Eschweiler-Clarke Reaction Research Articles

Simplified Version of the Eschweiler-Clarke Reaction.

The traditional Eschweiler-Clarke reaction is a three-component process involving formaldehyde, amine, and formic acid. In this work, we showed that the reductive potential of formaldehyde was sufficient to provide methylation of secondary amines in the absence of acidic additives. Various acid-sensitive moieties remain intact under developed conditions. The scalability of the elaborated approach was shown for several products. Synthesis of the antifungal agent butenafine demonstrated the preparative utility of the developed approach.

Impacts of norfloxacin on sewage sludge anaerobic digestion: Bioenergy generation and potential environmental risks

Norfloxacin is a broad-spectrum antibiotic which has been frequently detected in the sewage sludge. However, whether norfloxacin in sewage sludge would affect the anaerobic digestion for bioenergy generation and induce environmental risks remained unclear. Therefore, this study investigated the impact of norfloxacin on sewage sludge anaerobic digestion and evaluated potential environmental risks by exploring related antibiotic resistance genes (ARGs) and norfloxacin transformation pathways. The results showed that norfloxacin at environmental relevant concentration ranges would not significantly affect methane production (p < 0.05) during the sludge anaerobic digestion, as the sludge solubilization and hydrolysis is unaffected. However, the individual methanogenesis process was enhanced with the increase of Methanosaeta abundances. Meanwhile, the increase of norfloxacin concentration will not decrease the removal efficiencies of fluoroquinolones-family ARGs by the anaerobic digestion process. However, the norfloxacin concentration is found to be increased during the anaerobic digestion process, which could probably be due to the desorption from the sludge due to cell lysis. In addition, 13 norfloxacin transformation metabolites were identified with 5 potential norfloxacin degradation pathways being constructed. The metabolites of levofloxacin/ofloxacin could be generated through Eschweiler-Clarke reaction, which may be more toxic than norfloxacin. Thus, the results of this study suggested that although norfloxacin would not affect the bioenergy generation and ARG removal during sludge anaerobic digestion, measures should be taken to deal with the potential environmental risks caused by norfloxacin release and formation of more toxic metabolites.

Concise Enantioselective Total Synthesis of Isopavine Alkaloids.

Herein, we report a concise asymmetric total synthesis of isopavine alkaloids, which feature a special azabicyclo[3.2.2]nonane tetracyclic skeleton. The key steps include iridium-catalyzed asymmetric hydrogenation of unsaturated carboxylic acids, Curtius rearrangement, and Eschweiler-Clarke methylation, which enable an enantioselective approach to isopavine alkaloids in 6-7 linear steps. Furthermore, for the first time, isopavine alkaloids, especially (-)-reframidine (3), are found to display effective antiproliferative effects on various cancer cell lines.

A Brief Review: Advancement in the Synthesis of Amine through the Leuckart Reaction

This review presents a summary of reactions that take place during the “Leuckart-type reaction”. The significance of, as well as recent advancements in, the synthesis of amines through simple and inexpensive methods using readily available raw materials is discussed. This review includes all catalytic and noncatalytic reactions that involve the Leuckart method. Recent studies have shown that at least a quarter of C–N bond-forming reactions in the pharmaceutical industry are occur with the support of reductive amination. Recently, experimental conditions have achieved excellent yields. The “Leuckart-type reaction” is technically associated with Eschweiler–Clarke methylation. Compounds are grouped in accordance with the precept of action. This includes drugs affecting the central nervous system, cardiovascular system and gastrointestinal tract; anticancer drugs, antibiotics, antiviral and antifungal drugs; drugs affecting anxiety; convulsant, biotic, and HIV drugs; and antidiabetic drugs. Therefore, this review supports the development of the Leuckart-type preparation of nitrogenous compounds, as well as their advancement in other areas of human development.

Arylene Diimide Derivatives as Anolyte Materials with Two-Electron Storage for Ultrastable Neutral Aqueous Organic Redox Flow Batteries

Arylene Diimide Derivatives as Anolyte Materials with Two-Electron Storage for Ultrastable Neutral Aqueous Organic Redox Flow Batteries

N,N-dimethyl chitosan oligosaccharide (DMCOS) promotes antifungal activity by causing mitochondrial damage

By modifying chitosan oligosaccharide (COS) with the Eschweiler-Clarke reaction, the chitosan oligosaccharide derivative DMCOS was synthesized. FT-IR, 1D and 2D NMR spectra, MALDI-ToF MS, and elemental analysis were applied to analyze the structure of DMCOS, which revealed that the primary amines were converted into tertiary amines after methylation. DMCOS displayed less thermal stability than COS. In comparison to COS, it was discovered that DMCOS possessed more potent antimicrobial activity against four bacterial strains (Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa) and three yeast strains (Candida albicans, Candida tropicalis, and Candida parapsilosis). The antioxidant studies indicated that DMCOS had less antioxidant activity than COS. Consequently, ROS level elevated in C. albicans cells following treatment with DMCOS, which decreased mitochondrial membrane potential. It was recalled that DMCOS may kill C. albicans by causing mitochondrial damage. In addition, DMCOS was demonstrated to be non-cytotoxic.

A flow electrochemistry-enabled synthesis of 2-substituted N-(methyl-d)piperidines.

A synthesis of N-monodeuteriomethyl-2-substituted piperidines is described. An efficient and readily scalable anodic methoxylation of N-formylpiperidine in an undivided microfluidic electrolysis cell delivers methoxylated piperidine 3, which is a precursor to a N-formyliminium ion and enables C-nucleophiles to be introduced at the 2-position. The isotopically labelled N-deuteriomethyl group is installed using the Eschweiler-Clarke reaction with formic acid-d2 and unlabelled formaldehyde. Monodeuterated N-methyl groups in these molecular systems possess small isotropic proton chemical shift differences important in the investigation of molecules that are able to support long-lived nuclear spin states in solution nuclear magnetic resonance.

A density functional theory study of the hydride shift in the Eschweiler–Clarke reaction

AbstractThe Eschweiler–Clarke (the amine methylation) reaction was investigated by density functional theory (DFT) calculations. First, a reaction model of H3CNH2 + HC(O)OH + CH2O + (H2O)3 → (H3C)2NH + CO2 + (H2O)4 was employed for geometry optimizations. Geometries and activation free energies of transition states (TSs) by eight DFTs, B2PLYP‐D3, B3LYP, B3LYP‐D, BP86‐D, PBE0‐D, M06‐2X, wB97X‐D, and APF‐D, along with MP2 were compared. Four elementary processes were obtained. The rate‐determining step is of the hydride‐transfer TS, H3CN+HCH2 + HCO2− → H3CNHCH3 + CO2. Whereas BP86‐D and APF‐D gave underestimated energies, M06‐2X was found to be a reasonable DFT to trace the present reaction. Second, by the use of M06‐2X/6‐311++G**, hydride‐shift TSs were examined for various sizes of the water cluster (H2O)n, and the controversial two mechanisms were evaluated. It was suggested that the first formic acid contributes to formation of the iminium ion H3CN+HCH2 and the second formic acid works for the hydride transfer. The Eschweiler–Clarke reaction was described by the scheme, R1R2NH + H2CO + (HCOOH)2 + (H2O)n → R1R2NCH3 + CO2 + HCO2− + H3O+(H2O)n.

Frontispiz: Construction of Flexible Amine‐linked Covalent Organic Frameworks by Catalysis and Reduction of Formic Acid via the Eschweiler–Clarke Reaction

Frontispiz: Construction of Flexible Amine‐linked Covalent Organic Frameworks by Catalysis and Reduction of Formic Acid via the Eschweiler–Clarke Reaction

Frontispiece: Construction of Flexible Amine‐linked Covalent Organic Frameworks by Catalysis and Reduction of Formic Acid via the Eschweiler–Clarke Reaction

Covalent Organic Frameworks The synthesis of a series of flexible amine-linked COFs is reported by Lijian Ma et al. in their Research Article on page 12396.

Construction of Flexible Amine-linked Covalent Organic Frameworks by Catalysis and Reduction of Formic Acid via the Eschweiler-Clarke Reaction.

Compared to the current mainstream rigid covalent organic frameworks (COFs) linked by imine bonds, flexible COFs have certain advantages of elasticity and self-adaptability, but their construction and application are greatly limited by the complexity in synthesis and difficulty in obtaining regular structure. Herein, we reported for the first time a series of flexible amine-linked COFs with high crystallinity synthesized by formic acid with unique catalytic and reductive bifunctional properties, rather than acetic acid, the most common catalyst for COF synthesis. The reaction mechanism was demonstrated to be a synchronous in situ reduction during the formation of imine bond. The flexibilities of the products endow them with accommodative adaptability to guest molecules, thus increasing the adsorption capacities for nitrogen and iodine by 27 % and 22 %, respectively. Impressively, a novel concept of flexibilization degree was proposed firstly, which provides an effective approach to rationally measure the flexibility of COFs.

Construction of Flexible Amine‐linked Covalent Organic Frameworks by Catalysis and Reduction of Formic Acid via the Eschweiler–Clarke Reaction

AbstractCompared to the current mainstream rigid covalent organic frameworks (COFs) linked by imine bonds, flexible COFs have certain advantages of elasticity and self‐adaptability, but their construction and application are greatly limited by the complexity in synthesis and difficulty in obtaining regular structure. Herein, we reported for the first time a series of flexible amine‐linked COFs with high crystallinity synthesized by formic acid with unique catalytic and reductive bifunctional properties, rather than acetic acid, the most common catalyst for COF synthesis. The reaction mechanism was demonstrated to be a synchronous in situ reduction during the formation of imine bond. The flexibilities of the products endow them with accommodative adaptability to guest molecules, thus increasing the adsorption capacities for nitrogen and iodine by 27 % and 22 %, respectively. Impressively, a novel concept of flexibilization degree was proposed firstly, which provides an effective approach to rationally measure the flexibility of COFs.

Nebulization prior to ionization for mechanistic studies of chemical reactions

Many important chemical transformations proceed by way of ionic and/or neutral intermediates. Great effort has been expended to understand the mechanism, with only minimum attention given to separate associated ionic and neutral intermediates. Herein, we present a nebulization method followed by on-line ionization to isolate and characterize the ionic and neutral intermediates. The separation of nebulization and ionization and electrical deflection of ionic species guarantee that only neutrals undergo the subsequent on-line ionization. We present data that show the formation of neutral intermediates and iminium ions with short lifetime in Eschweiler-Clarke methylation of di-n-butylamine, as well as data that provide evidence for the formation of carbocation and its isomer lactone products resulting from copper-mediated oxidative cyclization of 4-phenylbutyric acid. Experiments in which dissociation behavior of these two isomers varied at the same collision energy confirmed the carbocation during the cyclization. The nature of this process, which online isolates the ionic and neutral intermediates prior to ionization, greatly advances in mechanistic studies.

Synthesis and Characterization of a Butenafine Analogue

Aims: The study aims: (I) To synthesise N-(4-(tert-butyl) benzyl)-1-(4-tert-butyl) phenyl)-N-methyl methanaminium chloride, an analogue of butenafine from tertiary-butyl benzyl derivatives, (II) to compare the solvent actions of Tetrahydrofuran (THF), acetonitrile, methanol and 1,2-dichloroethane (DCE), and the reducing efficiencies of NaBH4 and sodium triacetoxyborohydride (STAB) during the synthesis.&#x0D; Study Design: The study involved laboratory experiments leading to the synthesis of the target compound by varying the non-aqueous solvents used, the reducing agent and the temperature of the operations. Silica chloride catalyst was used to speed up the reaction in one of the syntheses and in each synthesis, Thin Layer Chromatography was used to monitor the progress of the reaction. The time taken by each reaction and the yield were used as the basis for determining the solvent action and the reducing efficiency. &#x0D; Place and Duration of Study: M.Sc. Access controlled Teaching Laboratory, School of Chemistry, Newcastle University, New castle upon Tyne, United Kingdom from June to August 2012.&#x0D; Methodology: Reductive amination was carried out by reacting 4-tert-butylbenzaldehyde and 4-tert-butylbenzylamine, using the direct and then the indirect approaches. This was followed by methylation using the Eschweiler-Clarke reaction in each of the two approaches. The time taken by each reaction was monitored and the product of each approach was characterised by EIS-MS, 1H NMR, 13C NMR and FTIR.&#x0D; Results: 1,2-dichloroethane gave the best solvent action at 40°C (Yield: 75%) and NaBH4 gave the best-reducing action with silica chloride catalyst at 25°C (Yield: 50%). At the end of each synthesis, in all obtained products, 1H NMR spectrum gave a single peak of 18 hydrogen atoms at 1.3 -1.5 ppm for the existence of 6 methyl groups in the two tertiary-butyl substituents, the 13C NMR spectrum also showed a peak at 31-32 ppm for the six methyl carbon atoms in the two tertiary-butyl substituents, the FTIR spectrum showed a strong band at 2460 cm-1 for the presence of a tertiary ammonium ion and finally the EIS-MS gave a mass to charge ratio of 324.2693 as a confirmation of the relative molecular mass of the compound.&#x0D; Conclusion: The target compound can be synthesised by both direct and the indirect approaches of reductive amination in any of the solvents tested with/without a catalyst at room or elevated temperature using NaBH4 or STAB as a reducing agent but the best solvent action can be achieved with DCE at 40°C and the best-reducing action can be achieved with NaBH4 in the presence of silica chloride.

Practical and Theoretical Study of the Adsorption Performances of Straw-Based Tertiary Amine-Supported Material toward Sulfur Dioxide in Flue Gas

The primary and secondary amines of tetraethylenepentamine (TEPA) were N-methylated into tertiary amines through the Eschweiler-Clarke reaction. A straw-based tertiary amine-supported material (STA) was developed for SO2 removal, using a wet impregnation process. The effect of the adsorption conditions, such as the moisture content, flow rate, and adsorption temperature, as well as the regeneration performances were studied. Experimental results showed that STA has high SO2 adsorption capacity (approximately 100 mg/g) and can be regenerated at 100 °C. Furthermore, the adsorption of SO2 molecules on tertiary amine was studied using density functional theory (DFT). The most stable geometries of the adsorption structure in five possible positions, the geometric changes after the adsorption, and the corresponding adsorption energies were analyzed. The results showed that modified TEPA (M-TEPA) has four potential adsorbed sites (N(1,3,4,5)) with a small adsorption energy, indicating that the adsorption is weak. Moreover, the energy of the adsorbed SO2 on the N(1,3,4,5) is less than zero, indicating that the adsorption process is exothermic and spontaneous. The theoretical investigation agreed well with the experimental results.

N,N-Dimethylation of Nitro-eugenol to its New 4-Allyl-2-(dimethylamino)-6-methoxyphenol via Eschweiler–Clarke Methylation Reaction

N,N-Dimethylation of Nitro-eugenol to its New 4-Allyl-2-(dimethylamino)-6-methoxyphenol via Eschweiler–Clarke Methylation Reaction

Template-directed syntheses of two 3D metal oxalates: in situ N-methylation and crystal structures

Two isomorphic organically templated zinc/cobalt oxalates, (dmdabco)[Zn2(C2O4)3]·4H2O (1), and (dmdabco)[Co2(C2O4)3]·4H2O (2) (C2O42− = oxalate; dmdabco = N,N′-dimethyl-1,4-diazabicyclo[2,2,2]octane), have been prepared under solvothermal conditions and characterized by X-ray structural analyses. The dmdabco2+ templating agent was derived from simple in situ N-alkylation between methanol and 1,4-diazabicyclo[2,2,2]octane (dabco). Distinct from conventional Eschweiler-Clarke methylation containing excess formic acid and formaldehyde, such one-step methylation from methanol molecules is convenient. Both 1 and 2 exhibit a uninodal 3-connected 3-D interrupted open-framework, in which oxalate ligands have in-plane and out-of-plane connection modes.

Aluminophosphates prepared using in situ generated tetramethylammonium cations as structure directing agents

A series of aluminophosphates (AlPOs) with open architectures, namely [dmdabco][Al2(HPO4)4] (1, dmdabco = N,N-dimethyl-1,4-diazabicyclo[2,2,2]octane), [tmpip]0.5[Al(HPO4)2] (2, tmpip = N,N,N,N-tetramethylpiperazinium) and [tmpip][Al6(PO4)6(HPO4)] (3) have been solvothermally synthesized and structurally characterized. The in situ generated templates (dmdabco2+ and tmpip2+) originated from the methylation reactions between methanol solvent and their corresponding aliphatic organic-amine parents: 1,4-diazabicyclo[2,2,2]octane (dabco) for 1, 1-methylpiperazine for 2 and 3. Such a characteristic in situ methylation is distinct from conventional Eschweiler–Clarke methylation with excessive formic acid and formaldehyde. Compounds 1 and 2 possess the same infinite inorganic chains, which are further linked by hydrogen bonds to form 3D supramolecular framework. Compound 3 is built from Al6P6 and Al6P8 building units, giving rise to an open architecture with three-dimensional channel system.

Fast screening of analytes for chemical reactions by reactive low-temperature plasma ionization mass spectrometry.

Approaches for analyte screening have been used to aid in the fine-tuning of chemical reactions. Herein, we present a simple and straightforward analyte screening method for chemical reactions via reactive low-temperature plasma ionization mass spectrometry (reactive LTP-MS). Solution-phase reagents deposited on sample substrates were desorbed into the vapor phase by action of the LTP and by thermal desorption. Treated with LTP, both reagents reacted through a vapor phase ion/molecule reaction to generate the product. Finally, protonated reagents and products were identified by LTP-MS. Reaction products from imine formation reaction, Eschweiler-Clarke methylation and the Eberlin reaction were detected via reactive LTP-MS. Products from the imine formation reaction with reagents substituted with different functional groups (26 out of 28 trials) were successfully screened in a time of 30 s each. Besides, two short-lived reactive intermediates of Eschweiler-Clarke methylation were also detected. LTP in this study serves both as an ambient ionization source for analyte identification (including reagents, intermediates and products) and as a means to produce reagent ions to assist gas-phase ion/molecule reactions. The present reactive LTP-MS method enables fast screening for several analytes from several chemical reactions, which possesses good reagent compatibility and the potential to perform high-throughput analyte screening. In addition, with the detection of various reactive intermediates (intermediates I and II of Eschweiler-Clarke methylation), the present method would also contribute to revealing and elucidating reaction mechanisms.

Synthesis of N-methyl alkylaminomethane-1,1-diphosphonic acids and evaluation of their complex-formation abilities towards copper(II)

A series of N-methyl alkylaminomethane-1,1-diphosphonic acids (3a–g) with a common tertiary nitrogen atom (CH3–N–R) bearing linear or branched alkyl, cycloheptyl or phenylalkyl R substituents was synthesized in the reaction of diethylphosphonate with triethyl orthoformate and secondary amine followed by hydrolysis, and by the Eschweiler–Clarke methylation of the alkylaminomethane-1,1-diphosphonic acids with formic acid and formaldehyde. Complex-formation abilities of 3a–g towards copper(II) in solution were studied by means of pH-potentiometry, ESI-MS spectrometry, UV–Vis and EPR methods.Evaluation of stability constants for the Cu(II) complexes of 3a–g has revealed their dependence on a combination of steric and electronic effects imposed by R substituents. It has been demonstrated that compounds with linear or branched alkyl on the N atom (3a, 3d, 3e) form the most stable complexes with Cu(II), the least stable are complexes of 3f, which can be attributed to the steric effect imposed by cycloheptyl ring attached directly to the N atom. In addition to the main [Cu(HL)2] complexes, with well-known {O, O} chelating binding mode, [Cu(HL)L] and [CuL2] species with the {O, N} donor set, protonated dinuclear [Cu2HxL3] (x=4, 5, 6) species have been detected in all studied systems. The nitrogen coordination in the [Cu(HL)L] and [CuL2] complex has been confirmed by Vis and EPR spectra.