Formamide Research Articles

Advances in the catalytic promiscuity of nitrilases

As important biocatalysts, nitrilases can efficiently convert nitrile groups into acids and ammonia in a mild and eco-friendly manner, being widely used in the synthesis of important pharmaceutical intermediates. Early studies reported that nitrilases only had the hydrolysis activity of catalyzing the formation of corresponding carboxylic acid products from nitriles, showing catalytic specificity. However, recent studies have shown that some nitrilases exhibit the hydration activity for catalyzing the formation of amides from nitriles, showing catalytic promiscuity. The catalytic promiscuity of nitrilases has dual effects. On the one hand, the presence of amide by-products increases the difficulties and costs of subsequent separation and purification of carboxylic acid products. On the other hand, however, if the catalytic reaction pathways of nitrilases can be precisely regulated to reshape enzyme functions, the reactions catalyzed by nitrilases can be broadened to provide new ideas for the biosynthesis of high-value amides, which is crucial for the development of artificial enzymes and biocatalysis. This review summarized the research progress in the catalytic promiscuity of nitrilases and discussed the key regulatory factors that may affect the catalytic promiscuity of nitrilases from the evolutionary origin, catalytic domains, and catalytic mechanisms, hoping to provide reference and inspiration for the application of nitrilases in biocatalysis.

Alkyl 4-Alkoxyvalerates: Characterization and Application in Pd-Catalyzed Aminocarbonylation of Iodo(hetero)arene Compounds.

The palladium-catalyzed aminocarbonylation is one of the most effective methods for the synthesis of carboxamides having great importance. Replacing fossil-based organic solvents in this routinely used catalytic protocol with biomass-derived media is crucial for developing environmentally safe alternatives and towards sustainability considerations. In this study, the open-chain derivatives of bio-originated substance γ-valerolactone i. e. alkyl 4-alkoxyvalerates (alkyl: methyl, ethyl, and propyl) were characterized and tested as potential polar aprotic alternatives of fossil-based common N,N-dimethylformamide (DMF) in aminocarbonylation protocols. First, the temperature-dependent physicochemical properties of alkyl 4-alkoxyvalerates were determined. Based on their characteristics, methyl 4-methoxyvalerate (Me-4MeOV) was selected and introduced in the Pd-catalyzed aminocarbonylation of iodobenzene and morpholine as a model reaction, and an optimization study was carried out. Using the optimized conditions, several substituted iodobenzenes, as well as heteroaryl iodides, were successfully applied resulting in the target carboxamides selectively in short reaction time. Furthermore, the aminocarbonylation of iodobenzene in the presence of various amines was also accomplished extending the scope of the carboxamides produced in this alternative medium. Considering our observations, such as high conversions (up to 95 %) in short reaction time and selective amide formation, it has been justified that Me-4MeOV could be an appropriate alternative medium in aminocarbonylation protocols.

Direct conversion of esters to aldehydes and ketones via piperazine amide under mild conditions

AbstractAldehydes and ketones are basic, versatile intermediates used in organic synthesis. Various substituted aldehydes and ketones were directly prepared from carboxylic esters under mild conditions with excellent yields. The in situ generated aminolysis intermediate, piperazine‐1,4‐diylbis(phenylmethanone) amide, is readily reacted with commercial DIBALH and n‐BuLi to obtain carbonyls in a one‐pot reaction. The key amide intermediate was obtained in quantitative yield among the screened secondary amines. Hence, the formation of piperazine amide from the ester group, eliminated the utility of cryogenic temperatures and reduction proceeded under mild conditions. In addition, gram‐scale preparation of aldehyde and ketone was reported in good yields.

Aqueous Synthesis of Membrane Lipids via Amide Formation between Amphiphilic Amines and Thioacids

Protocell membranes were likely formed through primitive metabolic reactions that synthesized more complex membrane lipid species from simpler precursors. Thioacids have been shown to be prebiotically plausible and chemoselective N‐acylating reagents. They have been successfully employed for the acylation of peptides and RNA. However, the ability of thioacids to acylate lipid species has not yet been explored. Here, we demonstrate N‐acylation of natural amine‐containing amphiphiles using fatty thioacids. This reaction occurs spontaneously in aqueous conditions, is chemoselective, and traceless. The synthesis of several natural sphingolipids via direct N‐acylation is possible and their subsequent de novo formation into vesicular membranes is shown. Aqueous thioacid coupling provides a route for generating membrane‐forming lipids in the context of protocells and for the in situ synthesis of relevant sphingolipid species.

Impact of soaking duration with phosphoric acid on the characteristics of halal gelatin obtained from New Zealand white rabbit bones (Oryctolagus cuniculus)

The demands of Indonesia's numerous industrial sectors for gelatin still rely on imports. In general, gelatin produced using pork can cause serious problems for Hindus and Muslims. The product extracted from New Zealand White rabbit bones in this research has the potential to become halal gelatin. This research aimed to analyze the characteristic amide group absorption of gelatin in the Fourier Transform Infra-Red (FTIR) spectrum of the isolated gelatin from New Zealand White rabbit bones and to determine the effect of changing soaking time on the yield and gelatin characteristics. In the pre-treatment process, the sample was soaked using a 9% phosphoric acid solution for 48, 96, and 144 hours. The gelatin is then extracted at gradual temperatures for 12 hours. The characterization involved analyzing functional groups, water content, ash content, pH, and protein content. The typical absorption of gelatin functional groups in the form of amides A, I, II, and III was detected from FTIR spectrophotometric analysis. This study indicated that the soaking time significantly affected the yield, pH, ash content, and protein content of the gelatin produced, but did not significantly influencethe water content. The yield of gelatin from New Zealand White rabbit bones ranges from 4.08-6.56%. The water content of the gelatin is between 6.96-7.05%, and the pH value is 3.61-3.98. Both parameters meet the gelatin quality standards. However, the ash content of gelatin from New Zealand White rabbit bones, which ranges from 6.86-9.29%, does not meet the gelatin quality standards according to SNI 06-3735-1995 and GMIA 2012. The protein content of the rabbit bone gelatin, which is not regulated by the quality standards, ranges from 75.46-83.37%. The longer the soaking time, the higher the yield and protein content of the gelatin produced, and the lower the ash content. Keywords: Gelatin, New Zealand White Rabbit Bones, Soaking Time, Phosphoric Acid

Synthesis and photochemical stability of polymeric derivatives formed by the reaction of acrylamide and succinic anhydride copolymer with dyes

A new derivative of PAM, acrylamide was copolymerized with succinic anhydride, and the reaction product reacted with three dyes, anthocyanin, bromophenol, and thymol. The prepared polymers were characterized by X-ray diffraction, FT-IR and UV-visible spectroscopy, proton nuclear magnetic resonance spectrometry, and thermal analysis. FT-IR spectroscopy showed the disappearance of two bands near 3450 and 3380 cm-1 for the stretching vibrations of the primary amine which indicates for the formation of amides. The UV-photolysis of aqueous solutions of different concentrations of the polymers was studied. Polyacrylamide-g-succinic anhydride showed an increase in polymerization under light. An increase of ~ 50% was observed for a 200 mg/L solution after 10 h of irradiation. The polyacrylamide-g-succinic anhydride-anthocyanin polymer also showed an increase in polymerization with continuous irradiation. The percentage increase was ~ 26% for a 1000 mg/L solution of the polymer after 10 h under UV-light. The same behavior was observed for anthocyanin, and the highest percentage increase was ~23% for 15000 mg/L of dye. On the other hand, the polyacrylamide-g-succinic anhydride-bromophenol, polyacrylamide-g-succinic anhydride-thymol polymers underwent photodegradation upon UV-illumination. This work has shown that the photodegradation of PAMs can be prevented by copolymerization with suitable dyes.

A Copper-Catalyzed Synthesis of Pyridoquinazolinones via C(sp2)-H Functionalization and Annulation of Benzoic Acids with 2-Aminopyridines.

A facile synthesis of pyridoquinazolinones has been accomplished via C(sp2)-H functionalization and annulation of benzoic acids with 2-aminopyridines using Cu(OAc)2 as catalyst in DMSO. The reaction involves the formation of amides which on ortho amination followed by trans-amidation afford a wide array of products under ligand/base-free conditions.

Recent Advances in Direct Amidation via Organocatalysis

The formation of amide bonds is essential for a wide range of applications in biological and organic systems, including proteins, pesticides, polymers, and pharmaceuticals. Moreover, it plays a critical role in the synthesis of numerous bioactive compounds with anticancer, antibacterial, and antifungal properties. Due to the limitations of conventional coupling reagents for amide synthesis, there is a growing demand for environmentally sustainable methodologies, particularly the direct formation of amides from carboxylic acids and amines. Over recent years, we have developed several catalytic reactions based on organocatalysis, advancing sustainable synthetic methods in both organic and medicinal chemistry. This review comprehensively discusses catalytic amidation reactions published up to January 2024, focusing on both organocatalysis and boron‐based catalysis for the direct condensation of carboxylic acids and amines. Additionally, it highlights our recent contributions to sustainable amidation protocols, which are progressively replacing traditional catalytic approaches in modern synthetic chemistry.

Three Is a Magic Number: Tailored Clickable Chelators Used to Determine Optimal RGD-Peptide Multiplicity in αvβ6-Integrin Targeted 177Lu-Labeled Cancer Theranostics.

The cellular adhesion receptor αvβ6-integrin is highly expressed in many cancers, e.g., pancreatic, lung, head-and-neck, cervical, bladder, and esophageal carcinoma. Multimerization of αvβ6-integrin-specific RGD peptides increases the target affinity and retention but affects biodistribution and pharmacokinetics. Amide formation of the terminal carboxylic acid moieties of the square-symmetrical bifunctional chelator DOTPI with 3-azidopropylamine yields derivatives with 4, 3, and 2 terminal azides and zero, 1, and 2 remaining carboxylic acids, respectively, whereby formation of the 2-cis-isomer is preferred according to NMR investigation of the Eu(III)-complexes. Cu(II)-catalyzed alkyne-azide cycloaddition (CuAAC) of the alkyne-functionalized αvβ6-integrin binding peptide cyclo[YRGDLAYp(NMe)K(pent-4-ynoic amide)] (Tyr2) yields the respective di-, tri-, and tetrameric conjugates for Lu-177-labeling. In mice bearing αvβ6-integrin-expressing xenografts of H2009 (human lung adenocarcinoma) cells, the Lu-177-labeled trimer's tumor-to-blood ratio of 112 exceeds that of the tetramer (10.4) and the dimer (54). Co-infusion of gelofusine (succinylated gelatin) reduces the renal uptake of the trimer by 89%, resulting in a 10-fold better tumor-to-kidney ratio, while no improvement of that ratio is observed with arginine/lysine, para-aminohippuric acid (PAH), and hydroxyethyl starch (HES) coinfusions. Since the Lu-177-labeled Tyr2-trimer outperforms the dimer and the tetramer, such trimers are considered the best lead structures for the ongoing development of αvβ6-integrin targeted anticancer theranostics.

Achieving Uniform Deposition of Zn with Amide Additives for Metal Anodes Stabilization.

The practical applications of aqueous zinc-ion batteries (AZIBs) are hindered by detrimental effects such as dendrites formation at the Zn metal anode interface and parasitic side reactions induced by H2O. Hence, we propose adding amide additives to the Zn sulfate electrolyte (ZSO) to regulate the composition and properties of the electrolytes, thereby stabilizing the Zn anode interface. Different amide molecules containing formamide (FA), acetamide (AA), or trifluoroacetamide (TFA) are discussed. The polar C═O group shared by amide molecules can interact with Zn2+, forming their solvation shells. The molecules can also facilitate the transport of Zn2+ and increase the conductivity of the electrolytes. Additionally, amide molecules can interact with H2O through hydrogen bonds to limit the erosion of active H2O on the Zn anode. The unique -H, -CH3, and -CF3 groups of the molecules result in different polarities and varying numbers of interaction sites with H2O and Zn2+, leading to some differences in the protective effects of the Zn anode. The stability and lifespan of Zn||Zn batteries assembled with amide electrolytes have significantly improved, especially those with TFA. Moreover, the Zn||NH4V4O10 full cells demonstrate remarkable capacity retention, and the overall performance of the batteries has also been enhanced.

Diastereoselective Synthesis of N-Heterocycle Substituted Cyclobutanes via Michael Addition onto Cyclobutenes.

Herein, we present a method for the diastereoselective synthesis of N-heterocycle-substituted cyclobutanes from commercially available bromocyclobutanes. This method enables the efficient formation of various heterocyclic aminocyclobutane esters and amides using simple reagents. Notably, N-nucleophiles such as imidazoles, azoles, and nucleobase derivatives were successfully incorporated, enhancing the chemical diversity of small ring building blocks for medicinal chemistry applications.

Strong and Environmental-Friendly Adhesive Glass Based on Chitin Nanoparticles

Chitin is a biopolymer that can be used as a candidate material for a strong and environmentally friendly glass adhesive. In the form of nanoparticles with needle-like morphology and attractive functional groups in the form of amide and hydroxyl, Chitin Nanoparticle (ChNP) shows a strong Van der Walls adhesive force against glass. In the study, ChNP was successfully isolated from crab shells from the sea of Lombok. The isolated ChNP has a characteristic size around 351 nm with -chitin conformation and needle-shaped morphology. Based on the results of shear strength testing, 0.42 mg of ChNP can withstand a load of 21 kg and the addition of Gum Arabic (GA) and Hen Egg White lysozyme (HEWL) in a ratio of 1: 1 to ChNP succeeded in increasing adhesion by 72%.

Copper‐Catalyzed Tandem Cyclization of 2‐(Alkynylaryl)Acetonitriles and Amines: Access to 3‐Hydroxyisoindolinones

AbstractHerein, we describe an approach to the synthesis of 3‐hydroxyisoindolinone derivatives via copper‐catalyzed tandem cyclization of 2‐(alkynylaryl)acetonitriles and amines. This reaction is compatible with 2‐(alkynylaryl)acetonitriles and primary alkyl amines containing various functional groups, providing the corresponding 3‐hydroxyindolinone derivatives with yields ranging from 44%–82%. Preliminary mechanistic studies suggest that the reaction involves oxidation of the benzylic carbon, amide formation, hydration of the alkyne and intramolecular cyclization to produce various 3‐hydroxyisoindolinones. The practicality of the strategy was further demonstrated by gram‐scale synthesis, late‐stage functionalizations, and the post modification of natural products.

Formation and Stability of Benzylic Amide [2]- and [3]Rotaxanes: An Intercomponent Interactions Study.

One of the most recent focuses in supramolecular chemistry is developing molecules designed to exhibit programmable properties at the molecular level. Rotaxanes, which function as molecular machines with movements controlled by external stimuli, are prime candidates for this purpose. However, the controlled synthesis of rotaxanes, especially amide-benzylic rotaxanes with more than two components, remains an area ripe for exploration. In this study, we aim to elucidate the formation of amide-benzylic [3]rotaxanes using a thread that includes a conventional succinamide station and an innovative triazole-carbonyl station. Including the triazole-carbonyl station introduces new perspectives into the chemistry of rotaxanes, influencing their conformation and dynamics. The synthesis of two-station rotaxanes with varying stoppers demonstrated that the macrocycle consistently occupies the succinamide station, providing greater stability as evidenced by NMR and SC-XRD analyses. The presence of a triazole-carbonyl station facilitated the formation of a second macrocycle exclusively when a secondary amide was employed as the stopper group, presumably due to decreased steric hindrance. Moreover, the second macrocycle directly forms at the triazole-carbonyl station. This investigation reveals that slight modifications in the thread structure can dramatically impact the formation, stability, and interactions between components of rotaxanes.

Reactions of an Anionic Gallylene with Azobenzene or Azide Compounds Through C(sp2)-H and C(sp3)-H Activation.

The activation of inert C-H bonds remains a challenge in current chemistry. Here, we report the excellent reactivity of the anionic gallylene species [LGa:][Na(THF)3] (L = [(2,6-iPr2C6H3)NC(CH3)]22-, 1) that allows the selective activation one ortho sp2 C-H bond of several azobenzene and azide derivatives at ambient temperature, with the transfer of the hydrogen atom to one of the nitrogen atoms. The process leads to the formation of the aryl amido products [LGa-κ2N,C-PhNN(H)(p-R-C6H3)][Na(solvent)3] (2, R = H solvent = DME (1,2-Dimethoxyethane); 3, R = -OMe, solvent = DME; 4, R = -NMe2 solvent = THF), [LGa-κ2N,C-(m-CH3-C6H4)NN(H)(m-CH3-C6H3)][Na(15-C-5)2] (5) with new Ga-C and Ga-N bonds. Moreover, 1 is also effective for the C-H activation of two azides RN3 (R = 2,4,6-Me3C6H2 or 2,6-iPr2C6H3), resulting in the formation of gallium amides [LGa(NH-2-(CH2)-4,6-Me2C6H2)][Na(15-C-5)2] (6) and [LGa(NH-2,6-iPr2C6H3)2][Na(THF)5] (7) through intra- or intermolecular sp3 C-H amination. Significantly, these reactions occur for the highly challenging activation of inert C(sp2)-H and C(sp3)-H bonds, thus demonstrating the excellent reactivity of the Ga(I) species 1. The products 2-7 were characterized by X-ray crystallography, 1H and 13C NMR, UV-vis spectroscopy, and density functional theory (DFT) calculations.

Visible-Light-Driven Method for the Selective Synthesis of Amides and N-Acylureas from Carboxylic Acids and Thioureas.

In this work, we developed a visible-light-driven method for the selective synthesis of amides and N-acylureas from carboxylic acids and thioureas. This protocol was featured as avoidance of additional oxidants and transition metal catalysts, simple manipulations, low cost, broad substrate scope, and good functional group tolerance. As only oxygen serves as the oxidation reagent, this method provides a promising synthesis candidate for the formation of N-aryl amides and N-acylureas, including late-stage functionalization of complex pharmaceutical molecules and biologically active molecules.

An Optical Au3+ Sensor Based on layer-by-layer PEI/PAA-Rho thin Films on ITO.

This study presents the development of a sensitive and selective gold ion (Au3+) sensor utilizing layer-by-layer (LbL) assembled thin films composed of polyethylenimine (PEI) and poly (acrylic acid) (PAA) conjugated with rhodamine (Rho). The first study revealed that the polymeric sensors (PAA-Rho) demonstrated significant selectivity and sensitivity in their colorimetric and fluorescence responses to Au3+ compared to other metal ions. In their spirolactam form, the polymeric sensors were non-fluorescent but could selectively transform into the fluorescent ring-opened amide form upon interaction with Au3+ ions, resulting in fluorescence enhancement and observable color changes. Common co-existing metal ions showed negligible interference in the detection of Au3+. The LbL sensor exhibited a linear increase in absorbance with the addition of bilayers, confirming successful film deposition. Surface morphology analysis using SEM, along with structural confirmation via ATR-FTIR and XRD, further validated the sensor's capability to detect cation. Results demonstrated that the LbL sensor exhibited selectivity for Au3+ ions within the range 1 × 10-6 to 1 × 10-3 M. This approach offers an easily understandable and intrinsically sensitive means for detecting Au3+ ions in both environmental and biological applications.

Earth-abundant catalyst for modification of wheat straw to enhance ammonia mitigation from fertilized alkaline soil

In this study, inexpensive earth-abundant catalyst of Co/TiO2 is coupled with a low-temperature modification approach to enhance NH3 adsorption capacity on wheat straw (WS). The highest NH3 uptake achieved is 111.9 mg/g, with 80.8 % retention even after 3 h of desorption. Mechanistic investigation indicates that the enhanced adsorption capacity stems from Co/TiO2, which facilitates generation of reactive oxygen species, leading improved ultra-micropore structure that enhances the interaction between NH3 and oxygen-containing functional groups through a trapping effect. The robust stability of adsorbed NH3 is attributed to the formation of amides or amines. Incorporation of only 1 wt% WS-Co to urea-fertilized alkaline soil reduced NH3 volatilization by 83.1 %. The significant effect is primarily attributed to the excellent adsorption capacity of WS-Co, rather than alterations in the relative abundance of the microbial community. These findings present a novel approach for development of effective fertiliser additive to mitigate NH3 volatilization from alkaline soil.

Pyrrolidine derivatives as α-amylase and α-glucosidase inhibitors: Design, synthesis, structure-activity relationship (SAR), docking studies and HSA binding

In our pursuit of developing effective inhibitors for the enzymes α-amylase and α-glucosidase, which play a crucial role in carbohydrate metabolism related to type-2 diabetes, we synthesized compounds featuring a pyrrolidine ring. The synthesis involved coupling N-Boc-proline with various aromatic amines, resulting in the formation of distinct N-Boc proline amides. To investigate the influence of the Boc group on enzyme inhibition, the Boc group was subsequently removed. In vitro, testing against α-amylase and α-glucosidase, with metformin and acarbose as reference standards, revealed that the 4-methoxy analogue 3g showed noteworthy inhibitory activity, with IC50 values of 26.24 and 18.04 μg/mL, respectively. Compounds 3a with an IC50 value of 36.32 μg/mL and 3f with an IC50 value of 27.51 μg/mL displayed significant inhibitory activity against α-amylase and α-glucosidase, respectively. The results of molecular docking studies of the most potent pyrrolidine derivatives 3a and 3g with α-amylase and 3f and 3g with α-glucosidase showed good agreement with experimental data. Moreover, compound 3g showed strong binding interactions with HSA having binding constant values of 7.08 × 105 M−1 and 4.77 × 105 M−1 using UV–visible and fluorescence spectrophotometry, respectively.

Organocatalytic asymmetric cyclization of aminochalcones and azlactones: Synthesis of 3,4-dihydroquinolinones

A novel and efficient reaction of aminochalcones and azlactones has been developed under the catalysis of bifunctional organocatalysts. The corresponding enantioenriched 3,4-dihydroquinolinones were efficiently assembled in moderate to excellent yield with excellent enantioselectivitiy. In this work, the synthons with tosylaminochalcones in an asymmetric approach were not confined to traditional unsaturated compounds via the aza-Michael/Michael addition pathway. Azlactones with highly nucleophilicity under a chiral base could promote the Michael addition to substituted 2-aminochalcones, followed by amide formation to deliver dihydroquinolinones in high enantiocontrol.