Free Amide Research Articles

Reaction of 2,3,4,5,6-Pentafluorobenzamide with Potassium Hydride: Unexpected Activation of the C–F Bond and Dimerization of Organofluorine Ligand

The reaction of potassium hydride with 2,3,4,5,6-pentafluorobenzamide (FBAm) in dimethoxyethane results in activation of the C–F bond in the para-position to the C(O)NH2 group followed by dimerization of FBAm to form a potassium salt with one free amide group. The structure of the binuclear reaction product {(DME)2K+[C6F5–C(O)N–C6F4–C(O)NH2]–}2 (I) was determined by X-ray diffraction (CCDC 2311402), the purity of the product was confirmed by NMR spectroscopy.

Reaction of 2,3,4,5,6-Pentafluorobenzamide with Potassium Hydride: Unexpected Activation of the C–F Bond and Dimerization of Organofluorine Ligand

The reaction of potassium hydride with 2,3,4,5,6-pentafluorobenzamide (FBAm) in dimethoxyethane results in activation of the C–F bond in the para-position to the C(O)NH2 group followed by dimerization of FBAm to form a potassium salt with one free amide group. The structure of the binuclear reaction product {(DME)2K+[C6F5–C(O)N–C6F4–C(O)NH2]–}2 (I) was determined by X-ray diffraction (CCDC 2311402), the purity of the product was confirmed by NMR spectroscopy.

Site-Selective Arylation of Carboxamides from Unprotected Peptides.

The amidated peptides are an important class of biologically active compounds due to their unique biological properties and wide applications as potential peptide drugs and biomarkers. Despite the abundance of free amide motifs (Asn, Gln, and C-terminal amide) in native peptides, late-stage modification of the amide unit in naturally occurring peptides remains very rare because of the intrinsically weak nucleophilicity of amides and the interference of multiple competing nucleophilic residues, which generally lead to undesired side reactions. Herein, chemoselective arylation of amides in unprotected polypeptides has been developed under an air atmosphere to afford the N-aryl amide peptides bearing various functional motifs. Its success relies on the combination of gold catalysis and silver salt to differentiate the relative inert amide among a collection of reactive nucleophilic amino acid residues (e.g., -NH2, -OH, and -COOH), favoring the C-N bond coupling toward amides over other more nucleophilic groups. Experimental and DFT studies reveal a crucial role of the silver cation, which serves as a transient coordination mask of the more reactive reaction sites, overcoming the inherently low reactivity of amides. The excellent biocompatibility of this strategy has been applied to functionalize a wide range of peptide drugs and complex peptides. The application could be further extended to peptide labeling and peptide stapling.

Selective nickel-electrocatalyzed benzylic C–H oxygenation of functionalized alkyl arenes

Herein, a site-selective paired electrochemical C–H oxidation of functionalized alkyl arenes promoted by nickel catalyst is disclosed. A Ni(II)-dioxygen species formed in situ efficiently enable the oxidation process under mild conditions with a broad substrate scope with excellent functional group compatibilities, such as free carboxylic acid, aldehyde, halogen (including aryl iodide), amide and amino acid. The use of the nickel catalyst in combination with water provides a safe, green and economical method for oxidation of a range of molecules varying in complexity and drug derivatives, demonstrating its potential application in organic synthesis and the pharmaceutical industry. Reaction outcomes and mechanistic studies revealed the key role of the in situ Ni(II)-dioxygen species for the subsequent oxidation of C(sp3)–H bonds, and short-lived reactive intermediates (aryl radical cation) was rapidly captured by the combination of a bipolar ultramicroelectrode (BUME) with nano-electrospray ionization mass spectrometry.

Abstract 3106: Design, synthesis, and screening of niclosamide analogs as androgen receptor degraders for hepatocellular carcinoma

Abstract Hepatocellular Carcinoma (HCC) is the leading form of liver cancer, the 6th most common type, and the 4th leading cause of cancer death worldwide. Interestingly, HCC occurs two to four times more in males than females. A possible explanation for this sexual dimorphism is the implication of androgen and the Androgen Receptor (AR). However, previous clinical trials among HCC patients have shown no significant survival benefit after the administration of antiandrogen drugs (e.g. Enzalutamide) that block the Ligand-Binding Domain (LBD) of the Full-length Androgen Receptor (AR-FL). Instead, our lab has developed a novel approach using small molecular analogs of the previously FDA-approved drug, Niclosamide, to degrade full-length AR and its spliced variants within HCC cell lines. The primary goal of this project was to evaluate the minimal necessary pharmacophores for the biological activity of the Niclosamide scaffold. To do so, 23 analogs were synthesized and tested on three different HCC cell lines (SNU 475, 423, and LM3) using a CCK8 cell viability assay. Preliminary results have shown that only Niclosamide analogs with i.) electron-withdrawing groups on the aniline ring; ii) a conserved hydroxy group on the salicylic ring, and iii) a free amide group in the middle have cytotoxic activity. Further work will be completed using western blot to determine if there’s any correlation between androgen receptor degradation and in vitro potency. In conclusion, Niclosamide analogs have indicated promising potential to inhibit HCC cell lines by targeting the Androgen Receptor. Citation Format: Jeffrey Cheng, Enming Xing, Shabber Mohammed, Emma Montgomery, Lauren Granchie, Christopher Coss, Pui-Kai Li. Design, synthesis, and screening of niclosamide analogs as androgen receptor degraders for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3106.

Relaxation behavior, crystallization and mechanical property of long chain polyamides via thermodynamic technologies

The relaxation spectra of Long Chain Polyamides (LCPAs) were obtained by adopting superposition principle of the characteristic structural information at different scales, which unveil the dynamic relaxation behaviors from local groups to whole chain over a broad frequency range of 107 − 10−2 Hz with Dielectric relaxation spectroscopy (DRS), dynamic mechanics analysis (DMA) and rheometer respectively and under a temperature interval of 150–30 °C. It has been systematically quantified the influences of the zero-shear viscosity (average macromolecular weight) and the density of hydrogen bonds on relaxation dynamics, the crystallization behavior and mechanical properties. Relaxation time is related to molecular weight, and the segment of LCPA with high molecular weight is difficult to be orderly arranged into crystalline structure, resulting in low crystallization temperature (Tc), thick lamellar thickness (Lc) determined by the increasing undercooling and high mechanical strength. A comparison of LCPAs with varying amide group density revealed the roles of the density of hydrogen bonds and the fraction of free amide groups on relaxation behaviors, which extended the relaxation spectra of LCPAs and furtherly clarified the relationship between structure and properties.

Temperature- and pH-Responsive Schizophrenic Copolymer Brush Coatings with Enhanced Temperature Response in Pure Water

Novel brush coatings were fabricated with glass surface-grafted chains copolymerized using surface-initiated atom transfer radical polymerization (SI-ATRP) from 2-(2-methoxyethoxy)ethyl methacrylate (OEGMA188) and acrylamide (AAm), taken in different proportions. P(OEGMA188-co-AAm) brushes with AAm mole fraction >44% (determined with XPS and TOF-SIMS spectroscopy) and nearly constant with the depth copolymer composition (TOF-SIMS profiling) exhibit unusual temperature-induced transformations: The contact angle of water droplets on P(OEGMA188-co-AAm) coatings increases by ∼45° with temperature, compared to 17-18° for POEGMA188 and PAAm. The thickness of coatings immersed in water and the morphology of coatings imaged in air show a temperature response for POEGMA188 (using reflectance spectroscopy and AFM, respectively), but this response is weak for P(OEGMA188-co-AAm) and absent for PAAm. This suggests mechanisms more complex than a simple transition between hydrated loose coils and hydrophobic collapsed chains. For POEGMA188, the hydrogen bonds between the ether oxygens of poly(ethylene glycol) and water hydrogens are formed below the transition temperature Tc and disrupted above Tc when polymer-polymer interactions are favored. Different hydrogen bond structures of PAAm include free amide groups, cis-trans-multimers, and trans-multimers of amide groups. Here, hydrogen bonds between free amide groups and water dominate at T < Tc but structures favored at T > Tc, such as cis-trans-multimers and trans-multimers of amide groups, can still be hydrated. The enhanced temperature-dependent response of wettability for P(OEGMA188-co-AAm) with a high mole fraction of AAm suggests the formation at Tc of more hydrophobic structures, realized by hydrogen bonding between the ether oxygens of OEGMA188 and the amide fragments of AAm, where water molecules are caged. Furthermore, P(OEGMA188-co-AAm) coatings immersed in pH buffer solutions exhibit a 'schizophrenic' behavior in wettability, with transitions that mimic LCST and UCST for pH = 3, LCST for pH = 5 and 7, and any transition blocked for pH = 9.

Polymer Grafting and its chemical reactions.

Polymer grafting is a technique to improve the morphology, chemical, and physical properties of the polymer. This technique has the potential to improve the existing conduction and properties of polymers other than charge transport; as a result, it enhances the solubility, nano-dimensional morphology, biocompatibility, bio-communication, and other property of parent polymer. A polymer's physicochemical properties can be modified even further by creating a copolymer with another polymer or by grafting. Here in the various chemical approaches for polymer grafting, like free radical, click reaction, amide formation, and alkylation have been discussed with their importance, moreover the process and its importance are covered comprehensively with their scientific explanation. The present review also covers the effectiveness of the graft-to approaches and its application in various fields, which will give reader a glimpse about polymer grafting and its uses.

Evaluation of the Ecotoxicity of New Polyurethane Composites on Target Organisms for Aquatic and Atmospheric Environments.

The present study investigated if new biocomposite materials, polyurethanes (PURs) added with functionalized cellulose fibers, produce potential toxic effects on two target organisms currently used in biomonitoring the quality of two different environmental compartments. Natural fibers were extracted from the species Spartium junceum L., a shrub commonly found in the southern region of the Mediterranean having a high cellulose content. All PURs produced were characterized by Fourier-transform infrared spectroscopy, and their structure was analyzed by scanning electron microscopy. We measured the effects of exposure to aromatic and aliphatic PUR composites (containing or not cellulose fibers) on the aquatic model organism Daphnia magna Straus, a freshwater crustacean (Cladocera), and a biomonitor of air quality, the fruticose epiphytic lichen Pseudevernia furfuracea (L.) Zopf. Leachates from aliphatic PUR composite not containing cellulose are more toxic to D. magna than all others, showing a slight acute toxicity in the case of the shortest exposure (24 h) and a moderate acute toxicity in the longer one (48 h). This effect is most likely due to the presence of free organic ammines and amides, which, in their turn, are immobilized in composites containing cellulosic fibers because of the considerable amount of chemical functional groups. Regarding lichens, both types of aliphatic PURs resulted in a toxic effect. Formulate not added with cellulose strongly promoted fungal peroxidation, whereas that which was functionalized affected the pigment concentration of the algal partner. Our results suggest that the use of cellulose in PUR production, in general, can limit the ecotoxicological effects on both test organisms and reduce the potential environmental impact due to this type of polymer. Environ Toxicol Chem 2023;42:421-436. © 2022 SETAC.

Facilitating uniform lithium deposition via nanoconfinement of free amide molecules in solid electrolyte complexion for lithium metal batteries

As a facile method to facilitate the uniform lithium deposition on the lithium metal anode, a unique solid electrolyte complexion consisted of polyethylene oxide, UiO-66-NH2, and deep eutectic solvents (PEMD) with nanoconfinement significantly improves the lithium metal cycling stability. Specifically, the free amide molecules of deep eutectic solvents are nanoconfined by UiO-66-NH2 in the polyethylene oxide (PEO) matrix, and an excellent symmetrical electrochemical cycling performance more than 3600 h is achieved, extended by ∼10 times comparing to the reference. Furthermore, the Li || PEMD || LiFePO4 cell not only exhibits satisfactory electrochemical performance at 60 °C inherited from PEO, but also presents unexpected capacity reversibility, cycling stability, and enhanced rate capability at low temperatures down to 10 °C. The design of the solid electrolyte complexion with nanoconfinement opens an innovative avenue to the practical implementation of the PEO based lithium metal batteries.

A One‐Pot Three‐Step Strategy Enables Robust and Efficient Synthesis of 2‐Aryl Benzoxazoles from Amides

AbstractA one‐pot three‐step tandem approach has been developed and enabled direct transformation of amides into 2‐aryl benzoxazoles. This approach demonstrated high tolerance to various of halogen atoms, heterocyclic and aryl substituents. Moreover, after three steps reactions, this method allowed synthesis of 2‐aryl benzoxazoles in excellent yield, indicating the high conversion of each step. It showed the feasibility of transition‐metal free amide activation and transformation approach in 2‐aryl benzoxazoles synthesis.

Intermolecular Metal‐Free Cyclopropanation and Aziridination of Alkenes with XH2(X=N, C) by Thianthrenation**

AbstractThree‐membered cyclic structures are widely existing in natural products and serve as enabling intermediates in organic synthesis. However, the efficient and straightforward access to such structures with diversity remains a formidable challenge. Herein, a general and practical protocol to aziridines and cyclopropanes synthesis using free XH2(X=C or N) with alkenes by thianthrenation is presented. This metal‐free protocol features the direct aziridination and cyclopropanation with unprotected XH2. Free sulfonamides, amides, carbamates, amines, and methylene with acidic protons, are good precursors, providing an attractive alternative for straightforward synthesis of aziridines and cyclopropanes from easily available starting materials.

Intermolecular Metal‐Free Cyclopropanation and Aziridination of Alkenes with XH2(X=N, C) by Thianthrenation**

Three-membered cyclic structures are widely existing in natural products and serve as enabling intermediates in organic synthesis. However, the efficient and straightforward access to such structures with diversity remains a formidable challenge. Herein, a general and practical protocol to aziridines and cyclopropanes synthesis using free XH2 (X=C or N) with alkenes by thianthrenation is presented. This metal-free protocol features the direct aziridination and cyclopropanation with unprotected XH2 . Free sulfonamides, amides, carbamates, amines, and methylene with acidic protons, are good precursors, providing an attractive alternative for straightforward synthesis of aziridines and cyclopropanes from easily available starting materials.

A flexible network polyimides binder for Si/graphite composite electrode inlithium‐ionbatteries

Although the high-capacity Si/graphite anode serves to advance the energy density of lithium-ion batteries, the volume change remains the main disfigurement of Si/graphite anode. Many studies show that crosslinked structure binders tend to play a good inhibitory effect on volume expansion. In this work, a three-dimensionally covalently cross-linked and flexible polyimides (C–PI–OH) is successfully synthesized and applied as silicon/graphite anode, which is composed through a tri-monomer co-polycondensation and crosslinking process. The as-formed free carboxylic acid groups and amide groups in C–PI–OH are efficient in structural stability, so the electrode bound by C–PI–OH exhibits the highest peeling strength than C–PI and polyvinylidene fluoride. The flexible network of the C–PI–OH binder is competent for accommodating the volume expansion and contraction of silicon particles during the deintercalation of lithium ion, which helps in the wholeness of solid electrolyte interface film and electrodes, and effectively boosting the cycle stability of the Si/graphite anode.

An expedient, efficient and solvent-free synthesis of T3P®-mediated amidation of benzhydrols with poorly reactive N-nucleophiles under MW irradiation

An expedient, efficient, economical, environmentally benign, and solvent free amidation protocol of benzhydrols with less reactive nitrogen nucleophiles assisted by propylphosphonic anhydride (T3P®) under microwave irradiation has been developed.

8-(Methyltosylaminoethynyl)-1-naphthyl (MTAEN) Glycosides: Potent Donors in Glycosides Synthesis.

With 8-(methyltosylaminoethynyl)-1-naphthyl (MTAEN) glycoside as donors, a novel and efficient glycosylation protocol has been established. The MTAEN glycosylation protocol exhibits the merits of shelf-stable donors, mild catalytic promotion conditions, considerably extended substrate scope encompassing both free alcohols, silylated alcohols, nucleobases, primary amides, and C-type nucleophile acceptors, and applicability to various one-pot strategies for highly efficient synthesis of oligosaccharides, such as orthogonal one-pot, single-catalyst one-pot, and acceptor reactivity-controlled one-pot strategies.

A New Saddle-Shaped Aza Analog of Tetraphenylene: Atroposelective Synthesis and Application as a Chiral Acylating Reagent

A New Saddle-Shaped Aza Analog of Tetraphenylene: Atroposelective Synthesis and Application as a Chiral Acylating Reagent

Palladium-Catalyzed sp3 C–H Benzoxylation of Alanine Derivatives Using Aldehydes under Ambient Conditions

AbstractThe Pd(II)-catalyzed sp3 C–H bond benzoxylation of N-phthaloylalanine derivatives possessing an 8-aminoquinolyl group as a directing group with aldehydes under ambient conditions is reported. When a solution of an alanine derivative and an aldehyde in a toluene/water co-solvent was reacted in the presence of palladium catalyst and tert-butyl hydroperoxide at room temperature, a benzoxylated product was formed in up to 68% yield. The protecting group of the obtained benzoxylated product was smoothly removed to afford a free amide in high yield.

Trifluoroacetic Acid Hydroxylamine System as Organocatalyst Reagent in a One-Pot Salt Free Process for the Synthesis of Caprolactam and Amides of Industrial Interest

In this work we studied the reactivity of the Trifluoroacetic acid hydroxylamine system in the one step salt free synthesis of amides from ketones. A particular regards was paid to the caprolactam synthesis because of its industrial relevance. Synthesis, reactivity and characterization of the hydroxylamine trifluoroacetate is given. Fast oximation reaction of several ketones was gained at room temperature (1 h of reaction quantitative conversion for several ketones). In the same reactor, by raising the temperature at 383 K, the Beckmann rearrangement of the so obtained oximes is easily accomplished in the presence of three equivalent of TFA. The possibility of obtaining the trifluoroacetate of the hydroxylamine with a modified nitric acid hydrogenation reactions was verified, too. Reuse of solvent and trifluoroacetic acid is easily achieved by distillation.Graphical abstractSalt free one-pot caprolactam and amides process catalyzed by CF3COOH, in the presence of NH2OH TFA as the oximation agent.

A stable Cd(II)-based MOF with efficient CO2 capture and conversion, and fluorescence sensing for ronidazole and dimetridazole

By employing the ligand 2-(isonicotinamido)terephthalic acid (H2L) containing the amide functional groups, a Cd-MOF, {[Cd2L2(H2O)2]·4H2O}n (1) has been constructed by solvothermal synthesis. The dinuclear clusters [Cd2(COO)2] in 1 are linked by the pyridinyl and carboxylate groups of ligands to form a three-dimensional (3D) skeleton, containing 1D channels with the free amide groups. The activated framework shows good stability in water and high selectivity for CO2 over CH4. The open Cd2+ site as Lewis acidic center makes the MOF achieve efficiently catalytic conversion for CO2 cycloaddition with epoxides. Furthermore, 1 also exhibits good chemical stability in water, allowing the detection for ronidazole (RDZ) and dimetridazole (DTZ) with the low detection limit and rapid response.