Amide Bond Formation Reaction Research Articles

Deoxyfluorinated amidation and esterification of carboxylic acid by pyridinesulfonyl fluoride.

Amide bond synthesis is one of the most used reactions in medicinal chemistry. We report an amide bond formation reaction through deoxyfluorinated carboxylic acids under mild conditions using 2-pyridinesulfonyl fluoride. The reaction procedure has been used in a one-pot synthesis of amides and esters via in situ generation of acyl fluoride. This one-pot synthetic method provides easy access to amides and esters. Using this method, we have sequentially synthesized a tetrapeptide and calceolarioside-B glycoside derivative with good yields.

Molecular basis for carrier protein-dependent amide bond formation in the biosynthesis of lincosamide antibiotics

In the biosynthesis of the lincosamide antibiotic celesticetin, the condensation enzyme CcbD generates the lincosamide pharmacophore by forming an amide bond between the carrier protein (CP)-tethered proline and ergothioneine-conjugated thiooctose. Although the function of CcbD has been investigated, its substrate specificity, structures and catalytic mechanisms remain unclear. Here we show the structure–function analyses of CcbD. Our biochemical analysis revealed that CcbD exhibits promiscuous substrate specificity towards CP-tethered acyl substrates to generate unnatural lincosamides. Furthermore, structural analyses indicated that CcbD possesses an unusual overall fold, while the N-terminal region shows weak similarity to cysteine proteases. Thus, CcbD, like cysteine proteases, utilizes the Cys-His-Glu catalytic triad to form amide bonds in a CP-dependent manner, which is significantly different from other known amide bond-forming enzymes. Furthermore, the structures of the CcbD/thiooctose complex and the cross-linked CcbD/CcbZ-CP complex, as well as structure-based mutagenesis, revealed the intimate structural details of the CP-dependent amide bond formation reaction.

Mechanistic Insight into the TBHP-Mediated Decarboxylative Condensation of α-Ketoacids: Reaction Development and Application to Oligopeptide Synthesis.

With the aim of achieving the convergent elongation of peptide chains, an amide bond formation reaction that enables a peptide fragment coupling has long been pursued. The decarboxylative amidation recently reported by our group is a potential solution to this problem. In this article, a mechanistic analysis of the t-butyl hydroperoxide (TBHP) mediated-decarboxylative amidation of α-ketoacids that results in a significant advance in convergent peptide synthesis is described. Despite the observation of epimerization with low bulk substrates in preliminary studies, a systematic examination and understanding of the reaction mechanism enabled the development of a modified epimerization-free reaction whereby peptide fragment couplings using peptide α-ketoacids were successfully achieved.

Amphiphilic Graphene Quantum Dots: Metal‐Free Photocatalyst for Hydrogen Evolution via Encapsulation of Organic Thermally Activated Delayed Fluorescence Photosensitizers

AbstractDesigning a metal‐free photocatalyst for the photocatalytic hydrogen evolution reaction (HER) is a very important research goal. Although graphene quantum dots (GQDs) have already been demonstrated as HER photocatalysts, it is necessary to address the poor visible light absorption of GQDs to achieve higher efficiency in the hydrogen evolution reaction (HER) rate. We have synthesized amphiphilic GQD by hexylamine (HA) functionalization through an amide bond formation reaction. We confirmed that HA functionalized GQD (GQD‐HA) is amphiphilic and can act as the photocatalyst and templating surfactant at the same time. GQD‐HA can form much more stable composite nanoparticles with thermally activated delayed fluorescence (TADF) photosensitizers than bare GQD. Importantly, the HER performance and the stability of the composite systems are remarkably enhanced after HA functionalization. Through electrochemical analyses, it was verified that composite photosensitizer nanoparticles with GQD‐HA have efficient charge separation and fast charge transfer properties.

Exploration of NMI-MsCl mediated amide bond formation for the synthesis of novel 3,5-substituted-1,2,4-oxadiazole derivatives: synthesis, evaluation of anti-inflammatory activity and molecular docking studies.

We herein report the facile synthesis of a series of 3,5-substituted-1,2,4-oxadiazole derivatives 9a-e and 10a-e in good to excellent yields by employing NMI-MsCl mediated amide bond formation reaction. The anti-inflammatory potential of the newly synthesized compounds were evaluated by anti-denaturation assay using diclofenac sodium as the reference drug. The compounds 9a and 9d demonstrated promising activity profile when compared to the reference standard. The SAR and molecular docking studies were also carried out for obtaining more details about the profound activity profile of the synthesized molecules. The synthesized compounds were docked against two target proteins TGF-β and IL-1 by AutoDock vina and Auto Dock 4.2.

CuO-Fe(III)-Zeolite-Y as efficient catalyst for oxidative alcohol-amine coupling reactions

CuO nanocatalyst with layered structure was supported over Fe-exchanged zeolite-Y (CuO-Fe(III)-Y) for selective synthesis of amides by oxidative coupling of aromatic primary alcohols and amines. The CuO-Fe(III)-Y catalyst was characterized by different physicochemical and spectroscopic techniques. The amide bond formation reaction was found to occur in absence of any external base and reagents. The temperature-programmed desorption (TPD) study predicted the development of strong basic sites in the CuO-Fe(III)-Y catalyst that boosted the dehydrogenative coupling process. The activity of the material in such coupling reaction was found to be comparable to those of other costly metal catalysts under different reaction conditions. The product yield of the reaction was found to be substrate-dependent giving moderate to maximum yield of 85%. The anomalies in the reaction appeared in case of 5-nitro-2‑chloro-benzylalcohol that undergoes a CN coupling product through CCl bond activation. The mechanism of the reaction was believed to proceed through FeIV=O species that helped in the activation of the benzylic CH bond.

Constructing Head-to-Tail Cyclic Peptide DNA-Encoded Libraries Using Two-Directional Synthesis Strategy.

Macrocyclic peptides are an important class of therapeutic agents for the biological targets that are difficult to modulate by small-molecule compounds. Meanwhile, DNA-encoded library technology (DELT) provides a powerful platform for hits discovery. The unity of both fields has proven highly productive in finding cyclic peptide hits against diverse pharmaceutical proteins. Many researchers have extended the chemical toolbox for constructing head-to-tail macrocyclic DNA-encoded libraries with various ring sizes. However, the linear peptides of different lengths necessitate tuning the distance between closing sites and DNA-linked sites to perform the macrocyclization process, presumably due to the constrained conformation of linear precursors. To tackle this issue and streamline the synthetic workflow, we report a two-directional synthesis strategy. This method starts from a trifunctional reagent and prepares DNA-linked macrocyclic peptides of ring size between 15 (5-mer) and 24 (8-mer) via amide bond formation reaction, a common method to create macrocyclic peptides.

Application of NMI-TfCl-mediated amide bond formation in the synthesis of biologically relevant oxadiazole derivatives employing less basic (hetero)aryl amines

We herein report a modified methodology for the synthesis of some oxadiazoles linked to amides under mild conditions. The developed protocol using NMI-TfCl has been found to be effective and tolerant for the amide bond formation reaction of a series of electronically deactivating and sterically challenging amines. The antioxidant potential of the newly synthesized compounds has been evaluated at the later stage.

Induction of Caspase-Mediated Apoptosis in HepG2 Liver Carcinoma Cells Using Mutagen-Antioxidant Conjugated Self-Assembled Novel Carbazole Nanoparticles and In Silico Modeling Studies.

In this study, novel self-assembled carbazole-thiooctanoic acid nanoparticles (CTNs) were synthesized from amino carbazole (a mutagen) and thiooctanoic acid (an antioxidant). The nanoparticles were characterized using hyperspectral techniques. Then, the antiproliferative potential of CTNs was determined in HepG2 liver carcinoma cells. This study employed a solvent–antisolvent interaction method to synthesize a spherical CTN of size less than 50 nm. Moreover, CT was subsequently capped to gold nanoparticles (AuNPs) in the additional comparative studies. The CT derivative was synthesized from carbazole and lipoic acid by the amide bond formation reaction using a coupling agent. Furthermore, it was characterized using infrared (IR), 1H nuclear magnetic resonance, dynamic light scattering (DLS), and transmission electron microscopy techniques. The CT-capped gold nanoparticles (CTAuNPs) were prepared from CT, chloroauric acid, and NaBH4. The CTAuNPs were characterized using ultraviolet–visible, high-resolution TEM, DLS, and Fourier transform IR techniques. The cytotoxicity and apoptosis-inducing ability of both nanoparticles were determined in HepG2 cells. The results demonstrate that CTNs exhibit antiproliferative activity in the cancerous HepG2 cells. Moreover, molecular docking and molecular dynamics studies were conducted to explore the therapeutic potential of CT against human EGFR suppressor protein to gain more insights into the binding mode of the CT, which may show a significant role in anticancer therapy.

π‐Conjugated Triazenes and Nitriles: Simple Photoinduced Synthesis of Anilides Using Mild and Metal‐Free Conditions

Metal-free, compatible and synchronized aryl–aryl cross-coupling and amide bond formation reactions were accomplished in a single step using π-conjugated triazenes as the versatile starting materials. This simple, mild, and direct photochemical approach afforded anilides in good to excellent yields (up to 99%). Interestingly, natural sunlight is also shown to provide effective delivery of amides at ambient temperature. The successful synthesis of an immunosuppressant and the commercial drug acetaminophen validates this methodology. More information can be found in the Full Paper by Enrique Barragan, Anurag Noonikara-Poyil, and Alejandro Bugarin.

Determination of mercury (II) in water samples by fluorescence using a dansyl chloride immobilized glass slide

This paper presents the preparation of stable fluorescence sensor slides for Hg2+ by covalent attachment of a fluorophore which can selectively chelate with the analyte. The fluorophore, dansyl chloride, was immobilized on the glass slide through an amide bond formation reaction with the amino group functionalized on the substrate using 3-aminopropyltriethoxysilane as the salinization agent. The dansyl chloride sensor slide was characterized by Fourier transform infrared (FTIR), ultraviolet-visible and fluorescence spectra. The size of sensor slide was precisely designed to fit in a common cuvette (10 × 10 mm). The ultraviolet-visible absorption and fluorescence response of the sensor to Hg2+ was directly investigated applying conventional spectrophotometers. The results showed that the sensor fluorescence may be linearly quenched by Hg2+ across the concentration range from 3.32 × 10−6 to 26.6 × 10−6 mol/L in 1:1 acetonitrile:water at pH 7.4. In addition, the sensor showed very high sensitivity to Hg2+ compared to other metal cations. Furthermore, the sensor slide was successfully applied for the determination of mercury ion in lake water with a recovery from 95.5 to 99.9%. This investigation has demonstrated that the proposed approach may be used to develop a stable, accurate, simple, and selective fluorescence sensor for Hg2+.

Visible Light-Induced Amide Bond Formation.

A metal-, base-, and additive-free amide bond formation reaction was developed under an organic photoredox catalyst. This green approach showed excellent functional selectivity without affecting other functional groups such as alcohols, phenols, ethers, esters, halogens, or heterocycles. This method featured a broad substrate scope, good compatibility with water and air, and high yields (≤95%). The potential utilities were demonstrated by the synthesis of important drug molecules such as paracetamol, melatonin, moclobemide, and acetazolamide.

A DFT study on reaction force approach of ammonia catalysed amide bond formation reaction between ammonia and formic acid

A reaction force approach of ammonia catalysed stepwise amide bond formation between ammonia and formic acid is investigated using B3LYP/6-31G (d,p) level of density functional theory in gas phase. The stepwise amide bond formation mechanism involves two transition states, namely, TS1, in initial stage and TS2, in final stage of reaction pathway. The potential energy surfaces obtained from IRC calculations on transition state geometries are subjected to reaction force and reaction work calculations. The estimated reaction works of structural and electronic activities in the progress of reaction reflect the unfavorable formation of diol intermediate and preferential formation of formamide. While 91% of the activation energy comes from structural changes in preparative region of TS1 path, the structural and electronic rearrangements respectively, share 57.6% and 42.4% of total activation energy of TS2 pathway. The atomic resolution of IRC pathways and natural charge analysis reveal the importance of hydrogen atom of catalyst in TS1 path and the oxygen of water molecule in TS2 path in the progress of reaction.

Preparation of Carbon-14 Labeled 2-(2-mercaptoacetamido)-3-phenylpropanoic Acid as Metallo-beta-lactamases Inhibitor (MBLI), for Coadministration with Beta-lactam Antibiotics.

Bacteria could become resistant to β-lactam antibiotics through production of β- lactamase enzymes like metallo-β-lactamase. 2-(2-mercaptoacetamido)-3-phenylpropanoic acid was reported as a model inhibitor for this enzyme. In order to elucidate the mechanism of action in the body's internal environment, preparation of a labeled version of 2-(2-mercaptoacetamido)-3-phenylpropanoic acid finds importance. In this regard, we report a convenient synthetic pathway for preparation of carbon-14 labeled 2-(2- mercaptoacetamido)-3-phenylpropanoic acid. This study was initiated by using non-radioactive materials. Then, necessary characterization was performed after each of the reactions. Finally, the synthesis steps were continued to produce the target labeled product. For labeled products, the process was started from benzoic acid-[carboxyl- 14C] which has been prepared from barium 14C-carbonate. Chromatography column and NMR spectroscopy were used for purifications and identification of desired products, respectively. Barium [14C]carbonate was purchased from Amersham Pharmacia Biotech and was converted to [14C]benzyl bromide. Radioactivity was determined using liquid scintillation spectrometer. We used [14C]PhCH2Br which was previously prepared from [14C]BaCO3, H2SO4, PhMgI, LAH and HBr, respectively. To neutralize the [14C]phenylalanine in acidic condition and to reach an isoelectric point of phenylalanine (pH = 5.48), Pb(OH)2 was used. Next, thioacetic acid and bromo acetic acid were used to prepare (acetylthio) acetic acid. A peptide coupling reagent was used in this stage to facilitating amide bond formation reaction between [14C]methyl-2-amino-3-phenyl propanoate hydrochloride and (acetylthio) acetic acid. Carbon-14 labeled 2-(2-mercaptoacetamido)-3-phenylpropanoic acid via radioactive phenylalanine was obtained with overall chemical yield 73% and radioactivity 65.3 nCi. The labeled target product will be used for in vivo pharmacological studies.

Electron-Deficient Borinic Acid Polymers: Synthesis, Supramolecular Assembly, and Examination as Catalysts in Amide Bond Formation.

The Lewis acidic character of borinic-acid-functionalized polymers suggests broad potential applications in supramolecular materials, chemo- and biosensors, as well as supported catalysts. Two highly electron-deficient borinic acid copolymers (3 a and 3 b) with variable steric hindrance at the boron center were prepared by reaction of aryldibromoboranes ArBBr2 (2, Ar=2,4-Cl2 Ph, 3,5-Cl2 Ph) with a 10 % stannylated polystyrene random copolymer, followed by conversion to the desired PS-B(Ar)OH functionalities. The supramolecular assembly of these polymers through Lewis acid-Lewis base interactions and reversible covalent B-O-B bond formation was investigated. Exposure of a polymer solution of 3 a to pyridine triggered spontaneous gelation, whereas 3 b only gelled upon addition of molecular sieves to favor formation of boroxane crosslinks. The crosslinking process was readily reversed by addition of small amounts of water or wet solvent. The dynamic processes were studied in detail by variable-temperature (VT) NMR by using molecular model compounds. The polymers and their corresponding model compounds were also examined as catalysts in the amide bond formation reaction between phenylacetic acid and benzylamine. The 3,5-dichlorophenyl borinic acid derivatives proved to be the more effective catalysts. Mechanistic studies suggested that the borane Lewis acid-catalyzed coupling involves initial acid-induced protodeboronation to release the dichlorophenyl boronic acid as the active catalyst.

A reaction force perspective of a model amide bond formation reaction

A reaction force approach of amide bond formation between ammonia and formic acid is demonstrated along with each atom’s contribution to structural changes and electronic reordering of the chemical reaction. The B3LYP/6-31G(d,p) level of density functional theory based calculations were carried out to explore transition states (TSs) of stepwise and concerted amide bond formation reaction pathways. Various stages that characterize structural and electronic properties in the progress of reaction are identified from reaction force calculations on energetics of geometries obtained from intrinsic reaction coordinate (IRC) pathways. The reaction works in preparative region of the pathway are less than that in relaxation stage, reflecting favorable formation of product geometries (Formamide and water). More than 80% of the activation energy comes from structural changes in preparative region. A comparison of reaction force profiles and reaction works in preparative region of TS1 and TS2 of stepwise path and TS3 of concerted path discloses that both the stepwise and concerted mechanisms are equally competent in terms of kinetic feasibility. The atomic resolution of pathways unveils that, hydrogen and oxygen forming the water molecule contribute significantly to the negative reaction energy of product geometries. The preferential contribution of the atoms comes from enhanced negative charge of the oxygen and positive charge on hydrogen in the progress of reaction.

Phosphine‐Promoted Amide Bond Formation Reactions from Carboxylic Acids and Tetraalkylthiuram Disulfides

Phosphine‐Promoted Amide Bond Formation Reactions from Carboxylic Acids and Tetraalkylthiuram Disulfides

Recent Advances in the Synthesis of Amides via Oxime Rearrangements and its Applications

Background: Amide bond formation reactions are the most important transformations in (bio)organic chemistry because of the widespread occurrence of amides in pharmaceuticals, natural products and biologically active compounds. The Beckmann rearrangement is a well-known method used for the preparation of secondary amides from ketoximes. But, most of the traditional protocols used for the Beckmann rearrangement create enormous amount of wastes. Thus, the atom economical synthesis of amides has got high priority among the chemists. However, under classical Beckmann conditions, aldoximes do not rearrange into the corresponding primary amides. Indeed, reactions of aldoximes lead to nitriles. In recent years, it has been demonstrated that the aldoxime rearrangements can be carried out efficiently and selectively with the help of metal catalysts. <p> Objective: This review focuses on the recent progress in the amides synthesis via ketoxime and aldoxime rearrangements. Applications of the rearrangements in the synthesis of heterocycles and natural products are also covered in this review. Conclusion: In the first part of the review, relevant pathways of oxime rearrangements are discussed and it is shown that several catalytic systems have been developed for the atom-economical synthesis of N-substituted amides from ketoximes. But similar reactions with aldoximes are, however, more challenging. The advances reached in the aldoxime rearrangement are also covered in this review. It is revealed that a large variety of homogeneous and heterogeneous metal catalysts have been developed to affect aldoxime rearrangements.

Amide Bond Formation Assisted by Vicinal Alkylthio Migration in Enaminones: Metal- and CO-Free Synthesis of α,β-Unsaturated Amides.

Amide bond formation is one of the most important transformations in organic synthesis, drug development, and materials science. Efficient construction of amides has been among the most challenging tasks for organic chemists. Herein, we report a concise methodology for amide bond (-CONH-) formation assisted by vicinal group migration in alkylthio-functionalized enaminones (α-oxo ketene N, S-acetals) under mild conditions. Simple treatment of such enaminones with PhI(OAc)2 at ambient temperature in air afforded diverse multiply functionalized α,β-unsaturated amides including β-cyclopropylated acrylamides, in which a wide array of functional groups such as aryl, (hetero)aryl, alkenyl, and alkyl can be conveniently introduced to a ketene moiety. The reaction mechanism was investigated by exploring the origins of the amide oxygen and carbon atoms as well as isolation and structural characterization of the reaction intermediates. The amide bond formation reactions could also be efficiently performed under solventless mechanical milling conditions.

Thioacids - synthons for amide bond formation and ligation reactions: assembly of peptides and peptidomimetics.

The synthesis of α-amino thioacids and peptide thioacids and their applications in chemoselective amide bond formation, ligation of peptides/proteins/glycopeptides and synthesis of peptidomimetics are reviewed. A variety of successful methods including both C-terminal and N-terminal activations for the coupling of α-amino thioacids and peptide thioacids have ascertained the thioacid-based protocol as a benign alternative to some of the traditional methods of amide/peptide bond formation which employs carboxyl activation. In addition to the couplings involving unprotected peptide fragments and solid phase synthesis, their use in the synthesis of different classes of peptidomimetics such as thioxopeptides, imide conjugates and acylsulfonamide-peptide conjugates only illustrates the versatility of this functionality in generating diverse classes of molecules, some of which are relevant to drug discovery and chemical biology. A note on more reactive seleno counterparts of thioacids, which can be useful in selective cases, is provided.