Amidation Reaction Research Articles

Enhancing Methylene Blue Adsorption Performance of Ti3C2Tx@Sodium Alginate Foam Through Pore Structure Regulation

Pore structural regulation is expected to be a facile way to enhance the adsorption performance of MXene. In this work, spherical foam composites consisting of Ti3C2Tx and sodium alginate (SA) were synthesized via a vacuum freeze-drying technique. By varying the solution volume of Ti3C2Tx, four distinct Ti3C2Tx@SA spherical foams with honeycomb-like and lamellar structures with a pore diameter in the range of 100–300 μm were fabricated. Their methylene blue (MB) adsorption performances were then systematically compared. The results revealed that the honeycomb-like porous-structured spherical foams have a significantly higher adsorption capacity than their lamellar counterparts. Notably, the Ti3C2Tx@SA honeycomb-like porous foam exhibited a remarkable maximum adsorption capacity (qm) of 969 mg/g, positioning it at the forefront of MB adsorbent materials. Respective analysis of the adsorption kinetics, thermodynamics, and isotherm model indicated that this MB adsorption of Ti3C2Tx@SA honeycomb-like porous foam is characterized to be a physical, endothermic, and monolayer adsorption. The Ti3C2Tx@SA honeycomb-like porous foam also demonstrated excellent resistance to ion interference and good reusability, further attesting to its substantial potential for practical applications. X-ray photoelectron spectroscopy (XPS) analysis was employed to elucidate the adsorption mechanism, which was found to involve the synergistic effect of electrostatic adsorption and amidation reaction. This work not only offers new avenues for the development of high-performance adsorption materials but also provides crucial insights into the structural design and performance optimization of porous materials.

Synthesis and Thiol-Ene Photopolymerization of Bio-Based Hybrid Aromatic–Aliphatic Monomers Derived from Limonene, Cysteamine and Hydroxycinnamic Acid Derivatives

Three novel bio-based monomers were synthesized through an amidation reaction involving allylated derivatives of coumaric, ferulic and phloretic acid and a diamine obtained from a thiol-ene coupling reaction between limonene and cysteamine. The monomers containing the enone bond of the cinnamic moiety underwent photoisomerization and photocycloaddition reactions upon UV light irradiation. All three monomers were photocured via thiol-ene photopolymerization using a glycerol-derived trifunctional thiol, resulting in fully bio-based poly(amide–thioether)s. The polymers derived from monomers that contain the enone bond exhibited glass transition (Tg) temperatures of 85 °C when a stoichiometric ratio of the thiol was used, whereas polymers in which an excess of thiol was used exhibited Tg temperatures of 61 and 74 °C. The higher Tg of the synthesized polymers, compared with other reported polymers produced from thiol-ene photopolymerizations, was attributed to the combination of the aromatic rings of the cinnamic moiety and the cycloaliphatic ring of limonene, as well as the presence of the amide groups in the polymer, which can induce hydrogen bonding. The development of high Tg polymers from bio-based monomers through thiol-ene photopolymerization represents a significant advancement in the polymer synthesis sector, offering an improved performance and sustainability.

Hypoxia-responsive liposome enhances intracellular delivery of photosensitizer for effective photodynamic therapy

Liposomes, especially polyethylene glycol (PEG)-modified long-circulating liposomes, have been approved for market use, due to good biocompatibility, passive tumor targeting, and sustained drug release. PEG-modified long-circulating liposomes address issues such as poor stability and rapid clearance by the reticuloendothelial system. However, they still face challenges like hindering drug uptake by tumor cells and preventing tumor penetration. Inspired by the hypoxic tumor microenvironment, we constructed a hypoxia-responsive liposome (PAO-L) to enhance the intracellular uptake and photodynamic therapy (PDT) effect of chlorin e6 (Ce6). The intelligent hypoxia-cleavable PEG-AZO-OA (PAO) was prepared by coupling PEG and octadecylamine (OA) to hypoxia-sensitive azobenzene-4,4′-dicarboxylic acid (AZO) through amide reaction. The synthesized PAO was further incorporated into Ce6-loaded liposomes to enhance the circulation stability, while promote the tumor penetration and internalization by the responsive shedding of PEG from liposome surface upon reaching the hypoxic tumor tissue. PAO-L mediated PDT significantly inhibited the growth of B16F10 and 4T1 tumors, as well as lung metastasis of 4T1 breast cancer. The excellent therapeutic effect and good tolerability make PAO-L a promising candidate for enhanced PDT.

Copper-Catalyzed γ-C(sp3)-H Lactamization and Iminolactonization.

Despite extensive efforts to develop γ-lactamization reactions for pyrrolidinone synthesis using either cyclometallation, C-H insertion, or radical C-H abstraction strategies, γ-lactamization reactions of aliphatic amides using practical catalysts and common protecting groups remain extremely rare. Herein we report copper-catalyzed γ-C(sp3)-H lactamization and iminolactonization of tosyl-protected aliphatic amides using inexpensive Selectfluor as the sole oxidant. A switchable selectivity of γ-lactams or γ-iminolactones can be obtained by using two different sets of reaction conditions. Notably, structurally diverse spiro-, fused-, and bridged-lactams and iminolactones, as well as isoindolinones are accessible by this method. Further derivatization of the γ-lactam products enables the synthesis of a range of biologically important motifs, including γ-amino acids, δ-amino alcohols, and pyrrolidines.

Copper‐Catalyzed γ‐C(sp3)−H Lactamization and Iminolactonization

AbstractDespite extensive efforts to develop γ‐lactamization reactions for pyrrolidinone synthesis using either cyclometallation, C−H insertion, or radical C−H abstraction strategies, γ‐lactamization reactions of aliphatic amides using practical catalysts and common protecting groups remain extremely rare. Herein we report copper‐catalyzed γ‐C(sp3)−H lactamization and iminolactonization of tosyl‐protected aliphatic amides using inexpensive Selectfluor as the sole oxidant. A switchable selectivity of γ‐lactams or γ‐iminolactones can be obtained by using two different sets of reaction conditions. Notably, structurally diverse spiro‐, fused‐, and bridged‐lactams and iminolactones, as well as isoindolinones are accessible by this method. Further derivatization of the γ‐lactam products enables the synthesis of a range of biologically important motifs, including γ‐amino acids, δ‐amino alcohols, and pyrrolidines.

Synthesis of 2‐(Pentafluoro‐λ6‐sulfanyl)acetamides and Impact of the Fluorinated Group on the Lipophilicity

AbstractThe synthesis of 2‐(pentafluoro‐λ6‐sulfanyl)acetamides is described via an amidation reaction between 2‐(pentafluoro‐λ6‐sulfanyl)acetic acid, the SF5‐containing building block, and various amines. A total of 27 examples of SF5‐containing amides were synthesized, with isolated yields going from 43 % to quantitative. We showed that a 2‐(pentafluoro‐λ6‐sulfanyl)acetamide could be converted to a N‐(2‐SF5‐ethyl)amine and a SF5‐containing oxadiazoles. Finally, the effect of the SF5 substituent on the lipophilicity of the amide of a model compound was evaluated.

Tunable Activated Esters Enable Lysine-Selective Protein Labeling and Profiling.

Lysine residues on protein surfaces are abundant and often found in enzyme active sites, making them critical targets for studying undruggable proteins. However, the varied microenvironment surrounding lysine residues results in a wide range of pKa values, complicating site-specific covalent binding. In this study, we address the challenges posed by the diverse reactivity of amino side chains by modulating the amide reaction activity of heteroaromatic activated esters. By fine-tuning the type, position, and number of heteroatoms, we successfully rationalized the regulation of their amide reaction activity, leading to the design of probes for selective lysine labeling within the proteome for profiling purposes. Systematic optimization of these esters' reactivity and selectivity has yielded a series of effective probes suitable for both in vitro and cellular applications. These findings significantly enhance our understanding of protein functions and mechanisms, facilitated by the precise identification and analysis of protein labeling and profiling.

A pH-responsive phase-transition bi-affinity nanopolymer-assisted exosome metabolomics for early screening of osteoarthritis

Exosomes, emerging as ideal non-invasive biomarkers for disease diagnosis and monitoring, have seldom been explored based on metabolite levels. In this study, we designed and synthesized a pH-responsive phase-transition bifunctional affinity nanopolymer (pH-BiAN) that could efficiently and homogeneously separate exosomes from urine. Specifically, poly-4-vinylpyridine (P4VP) was chosen as the pH-responsive polymer and simultaneously modified with two exosome-affinity components CD63 aptamer and distearoyl phosphoethanolamine (DSPE) through a one-step amide reaction at room temperature. By utilizing two distinct but synergistic affinity mechanisms—the immune affinity between CD63 aptamer and exosomal CD63 proteins, and hydrophobic interactions between the DSPE and the exosomal lipids—pH-BiAN can enable efficient and specific exosome separation. Moreover, during the urine exosome capture procedure, the pH-BiAN outperforms conventional solid exosome separation materials by remaining soluble in the urine sample, significantly enhancing mass transfer and contact efficiency. After exosome capture, pH-BiAN can quickly aggregate and convert to solid upon pH adjustment, allowing for easy centrifugation separation. Afterwards, multiple machine learning models were established by combining liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) untargeted metabolomics for isolated exosomes, and the clinical accuracy of the training and test sets was more than 0.919, which could well distinguish early osteoarthritis patients from healthy people.

Cascade Reactions of Alkynyl Ketones and Amides to Generate Unsaturated Oxacycles and Aromatic Carbocycles.

We describe novel amine-mediated transformation of alkynyl ketones and amides to generate 2-methylene-2H-pyrans, substituted 3-hydroxy-9H-fluoren-9-ones, and amine-incorporated arenes. These cascade processes are initiated by conjugate addition of secondary amine followed by hydrolysis of the enamine/vinylogous amide intermediates. The product distribution is highly sensitive to the steric and electronic effects of the substituents on both the alkyne moieties, the tether structure connecting them, and the nature of the amine. Alkynyl amide participates in the Alder-ene reaction favorably to generate more reactive allene amide that reacts with amine to generate amine-incorporated arene products. These metal-free cascade reactions are a useful synthetic method that can be exploited for the construction of various hetero- and carbocyclic systems.

Serotonin-functionalized starch-based hemostatic sponges enhance platelet activation in the management of non-compressible hemorrhage

Massive hemorrhage poses a serious threat to human health and even life. Access to rapid and potent hemostatic materials is crucial for lowering mortality rates. Starch-based materials exhibit good biocompatibility and are extensively utilized in hemostatic. However, existing starch-based hemostatic products suffer from limited hemostatic efficacy. Serotonin, an indoleamine naturally occurring in the human body, is recognized for its potent platelet-activating properties. Therefore, this study focused on enhancing the procoagulant activity of starch by incorporating serotonin into the starch backbone via esterification and amidation reactions, yielding a novel serotonin-loaded starch-based hemostatic sponge (SLS sponge). The SLS sponges featured exceptional porosity (≥80 %) and water absorption capacity (≥2000 %), which rapidly initiated the coagulation cascade reaction, promoted the adhesion and aggregation of red blood cells and platelets, and intensified platelet activation. This multifaceted approach synergistically enhanced hemostasis via both active and passive coagulation mechanisms. Notably, the SLS sponges adhered firmly to the wound surfaces without pressure. Compared with gelatin sponges, the SLS sponges significantly reduced blood loss by approximately 40.5 % and shortened the time to achieve hemostasis by approximately 28.9 %. These findings indicate that the newly developed SLS sponges are a promising active hemostatic material, particularly effective in managing non-compressible hemorrhages.

Copper‐Catalyzed Carboamination of Unactivated Alkenes to Synthesize β‐Lactams with Trichloroacetonitrile

ABSTRACTβ‐Lactams, as nitrogen‐containing heterocycles with distinctive biological activities, have made significant contributions to the treatment of infectious diseases. This study which used inexpensive copper salts as catalysts, trichloroacetonitrile as a radical precursor, and potassium carbonate as base offers a concise route for the synthesis of β‐lactam compounds substituted with potentially pharmacologically active dichloroacetyl moieties. Preliminary mechanistic studies indicate that unactivated alkenes undergo sequential intermolecular radical addition and intramolecular amidation reactions. The copper salts undergo catalytic cycles involving Cu(I)/Cu(II)/Cu(III) species.

Chemoselective Pd-Based Dyotropic Rearrangement: Fluorocyclization and Regioselective Wacker Reaction of Homoallylic Amides.

Fluorocyclization of alkenes tethered with a pronucleophile is an efficient transformation that converts easily accessible starting materials to fluorinated heterocycles in a single step. We report herein an unprecedented Pd(II)-catalyzed oxidative domino process that transforms homoallylic amides to 5,6-dihydro-4H-1,3-oxazines through a domino oxypalladation/PdII-oxidation/dyotropic rearrangement/reductive elimination sequence. Three chemical bonds are created under these operationally simple conditions. Taking advantage of the facile hydrolysis of the α-fluoro tertiary alkyl ether under acidic conditions, a one-pot conversion of homoallylic amides to homologated ketones is subsequently developed, which represents a rare example of regioselective Wacker oxidation reaction of 1,1-disubstituted alkenes.

A novel type of quantum-delivery system (salicylic acid conjugation based on ZnO quantum dots) alleviates the bacterial fruit blotch disease of melon plants by activating defense response

The use of nano-pesticide delivery systems to suppress crop disease has great potential in sustainable agriculture. Herein, a pH-responsive salicylic acid (SA) conjugation based on aminopropyl-functionalized ZnO quantum dots (SA-ZnO QDs) with a loading capacity of 13.4 wt% was prepared by an amidation reaction. Results indicated that SA-ZnO QDs could release SA rapidly in an acidic condition, which corresponded to the pH of the water-soaked lesions where the bacterial fruit blotch disease often spread. The antibacterial activity of the synthesized SA-ZnO QDs was about 1.6 times and 1.3 times higher than that of SA and aminopropyl-functionalized ZnO QDs, respectively. A pot experiment showed that foliar application of SA-ZnO QDs could reduce the incidence of bacterial fruit blotch disease (54.46%) by increasing the antioxidant defense systems (44.33–79.59%) and nutrient absorption (23.19–26.95%). More importantly, we observed that, after the application of SA-ZnO QDs, the systemic acquired resistance and flavone biosynthesis were activated in infected melon seedlings, which was revealed by metabolomics. This work demonstrates the important role of the quantum-delivery system in improving crop disease suppression for sustainable agriculture.

Metal‐Free Direct Synthesis of N‐Sulfonyl Amidines from Thioamides and Electron Deficient N‐Sulfonylamides

AbstractA metal‐free, efficient synthesis of N‐sulfonyl amidines has been demonstrated from easily accessible thioamides and electron‐deficient sulfonyl amides. The amidation reaction is facile at room temperature with low sulfonyl amide loading. The reaction with thioamides is illustrated with various thioamides and electron‐deficient sulfonyl amides with broad substrate scope. The utility of N‐sulfonyl amidine synthesis is validated with late‐stage drug functionalization.

Lignin‐based nitrogen and phosphorus‐containing polylactic acid with flame‐retardant performances

AbstractPolylactic acid (PLA) is a new type of biodegradable material that has been applied in many fields such as extrusion, injection molding, film drawing, and spinning. In contrary, it does not have flame retardancy. In this paper, N‐PCDL was synthesized by amidation reaction between COOH of PCDL and NH2 of tetraethylenepentamine (TEPA), followed by an Atherton‐Todd reaction of unreacted NH2 at the other end of TEPA with PH of DOPO to prepare a novel lignin‐based flame retardant containing nitrogen and phosphorus (NP‐PCDL). The Fourier transform infrared spectroscopy (FT‐IR) and nuclear magnetic hydrogen spectroscopy (1H NMR) analysis results showed that proton peaks of CONH, PN, and NH appeared in the NP‐PCDL spectrum, while the characteristic absorption peak of PH bond disappeared in DOPO, the X‐ray photoelectron spectroscopy (XPS) results showed that the degraded lignin consisted of elements C and O, while NP‐PCDL consisted of elements C, O, N and P. The above results indicated that NP‐PCDL was successfully prepared. NP‐PCDL accounted for 3% (mass percentage, the same below), 5% and 10% of PLA, then lignin based flame‐retardant PLA composites were prepared by internal mixing and injection molding. Thermogravimetric analysis (TGA) showed that the residual carbon of PLA/3% NP‐PCDL, PLA/5% NP‐PCDL and PLA/10% NP‐PCDL at 800°C were higher than that of pure PLA, with the increase of 56.56%, 97.54%, and 301.64%, respectively; The analysis of SEM, XPS, and Raman showed that PLA/NP‐PCDL formed dense, regular and highly graphitized residual carbon with phosphorus nitrogen structure during the combustion process. At the same time, NH3, H2O and PO˙ free radicals were released, which could dilute combustible gases, destroy free radical chain reaction, isolate combustible gases and heat, so as to play a flame‐retardant role.

Synthesis of chiral hollow polymer microspheres and their applications in the spectroscopic chiral discrimination of tryptophan isomers

Hollow polymer microspheres (HPMs) were synthesized, which were then hydrolyzed in aqueous ammonia to produce carboxyl (–COOH) groups on their surface. L-phenylalanine (L-Phe) was grafted to the hydrolyzed HPMs (H-HPMs) through amidation reactions, endowing the H-HPMs with chirality. The resultant chiral HPMs (C-HPMs) were used for the chiral discrimination of tryptophan (Trp) isomers. Due to the same rotatorydirection of L-Phe and L-Trp, the C-HPMs showed greatly higher selectivity toward L-Trp than its isomer. After being adsorbed by the C-HPMs, the absorbance of the residual L-Trp is significantly lower than that of the residual D-Trp, and thus spectroscopic chiral discrimination of the Trp isomers was successfully achieved. The Trp isomers were also discriminated by the chiral solid polymer microspheres (C-SPMs), while the difference in the absorbance of the residual L-Trp and D-Trp is remarkably smaller than that obtained by the C-HPMs. The outstanding discrimination capability of the C-HPMs might be ascribed to their high surface permeability resulted from their unique hollow structure.

A MnO2 nanosheets doping double crosslinked hydrogel for cartilage defect repair through alleviating inflammation and guiding chondrogenic differentiation

The inflammatory microenvironment and inferior chondrogenesis are major symptoms after cartilage defect. Although various modifications strategies associated with hydrogels exhibit remarkable capacity of pro-cartilage regeneration, the adverse effect by prolonging inflammation is still formidable to hamper potential biomedical applications of different hydrogel implants. Herein, inspired by the repair microenvironment of articular cartilage defects, an injectable, immunomodulatory, and chondrogenic L-MNS-CMDA hydrogel is prepared through grafting vinyl and catechol groups to chitosan macromolecules using amide reaction, then further loading MnO2 nanosheets (MNS). The double crosslinking of photopolymerization and catechol oxidative polymerization endows L-MNS-CMDA hydrogel with preferable mechanical property, affording a suitable mechanical support for cartilage defect repair. Additionally, the robust tissue adhesion capability stemming from catechol groups guarantees the long-term retention of the hydrogel in the defect site. Meanwhile, L-MNS-CMDA hydrogel decomposes exogenous and intracellular H2O2 into O2 and H2O, to effectively alleviate cellular oxidative stress caused by long-term hypoxia. Under the synergies of catechol groups and MNS, L-MNS-CMDA hydrogel not only inhibits macrophages polarizing into M1 phenotype, but encourages them turn into M2 phenotype, thereby, reconstructing an immunization friendly microenvironment to ultimately enhance cartilage regeneration. Predictably, the hydrogel markedly induces rat bone marrow mesenchymal stem cells differentiating into chondrocytes by expressing abundant glycosaminoglycan and type II collagen. A cartilage defect model of rat knee joint indicates that L-MNS-CMDA hydrogel visually regulate the early inflammatory response of post-implantation, and facilitate cartilage regeneration and recovery of joint function after 12 weeks of post-implantation. All in all, this multifunctional L-MNS-CMDA hydrogel exhibits superior immunomodulatory and chondrogenic properties, holding immense clinical potential in the treatment of cartilage defects.

Synthesis and biological activity of substituted 5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamides

A four-component solvent-free reaction of acetoacetic acid amide with dimedone, aromatic aldehydes and ammonium acetate leads to new substituted 5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamides. The structures of the products were proved using IR, 1H and 13C NMR spectroscopy, mass spectrometry and X-ray diffraction analysis. The synthesized compounds were tested for antimicrobial and antinociceptive activities.

Citric acid/sucrose-modified pMDI for constructing high-performance straw particleboard based on multiple cross-linked networks

Polymeric diphenylmethane diisocyanate (pMDI) is an indispensable material used to produce straw particleboard. However, prolonged exposure to high concentrations of pMDI significantly increases the health risks to relevant professionals. Herein, we report a strategy for reducing safety hazards by partially replacing the pMDI with a bio-based adhesive. An adhesive with multiple cross-linked networks were synthesized using citric acid (CA), sucrose (SU), and pMDI first, and then applied to the preparation of straw particleboard. The amide and esterification reactions between the adhesives and rice straw particles form covalent bonds, enhancing boards adhesion and water resistance. Furthermore, acidic conditions provided by citric acid facilitate to convert SU into 5-hydroxymethyl furfural (5-HMF), which plays a positive role in straw adhesion. Adhesives made with 2.4 % pMDI, 8 %, and 4.8 % SU were used to bond particleboard, achieving internal bond strength, bending strength and elastic modulus of 0.57 MPa, 25.87 MPa, and 3.77 GPa, respectively, whose mechanical properties are comparable to the particleboard prepared with 4 % pMDI. The board showed superb mechanical performances, mould resistance, as well as water resistance. The CA/SU-modified pMDI adhesive system shows significant potential and promising application value in straw particleboard.

Enhancing De Novo Protein Sequencing through the C-Terminal Labeling Strategy: Resolving Isobaric Ambiguities by Electron-Transfer/Higher Energy Collision Dissociation (EThcD).

De novo protein sequencing via a bottom-up approach requires various proteases to produce overlapping peptides. However, peptides generated by proteases other than trypsin, LysC, and ArgC often yield C-terminal fragments with suboptimal ionization in positive mode mass spectrometry (MS). This study introduces a novel peptide labeling strategy that involves modifying peptides at the C-terminal and at the carboxyl groups of Aspartic and Glutamic acid with arginine methyl ester (R-met) to improve peptide fragmentation and resolve isobaric ambiguities encountered during sequencing. An amidation reaction is used with coupling reagents to conjugate R-met to the peptide's C-terminal end, introducing a functional group that enhances the detectability of C-terminal peptide fragment ions by mass spectrometry. Subsequently, selecting a charge state of +2 or higher can facilitate optimal fragmentation of the derivatized peptides using electron-transfer/higher energy collision dissociation (EThcD), thereby generating essential w-ions to resolve common isobaric ambiguities. Demonstrating this strategy across diverse protein types, including albumin and antibodies and using different proteases for digestion, highlights the unique characteristics of combining the proposed amidation reaction with the specific proteases tested.