standing challenge due to the process occurring statistically. Generally, the cross-coupling selectivity is achieved by the persistent radical effect (PRE), resulting in limited radical precursors. In this paper, a highly selective cross-coupling of alkyl radicals with acyl radicals to construct C(sp2)-C(sp3) bonds, or with alkyl radicals to construct C(sp3)-C(sp3) bonds have been achieved with the readily available carboxylic acids and their derivatives (NHPI ester) as coupling partners. The success originates from the use of tridentate ligand (L1) to enable radical cross-coupling process to Ni-mediated organometallic mechanism. This protocol offers a facile and flexible access to structurally diverse ketones (up to 90% yield), and also a new solution for the challenging double decarboxylative C(sp3)-C(sp3) coupling. The broad utility and functional group tolerance are further illustrated by the late-stage functionalization of natural-occurring carboxylic acids and drugs.

C-Terminal Decarboxylation of Proline-Derived Building Blocks for Protein-Binding Peptides.

Using a set of conformationally restricted Proline-derived Modules (ProMs), our group has recently succeeded in developing inhibitors for the enabled/vasodilator-stimulated phosphoprotein homology 1 (EVH1) domain, which is a key mediator of cell migration and plays an important role in tumor metastasis. While these (formally) pentapeptidic compounds show nanomolecular binding affinities towards EVH1, their drug-like properties and cell permea-bility need to be further optimized before they can be clinically tested as therapeutic agents against metastasis. In this study, we sought to improve these properties by removing the C-terminal carboxylic acid function of our peptoids, either by late-stage decarboxylation or by direct synthesis. For late-stage decarboxy-lation of ProM-like systems, a method for reductive halo decarboxylation was optimized and applied to several proline-derived substrates. In this way, a series of new decarboxy ProMs suitable as building blocks for decarboxy EVH1 inhibitors were obtained. In addition, we incorporated decarboxy-ProM-1 into the penta-peptide-like compound Ac[2-Cl-F][ProM-2][Decarb-ProM-1], which showed similar affinity towards EVH1 as the methyl ester derivative (Ac[2-Cl-F][ProM-2][ProM1]OMe). However, despite better calculated drug-like properties, this compound did not inhibit chemotaxis in a cellular assay.

Exploring different classification-dependent QSAR modelling strategies for HDAC3 inhibitors in search of meaningful structural contributors.

Histone deacetylase 3 (HDAC3), a Zn2+-dependent class I HDACs, contributes to numerous disorders such as neurodegenerative disorders, diabetes, cardiovascular disease, kidney disease and several types of cancers. Therefore, the development of novel and selective HDAC3 inhibitors might be promising to combat such diseases. Here, different classification-based molecular modelling studies such as Bayesian classification, recursive partitioning (RP), SARpy and linear discriminant analysis (LDA) were conducted on a set of HDAC3 inhibitors to pinpoint essential structural requirements contributing to HDAC3 inhibition followed by molecular docking study and molecular dynamics (MD) simulation analyses. The current study revealed the importance of hydroxamate function for Zn2+ chelation as well as hydrogen bonding interaction with Tyr298 residue. The importance of hydroxamate function for higher HDAC3 inhibition was noticed in the case of Bayesian classification, recursive partitioning and SARpy models. Also, the importance of substituted thiazole ring was revealed, whereas the presence of linear alkyl groups with carboxylic acid function, any type of ester function, benzodiazepine moiety and methoxy group in the molecular structure can be detrimental to HDAC3 inhibition. Therefore, this study can aid in the design and discovery of effective novel HDAC3 inhibitors in the future.

PH-sensitive release of nitric oxide gas using peptide-graphene co-assembled hybrid nanosheets

Nitric oxide (NO) donating drugs such as organic nitrates have been used to treat cardiovascular diseases for more than a century. These donors primarily produce NO systemically. It is however sometimes desirable to control the amount, location, and time of NO delivery. We present the design of a novel pH-sensitive NO release system that is achieved by the synthesis of dipeptide diphenylalanine (FF) and graphene oxide (GO) co-assembled hybrid nanosheets (termed as FF@GO) through weak molecular interactions. These hybrid nanosheets were characterised by using X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, zeta potential measurements, X-ray photoelectron spectroscopy, scanning and transmission electron microscopies. The weak molecular interactions, which include electrostatic, hydrogen bonding and π-π stacking, are pH sensitive due to the presence of carboxylic acid and amine functionalities on GO and the dipeptide building blocks. Herein, we demonstrate that this formulation can be loaded with NO gas with the dipeptide acting as an arresting agent to inhibit NO burst release at neutral pH; however, at acidic pH it is capable of releasing NO at the rate of up to 0.6 μM per minute, comparable to the amount of NO produced by healthy endothelium. In conclusion, the innovative conjugation of dipeptide with graphene can store and release NO gas under physiologically relevant concentrations in a pH-responsive manner. pH responsive NO-releasing organic-inorganic nanohybrids may prove useful for the treatment of cardiovascular diseases and other pathologies.

Selective detection of nanomaterials: Gold nanorod imprinted matrices

Anisotropic nanostructures such as nanorods can be found in an increasing number of applications such as catalysis and imaging. Although their synthesis is well developed, their selective detection and separation are still in their infancy. Here, we demonstrate for the first time the selective recognition of gold nanorods (GNRs) by the nanoparticle-imprinted matrix (NAIM) approach. Specifically, GNRs stabilized by citrate (GNRs-cit) were adsorbed on an electrode surface modified with a positively charged polymer. The adsorption was followed by the electrochemical deposition of an aryldiazonium-based matrix around the GNRs-cit. Nanocavities having the shape of the imprinted GNRs were formed upon the removal of the nanoobject by electrochemical dissolution. We find that these nanocavities showed the ability to reuptake selectively GNRs similar to those initially imprinted. Furthermore, our findings clearly show that the recognition of the GNRs, namely, their reuptake by the nanocavities, depends on both the physical, i.e., structural fitness, and the chemical interactions between the imprinted GNRs and the matrix. For example, whereas a matrix bearing carboxylic acid functionalities repelled the GNRs stabilized by citric acid, a matrix formed by the electropolymerization of 4-acetylbenzenediazonium (ABD) exhibited good reuptake. A reuptake percentage, which is the ratio between the number of GNRs uptaken by the nanocavities divided by the number of the originally imprinted GNRs, of ca. 50% was obtained.

Casein-based conjugates and graft copolymers. Synthesis, properties, and applications.

Biobased natural polymers, including polymers of natural origin such as casein, are growing rapidly in the light of the environmental pollution caused by many mass-produced commercial synthetic polymers. Although casein has interesting intrinsic properties, especially for the food industry, numerous chemical reactions have been carried out to broaden the range of its properties, most of them preserving casein's nontoxicity and biodegradability. New conjugates and graft copolymers have been developed especially by Maillard reaction of the amine functions of the casein backbone with the aldehyde functions of sugars, polysaccharides, or other molecules. Carried out with dialdehydes, these reactions lead to the cross-linking of casein giving three-dimensional polymers. Acylation and polymerization of various monomers initiated by amine functions are also described. Other reactions, far less numerous, involve alcohol and carboxylic acid functions in casein. This review provides an overview of casein-based conjugates and graft copolymers, their properties, and potential applications.

A Convenient Oligonucleotide Conjugation via Tandem Staudinger Reaction and Amide Bond Formation at the Internucleotidic Phosphate Position.

Staudinger reaction on the solid phase between an electronodeficit organic azide, such as sulfonyl azide, and the phosphite triester formed upon phosphoramidite coupling is a convenient method for the chemical modification of oligonucleotides at the internucleotidic phosphate position. In this work, 4-carboxybenzenesulfonyl azide, either with a free carboxy group or in the form of an activated ester such as pentafluorophenyl, 4-nitrophenyl, or pentafluorobenzyl, was used to introduce a carboxylic acid function to the terminal or internal internucleotidic phosphate of an oligonucleotide via the Staudinger reaction. A subsequent treatment with excess primary alkyl amine followed by the usual work-up, after prior activation with a suitable peptide coupling agent such as a uronium salt/1-hydroxybenzotriazole in the case of a free carboxyl, afforded amide-linked oligonucleotide conjugates in good yields including multiple conjugations of up to the exhaustive modification at each phosphate position for a weakly activated pentafluorobenzyl ester, whereas more strongly activated and, thus, more reactive aryl esters provided only single conjugations at the 5'-end. The conjugates synthesized include those with di- and polyamines that introduce a positively charged side chain to potentially assist the intracellular delivery of the oligonucleotide.

Detection of basic amino acids under highly alkaline conditions using a perylene amine-derived probe

pH plays a crucial part in numerous chemical and physiological processes. In this work, a new perylene diimide derivative that acts as a pH-sensitive dye with Bay Area Carboxylic Acid functionality. The derivative utilizes the outstanding thermal, chemical and photochemical stability found in PDI materials and has remarkable UV–visible absorption and fluorescence emission qualities. Based on these properties, a fluorescent probe (PCA) was synthesised using a perylene tetracarbodiimide (PDI) backbone for the recognition of alkaline pH. In alkaline environments where the pH values are between 10 and 14, the fluorescence intensity significantly decreases, and a blue shift occurs, which is a standard feature of alkaline pH probes. The probe demonstrates exceptional sensing ability within the pH range of 10.00–14.00, with notable stability and reversibility. Encapsulation of the probe in a thin polymer film material enhances the pH sensing capability of the system. New sensor has been developed to detect basic amino acids by utilizing the probes' pH response characteristics. this sensor has also been applied to detect the concentration of arginine.

Site‐selective Mono‐ and Bifunctionalization of Graphene Oxide: Screening Nanocatalysts for Organophosphate Degradation

AbstractTargeted multiple functionalization is a promising tool for developing nanocatalysts for the degradation of toxic organophosphates, present in many agrochemicals and chemical warfare. Herein, we functionalized graphene oxide with two different functional groups (thiol and imidazole), focused on two distinct anchoring sites: epoxide and carboxylic acids. The mono‐ and bifunctionalized materials showed pronounced catalytic activity in the degradation of a toxic organophosphate. This was attributed to cooperative multiple catalyses by the reactive imidazole/thiol groups and neighbouring groups (carboxylate/hydroxyl) on the nanocatalyst backbone. The best nanocatalyst was monofunctionalized via epoxides, which showed the lowest degree of functionalization and highest amount of carboxylic acids. In this case, it could benefit from a bifunctional nucleophilic and general base catalysis involving the thiol and carboxylate groups, respectively. The bifunctionalization strategy via both epoxide and carboxylic acids showed to be better than the analogue bifunctionalized solely via the carboxylic acids, evidencing the importance of the spatial distribution of the anchoring sites. Overall, the functionalization strategy varies the positioning and availability of reactive groups which directly affects the catalytic outcome.

A Formal γ-C-H Functionalization of Carboxylic Acids Guided by Metal-Nitrenoids as an Unprecedented Mechanistic Motif.

Harnessing the key intermediates in metal-catalyzed reactions is one of the most essential strategies in the development of selective organic transformations. The nitrogen group transfer reactivity of metal-nitrenoids to ubiquitous C-H bonds allows for diverse C-N bond formation to furnish synthetically valuable aminated products. In this study, we present an unprecedented reactivity of iridium and ruthenium nitrenoids to generate remote carbocation intermediates, which subsequently undergo nucleophile incorporation, thus developing a formal γ-C-H functionalization of carboxylic acids. Mechanistic investigations elucidated a unique singlet metal-nitrenoid reactivity to initiate an abstraction of γ-hydride to form the carbocation intermediate that eventually reacts with a broad range of carbon, nitrogen, and oxygen nucleophiles, as well as biorelevant molecules. Alternatively, the same intermediate can lead to deprotonation to afford β,γ-unsaturated amides in a less nucleophilic solvent.

Dual functional behaviour of dicationic ionic liquid as extractant and hydrophobic biphasic solvent for extraction of Pb(II) in water

Herein, it was aimed to investigate the extraction ability of hydrophobic di-cationic imidazolium-based ionic liquid with inbuilt carboxylic acid functionalities for one of the heavy metals, Pb(II) from aqueous solution. Two dicationic ionic liquids, IL-1 named 1,1′(butane-1,4-diyl)bis(3-(4carboxyphenyl)-2-methyl-1H-imidazol-3-ium) chloride and IL-2 named 1,1′(dodecane-1,12-diyl)bis(3-(4carboxyphenyl)-2-methyl-1H-imidazol-3-ium)chloride tailored with (CH2)n bridging spacer chains, n = 4 and n = 12 respectively were synthesized. The Pb(II) displayed extraction percentages greater than 90% with both the aqueous biphasic system of IL-1 and IL-2. An efficient back-stripping of the Pb(II) metal ion was done using with aqueous solution of oxalic acid. Calcination of lead oxalate salt obtained showed highest purity of PbO confirmed by PXRD and EDX data. The established experimental condition with the synthesized ionic liquids is a distinguished one as no salting out agent, no extra extracting agents other than the synthesized ionic liquids were used. Moreover, the regeneration of the ionic liquid (IL-2), and back stripping of Pb(II) as oxalate salt makes this system an efficient one with negligible loss of the ionic liquid (IL-2) into the aqueous medium thus obliging the standards of environment-friendly sustainable development.

Carboxyl-Alkyl Functionalized Conjugated Polyelectrolytes for High Performance Organic Electrochemical Transistors.

Contemporary design principles for organic mixed ionic electronic conductors (OMIECs) are mostly based on the ethylene glycol moiety, which may not be representative of the OMIEC class as a whole. Furthermore, glycolated polymers can be difficult to synthesize and process effectively. As an emerging alternative, we present a series of polythiophenes functionalized with a hybrid carboxyl-alkyl side chain. By variation of the alkyl spacer length, a comprehensive evaluation of both the impact of carboxylic acid functionalization and alkyl spacer length was conducted. COOH-functionalization endows the polymer with preferential intrinsic low-swelling behavior and water processability to yield solvent-resistant conjugated polyelectrolytes while retaining substantial electroactivity in aqueous environments. Advanced in situ techniques, including time-resolved spectroelectrochemistry and Raman spectroscopy, are used to interrogate the materials' microstructure, ionic-electronic coupling, and operational stability in devices. To compare these materials' performance to state-of-the-art technology for the design of OMIECs, we benchmarked the materials and demonstrated significant application potential in both planar and interdigitated organic electrochemical transistors (OECTs). The polythiophene bearing carboxyl-butyl side chains exhibits greater electrochemical performance and faster doping kinetics within the polymer series, with a record-high OECT performance among conjugated polyelectrolytes ([μC*]pOECT = 107 ± 4 F cm-1 V-1 s-1). The results provide an enhanced understanding of structure-property relationships for conjugated polyelectrolytes operating in aqueous media and expand the materials options for future OMIEC development. Further, this work demonstrates the potential for conjugated polymers bearing alkyl-COOH side chains as a path toward robust OMIEC designs that may facilitate further facile (bio)chemical functionalization for a range of (bio)sensing applications.

Ligand‐Enabled Double γ‐C(sp3)−H Functionalization of Aliphatic Acids: One‐Step Synthesis of γ‐Arylated γ‐Lactones

Abstractγ‐methylene C(sp3)−H functionalization of linear free carboxylic acids remains a significant challenge. Here in we report a Pd(II)‐catalyzed tandem γ‐arylation and γ‐lactonization of aliphatic acids enabled by a L,X‐type CarboxPyridone ligand. A wide range of γ‐arylated γ‐lactones are synthesized in a single step from aliphatic acids in moderate to good yield. Arylated lactones can readily be converted into disubstituted tetrahydrofurans, a prominent scaffold amongst bioactive molecules.

Ligand-Enabled Double γ-C(sp3 )-H Functionalization of Aliphatic Acids: One-Step Synthesis of γ-Arylated γ-Lactones.

γ-methylene C(sp3 )-H functionalization of linear free carboxylic acids remains a significant challenge. Here in we report a Pd(II)-catalyzed tandem γ-arylation and γ-lactonization of aliphatic acids enabled by a L,X-type CarboxPyridone ligand. A wide range of γ-arylated γ-lactones are synthesized in a single step from aliphatic acids in moderate to good yield. Arylated lactones can readily be converted into disubstituted tetrahydrofurans, a prominent scaffold amongst bioactive molecules.

Comparison between Chemical and Biological Degradation Processes for Perfluorooctanoic Acid

Perfluorooctanoic acid (PFOA) is a perfluoro compound that contains an eight-carbon perfluoroalkyl chain followed by a carboxylic acid function group. The C-F bound possesses a strong bond energy of approximately 485 kJ/mol, rendering PFOA thermally and chemically stable. It has found applications in water-resistant coating and is produced either by degrading other long-chain perfluorinated carboxylic acids or fluorotelomer alcohol. PFOA is challenging to further degrade during water treatment processes, leading to its accumulation in natural systems and causing contamination. Research has been conducted to develop several methods for its removal from the water system, but only a few of these methods effectively degrade PFOA. This review compares the most common chemical degradation methods such as photochemical, electrochemical, and sonochemical methods, to the cutting-edge biodegradation method. The chemical degradation and biodegradation methods both involve the stepwise degradation of PFOA, with the latter capable of occurring both aerobically and anaerobically. However, the degradation efficiency of the biological process is lower when compared to the chemical process, and further research is needed to explore the biological degradation aspect.

Designing of molecularly imprinted polymer with carboxylic acid functionality for chiral separation of (±)‐3,4‐methylenedioxymethamphetamine

AbstractIn this work, we discuss the development of a long‐lasting enantioselective material for the effective enantio‐recognition of S‐3,4‐methylenedioxymethamphetamine (S‐MDMA) and chiral separation of the (±)‐MDMA racemate using a crosslinked poly(acrylic acid‐4‐vinylpyridine) copolymer. The first step was the synthesis and characterization of an acryloyl‐S‐MDMA amide. After that, the free radical initiator azobisisobutyronitrile was used to copolymerize the synthesized chiral amide with 4‐vinylpyridine and divinylbenzene. The incorporated S‐MDMA species were extracted from the polymeric particles by heating them with sodium hydroxide, followed by rinsing with hydrochloric acid. This developed the molecularly imprinted S‐MDMA particles, which were visualized with a scanning electron microscope and Fourier transform infrared spectroscopy. The selectivity parameters indicated a higher affinity of the fabricated S‐MDMA imprinted particles toward S‐MDMA, around 10‐fold higher than that related to R‐MDMA. Results from Langmuir adsorption experiments at pH 6 demonstrated a maximal capacity of 142 mg g−1. In addition, the values of enantiomeric excess were found to be 94.5% and 79.4% for R‐ and S‐MDMA in the loading and eluant solutions, respectively, after optical separation was done using the column technique. © 2023 Society of Industrial Chemistry.

Methodology for evaluating the mechanical performances of a bonded assembly through complementary mechanical tests

ABSTRACT Bifunctional polymers have been studied as bonding layers (BL) on aluminum surfaces to promote adhesion of adhesives for structural bonding applications. The BL are located at the interface between the aluminum substrate and the adhesive. The mechanical performances of the BL in a bonded assembly were evaluated via several complementary mechanical tests, before and after ageing cycle: single lap shear, Arcan test, three-point bending test, and micro-scratch. The results of these four mechanical tests were compared with those of a raw reference (without any treatment) and a reference that had undergone standard surface preparation (cleaning and etching), in order to assess the mechanical performances of the surface treatment products (BL), and to value these products on the surface treatment market. In order to follow a methodology for selecting the best surface treatments, the mechanical results were compared with each other, and even correlated for samples with bonding layers (containing phosphorus and carboxylic acid functions). The correlation of the results obtained from the four mechanical tests (single lap shear, Arcan, three-point bending, and micro-scratch tests) therefore makes it possible to validate the methodology for evaluating these surface treatments.

Peptide nucleic acid-zirconium coordination nanoparticles

Ideal drug carriers feature a high loading capacity to minimize the exposure of patients with excessive, inactive carrier materials. The highest imaginable loading capacity could be achieved by nanocarriers, which are assembled from the therapeutic cargo molecules themselves. Here, we describe peptide nucleic acid (PNA)-based zirconium (Zr) coordination nanoparticles which exhibit very high PNA loading of >,94% w/w. This metal-organic hybrid nanomaterial class extends the enormous compound space of coordination polymers towards bioactive oligonucleotide linkers. The architecture of single- or double-stranded PNAs was systematically varied to identify design criteria for the coordination driven self-assembly with Zr(IV) nodes at room temperature. Aromatic carboxylic acid functions, serving as Lewis bases, and a two-step synthesis process with preformation of Zr_{6} O_{4} (OH)_{4} turned out to be decisive for successful nanoparticle assembly. Confocal laser scanning microscopy confirmed that the PNA-Zr nanoparticles are readily internalized by cells. PNA-Zr nanoparticles, coated with a cationic lipopeptide, successfully delivered an antisense PNA sequence for splicing correction of the beta-globin intron mutation IVS2-705 into a functional reporter cell line and mediated splice-switching via interaction with the endogenous mRNA splicing machinery. The presented PNA-Zr nanoparticles represent a bioactive platform with high design flexibility and extraordinary PNA loading capacity, where the nucleic acid constitutes an integral part of the material, instead of being loaded into passive delivery systems.

Design and Synthesis of Novel 1‐((1‐Phenyl‐1H‐1,2,3‐triazol‐4‐yl)methyl)pyridin‐2(1H)‐one Derivatives

AbstractThe synthesis of a new class of compounds, namely 1‐((1‐phenyl‐1H‐1,2,3‐triazol‐4‐yl)methyl)pyridin‐2(1H)‐one derivatives starting from 2‐hydroxynicotinic acid was reported. Initially, the carboxylic acid functionality connected to the pyridinone ring was converted to either the ester, amide or aldehyde functionality to obtain the precursor for the propargylation step. The incorporation of a propargyl group into the nitrogen atom of pyridinones was achieved in the presence of K2CO3 as a base. Different organic azides were also synthesized starting from the corresponding aniline derivatives. To obtain target molecules, the facile click cycloaddition reactions of alkynes with aryl azide derivatives in the presence of copper(I) catalyst were applied. Using this protocol, novel 1‐((1‐phenyl‐1H‐1,2,3‐triazol‐4‐yl)methyl)pyridin‐2(1H)‐one derivatives with different substitution patterns were prepared in good to excellent yields under the mild reaction conditions. The structures of the compounds were confirmed by 1D and 2D NMR, FTIR, and HRMS analysis data. Overall, this protocol offers a straightforward method for synthesizing these novel compounds.

Total Synthesis of a Structurally Complex Tetrasaccharide Repeating Unit of Vibrio cholerae O43.

Herein we report the first total synthesis of a densely functionalized tetrasaccharide repeating unit of Vibrio cholerae O43, which contains rare deoxy amino sugars d-quinovosamine and d-viosamine attached with the rare amino acid N-acetyl-l-allothreonine. Synthesis of orthogonally protected rare sugars and unnatural amino acid building blocks, stereoselective construction of three consecutive 1,2-cis glycosidic linkages, amide coupling, and the presence of five nitrogen atoms dispersed over four sugar units as well as the carboxylic acid functionality make the total synthesis a formidable task.