Nucleophilic Addition Reactions Research Articles

Kinetic Characterization and Identification of Key Active Site Residues of the L-Aspartate N-Hydroxylase, CreE.

CreE is a flavin-dependent monooxygenase (FMO) that catalyzes three sequential nitrogen oxidation reactions of L-aspartate to produce nitrosuccinate, contributing to the biosynthesis of the antimicrobial and antiproliferative nautral product, cremeomycin. This compound contains a highly reactive diazo functional group for which the reaction of CreE is essential to its formation. Nitro and diazo functional groups can serve as potent electrophiles, important in some challenging nucleophilic addition reactions. Formation of these reactive groups positions CreE as a promising candidate for biomedical and synthetic applications. Here, we present the catalytic mechanism of CreE and the identification of active site residues critical to binding L-aspartate, aiding in future enzyme engineering efforts. Steady-state analysis demonstrated that CreE is very specific for NADPH over NADH and performs a highly coupled reaction with L-aspartate. Analysis of the rapid-reaction kinetics showed that flavin reduction is very fast, along with the formation of the oxygenating species, the C4a-hydroperoxyflavin. The slowest step observed was the dehydration of the flavin. Structural analysis and site-directed mutagenesis implicated T65, R291, and R440 in the binding L-aspartate. The data presented describes the catalytic mechanism and the active site architecture of this unique FMO.

Application of Cations, Acids, and Antioxidants on Mitigating Acrylamide Formation in Food with a Special Focus on Potato and Cereal Based Foods - A Review

Acrylamide is a toxic substance that formsin food during high-temperature processing methods such as deep-frying, baking, and roasting, through the Maillard reaction or the acrolein pathway. Since acrylamide has been identified for its carcinogenicity, genotoxicity, and neurotoxicity, global food authorities have established benchmark levels for different food categories. Consequently, researchers have proposed various mitigation strategies, focusing on agronomical, chemical, physical, and microbial approaches. However, most of these approaches are associated with high cost, technology, extended time, and poor sensory and nutritional quality. In this context, application of various additives such as metal cations, organic and inorganic acids, and antioxidants in optimum amounts have been effective in reducing acrylamide formation. Additives contribute to reducing acrylamide either by interacting with its precursors and/or intermediate products or by breaking down acrylamide into other non-toxic substances. Since cations can form thermostable asparagine/matrix intermediates through chelation reaction between asparagine and metal cations, asparagine will be unavailable to react with carbonyl compounds to form the Schiff base. Lower pH conditions inhibit the acrylamide formation by blocking the protonation of the α-amino group of asparagine and reducing any possibility for nucleophilic addition reactions with carbonyl groups. Toxicity associated with Maillard products can be reduced by using antioxidants in the frying oil or the food. Polyphenols are capable of reducing the acrylamide formation by directly trapping acrylamide at elevated temperature. It is essential to identify the most appropriate additive, its concentration and the optimum process conditions when applying additives to get an optimal acrylamide inhibition. This review article highlights the effect of various additive applications, their effectiveness and possible future advances in food to control acrylamide formation within the accepted level.Keywords: Acrylamide, Antioxidant, Carcinogenicity, Deep-frying, Maillard reaction

Surface-enhanced Raman scattering sensor based on cysteine-mediated nucleophilic addition reaction for detection of patulin

Fruits are susceptible to fungal infection and propagation during storage and transportation, and carry toxic metabolites of fungi. Patulin (PAT) is a primary mycotoxin contaminant in fruits and their products, with neurotoxicity, teratogenicity and carcinogenicity. The current chromatographic methods have limitations such as time-consuming, high-cost and the need for professional training. For rapid and sensitive detection of PAT, a surface-enhanced Raman scattering (SERS) method based on nucleophilic addition reaction was described in this paper. 4-aminothiophenol (4-ATP), silver ion, and cysteine (Cys) were successively attached to the surface of the Au-core-Ag-shell nanoparticles to form SERS sensors. PAT reacted with Cys to form a complex covering the surface of the sensor, attenuating the Raman signal from 4-ATP. Combined with the chemometrics algorithms, the hidden spectral information can be extracted effectively. Among these algorithms, the ant colony optimization partial least squares (ACO-PLS) model demonstrated the best predictive performance (Rc = 0.9985, RMSEC = 0.0494). The recovery rate of PAT was 96.58 ∼ 101.74 % with the RSD ≤ 1.42 %. HPLC was used to verify the applicability of this SERS method, and the results indicated that the SERS method was consistent with the HPLC method (p = 0.283 > 0.05). Furthermore, the SERS sensor was not subject to interference from ochratoxins A, alternariol, and the PAT structural analogues. Consequently, the proposed SERS sensor can realize rapid and highly selective detection of PAT, providing a new strategy for the rational design of SERS sensor based on chemical reaction for indirect detection of harmful substances.

Esters-targeted colorimetric sensor array for the authenticity discrimination of strong-aroma baijiu with different origins

Baijiu authenticity has been a frequent problem driven by economic interests in recent years, so it is important to discriminate against baijiu with different origins. Herein, we proposed a simple and efficient esters-targeted colorimetric sensor array mediated by hydroxylamine hydrochloride. Esters undergo a nucleophilic addition reaction with hydroxylamine hydrochloride to form hydroxamic acid, which rapidly forms a purplish red ferric hydroxamate under FeCl3·6H2O. Bromophenol blue and rhodamine B enrich the color effects. The array detected 12 esters with a detection limit on the order of 10−5 of most esters and 16 mixed esters with R2 > 0.999 and recoveries close to 100%. Otherwise, for discriminating 34 strong-aroma baijius (SABs), the array has an accuracy of 98% according to the origin, and 95% according to the grades, with a response time of 1 min. This study provides a new strategy for authenticity determination and quality control of baijiu.

Effect of montmorillonite K-10 catalyst on the synthesis of (E)-1-phenyl-3-(2-methoxyphenyl)-2-propen-1-one using the microwave irradiation method

Background: A research investigation was conducted to examine how the utilisation of the montmorillonite K-10 catalyst impacts the production of (E)-1-phenyl-3-(2-methoxyphenyl)-2-propen-1-one (PMPP) using the microwave irradiation method since the conventional method has not been successful. Objective: The aim of this research was to investigate the impact of employing the montmorillonite K-10 catalyst in the synthesis of PMPP using the microwave irradiation method. Method: The compound was created using the Claisen-Schmidt condensation technique through a nucleophilic addition reaction. Results: The result of the synthesis was a yellowish powder. The percentage of synthesis of PMPP using the microwave irradiation method was 4.98%, with a melting point of 53-54oC. The synthesised compounds were identified by UV-Vis, Infrared and H-NMR spectroscopy. Conclusion: Synthesis of PMPP with montmorillonite K-10 catalyst can be carried out using microwave irradiation. The synthesis using the montmorillonite K-10 catalyst gave a relatively small yield of (E)-1-phenyl-3-(2-methoxyphenyl)-2-propen-1-one compared to a strong base catalyst.

Preparation and Properties of Polycarboxylate Superplasticizer Based on Chain Transfer Agents with Various Structures

AbstractPolycarboxylate superplasticizer (PCE) is a common admixture in high performance concrete. In the design of PCE molecules, it is necessary to ensure that the molecular weight of the polymer is moderate and the acid‐ether ratio is appropriate to improve the dispersion effect. Chain transfer agent is usually added in the synthesis of PCE to adjust the molecular weight and distribution of PCE. In this study, three sulfhydryl chain transfer agents with different electron‐withdrawing groups or electron‐donating groups were synthesized by nucleophilic addition reaction based on sodium hydrosulfide method. Then, three kinds of PCE containing sulfhydryl chain transfer agent were prepared and compared with commercial β‐mercaptopropionic acid superplasticizers. The yield stress and plastic viscosity of cement paste samples prepared by PCE−A and PCE−M were close to those prepared by PCE−P. PCE−M and PCE−A prepared by chain transfer agent with electron‐withdrawing group had higher dispersion and retention capacity than PCE−P, and had more obvious delay of cement hydration and lower hydration accumulated heat. Therefore, the optimization of molecular structure of chain transfer agent is helpful to improve the properties of concrete superplasticizer.

Efficient electrosynthesis of new mono- and bis-sulfonamide derivatives via electrooxidation of o-tolidine

This work is the first documentation on synthesizing new mono- and bis-sulfonamide derivatives with o-tolidine (3,3′-dimethylbenzidine) in the central core. Using o-tolidine as a substrate and its electrochemical oxidation as well as the subsequent nucleophilic addition reaction between the oxidized o-tolidine and sulfinic acid derivatives, new mono- and bis-sulfonamide derivatives were synthesized in a solution of acetonitrile/water (30/70 v/v) at pH = 2.0 in 32–73% yields. The chemical structures of all synthesized compounds were identified and corroborated through various analyses, including melting point, IR, 1HNMR , 13CNMR , and MS. Also, density functional theory (DFT) calculations at the B3LYP/6–311++G(d,p) theoretical level were employed to study the chemical reactivity regarding local and global electrophilicity through the Fukui function reactivity index analysis. The results achieved by the DFT calculations are entirely consistent with the experimental data.

One-Pot Three-Component Reaction for the Synthesis of 3,4-Dihydroquinazolines and Quinazolin-4(3H)-ones.

A highly efficient and straightforward one-pot synthesis of diversely substituted 3,4-dihydroquinazolines and quinazolin-4(3H)-ones has been achieved through a domino three-component assembly reaction of arenediazonium salts, nitriles, and bifunctional aniline derivatives. This new protocol involves three C-N bond formations through the initial formation of N-arylnitrilium intermediates from arenediazonium salts and nitriles, followed by the sequential nucleophilic addition and cyclization reactions with bifunctional anilines, leading to such N-heterocyclic compounds of biological and pharmacological importance. This method offers a simple, expedient, and robust approach with the use of amenable and easily accessible reactants/reagents under metal-free mild conditions, good functional group tolerance, and high efficiency. The synthetic applications were also demonstrated by derivatization of the products obtained from these processes and syntheses of a diverse range of valuable polycyclic N-heterocycles.

Nucleophilic Addition of Amides to Haloalkynes: Synthesis of (Z)-β-Halovinyl Amides as Dual Precursors of Alkylidene Carbenes and Allyl Halides.

Toward a regioselective method for the synthesis of β-halovinyl amides, we developed a transition-metal-free nucleophilic addition reaction of amides to haloalkynes. The regioselective nucleophilic addition was achieved under solvent-free conditions using phosphonates to protonate the intermediate alkylidene carbenoids, thus suppressing their decomposition. Furthermore, we demonstrate that β-halovinyl amides can serve as dual precursors of allyl halides and alkylidene carbenes to obtain functionalized indoles and pyrrolidones.

Sustained zero-order release of dexamethasone after incorporation into crosslinked PEG-dendrons using click reactions

Hydrogel-based localised drug delivery minimises systemic side effects and a linear release profile ensuring a sustained drug release over time, crucial for long-term therapy. The current paper describes the use of the Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAc) to append azidified Dexamethasone (Dex) onto dendrons of first- and second-generation PEGs. Crosslinking with thiolated PEGs using either thiol-acrylate or nucleophilic addition reactions yielded gels containing β-thio-ether ester groups that imparted enhanced hydrolytic susceptibility. In vitro gel degradation was followed gravimetrically and expressed as swelling ratios. Thiol-acrylate crosslinked hydrogels exhibited zero-order Dex release kinetics over 11, 27, and 16 days (G1, G1-star, and G2). Crosslinking the G1-gels by nucleophilic addition also resulted in linear release and the end point was reached in 5 days. Hydrolysis was accounted as the main release mechanism for covalently bound Dex, while physically incorporated Dex showed undefined rapid burst or first-order release, with most of the drug released in the initial 1–3 days. Eluates from covalently bound Dex maintained high activity, whereas Trap-Dex gels lost activity over time, as detected by the upregulation of luciferase expression from a transformed cell line. This novel chemistry combination offers precise drug release control applicable beyond Dex to drugs with suitable nucleophilic groups.

Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived Cyclolignan.

Podophyllotoxin, a cyclolignan natural product, has been the object of extensive chemomodulation to obtain better chemotherapeutic agents. Among the obtained podophyllotoxin derivatives, podophyllic aldehyde showed very interesting potency and selectivity against several tumoral cell lines, so it became our lead compound for further modifications, as described in this work, oriented toward the enlargement of the cyclolignan skeleton. Thus, modifications performed at the aldehyde function included nucleophilic addition reactions and the incorporation of the aldehyde carbon into several five-membered rings, such as thiazolidinones and benzo-fused azoles. The synthesized derivatives were evaluated against several types of cancer cells, and although some compounds were cytotoxic at the nanomolar range, most of them were less potent and less selective than the parent compound podophyllic aldehyde, with the most potent being those having the lactone ring of podophyllotoxin. In silico ADME evaluation predicted good druggability for most of them. The results indicate that the γ-lactone ring is important for potency, while the α,β-unsaturated aldehyde is necessary to induce selectivity in these cyclolignans.

Mechanism of Dihydromyricetin-Induced Reduction of Furfural Derived from the Amadori Compound: Formation of Adducts between Dihydromyricetin and Furfural or Its Precursors.

Dihydromyricetin (DMY) was employed to reduce the yield of furfural derived from the Amadori rearrangement product of l-threonine and d-xylose (Thr-ARP) by trapping Thr-ARP, 3-deoxyxyosone (3-DX), and furfural to form adducts. The effect of different concentrations of DMY at different pH values and temperatures on the reduction of furfural production was studied, and the results showed that DMY could significantly reduce furfural production at higher pH (pH 5-7) and lower temperature (110 °C). Through the surface electrostatic potential analysis by Gaussian, a significant enhancement of the C6 nucleophilic ability at higher pH (pH ≥ 5) was observed on DMY with hydrogen-dissociated phenol hydroxyl. The nucleophilic ability of DMY led to its trapping of Thr-ARP, 3-DX, and furfural with the generation of the adducts DMY-Thr-ARP, DMY-3-DX, and DMY-furfural. The formation of the DMY-Thr-ARP adduct slowed the degradation of Thr-ARP, caused the decrease of the 3-DX yield, and thereby inhibited the conversion of 3-DX to furfural. Therefore, DMY-Thr-ARP was purified, and the structure was identified by nuclear magnetic resonance (NMR). The results confirmed that C6 or C8 of DMY and carbonyl carbon in Thr-ARP underwent a nucleophilic addition reaction to form the DMY-Thr-ARP adduct. In combination with the analysis results of Gaussian, most of the DMY-Thr-ARP adducts were calculated to be C6-DMY-Thr-ARP. Furthermore, the formation of DMY-furfural caused furfural consumption. The formation of the adducts also shunted the pathway of both Thr-ARP and 3-DX conversion to furfural, resulting in a decrease in the level of furfural production.

Aqueous-phase chemistry of glyoxal with multifunctional reduced nitrogen compounds: a potential missing route for secondary brown carbon

Abstract. The aqueous-phase chemistry of glyoxal (GL) with reduced nitrogen compounds (RNCs) is a significant source for secondary brown carbon (SBrC), which is one of the largest uncertainties in climate predictions. However, a few studies have revealed that SBrC formation is affected by multifunctional RNCs, which have a non-negligible atmospheric abundance. Hence, we assessed theoretical and experimental approaches to investigate the reaction mechanisms and kinetics of the mixtures for ammonium sulfate (AS), multifunctional amine monoethanolamine (MEA), and GL. Our experiments indicate that light absorption and growth rate are enhanced more efficiently in the MEA–GL mixture relative to AS–GL and MEA–AS–GL mixtures and MEA reactions of the chromophores than in the analogous AS reactions. Quantum chemical calculations show that the formation and propagation of oligomers proceed via four-step nucleophilic addition reactions in three reaction systems. The presence of MEA provides the two extra branched chains that affect the natural charges and steric hindrance of intermediates, facilitating the formation of chromophores. Molecule dynamics simulations reveal that the interfacial and interior attraction on the aqueous aerosols with MEA is more pronounced for small α-dicarbonyls to facilitate further engagement in the aqueous-phase reactions. Our results show a possible missing source for SBrC formation on urban, regional, and global scales.

Facile Synthesis of Quinoline-Substituted 3-Hydroxy-2-oxindoles and 3-Amino-2-oxindoles via a Palladium-Catalyzed Cascade Intramolecular Cyclization/Intermolecular Nucleophilic Addition Reaction.

An efficient cascade intramolecular cyclization/intermolecular nucleophilic addition reaction of allenyl benzoxazinone with isatin or isatin-derived ketimine has been established by using Pd0-π-Lewis base catalysis. A series of 3-hydroxy-2-oxindoles and 3-amino-2-oxindoles with quaternary carbon atoms at the C3 position were synthesized in good yields under mild conditions through this protocol.

The synthesis of biphenyl ether/vanillin‐based flame retardants for enhancing both the flame retardant properties and mechanical performance of epoxy resin

AbstractImparting good flame retardancy and mechanical properties to epoxy resin (EP), while pursuing the sustainable and safe application of EP, we synthesized a novel reactive phosphorus/nitrogen flame retardant for biomass through nucleophilic addition reaction, which contains flexible ether bonds and rigid aromatic ring structure (DVD). Owing to the cooperative effect of aryl ether diamine, phosphorus phenanthrene, and biomass vanillin, the DVD exhibited excellent flame retardancy. EP/DVD‐1 (0.4 wt% phosphorus content) achieved UL‐94 V‐0 rating, with an improvement in limiting oxygen index value from 26.5% (pure EP) to 32.5%. In the CCT, the modified DVD EP showed a 44.5% reduction in peak peak of heat release rate (PHRR) and a 38.0% reduction in total heat release compared to pure EPs. And flame retardant epoxy resin (FREP) still had good transparency after the addition of DVD, which indicated the nice compatibility between DVD andEP. What was noteworthiness was that at high levels of addition, the mechanical properties of modified EP for DVD was still improved compared to pure EP. These results demonstrate that DVD is an excellent and multifunctional bio‐based flame retardant with broad application prospects in the field of EP material modification.

Chemoselectivity of the CuAAC/Ring Cleavage/Cyclization Reaction between Enaminones and α-Acylketenimine.

Ketenimines represent an important class of reactive species, useful synthetic intermediates, and synthons. However, in general, ketenimines preferentially undergoes nucleophilic addition reactions with hydroxyl and amino groups, and carbon functional groups remain a less studied subset of such systems. Herein, we develop a straightforward syntheses of pyridin-4(1H)-imines that is achieved by cyclization of a reacting enaminone unit with α-acylketenimine which is generated from the reactions of sulfonyl azides and terminal ynones in situ (CuAAC/Ring cleavage reaction). The cascade process preferentially starts with the nucleophilic α-C of the enaminone unit instead of an amino group, attacking the electron-deficient central carbon of ketenimine, and the chemoselectivity unconventional products pyridin-4(1H)-imines were formed by intramolecular cyclization.

Mechanochemical synthesis of organoselenium compounds

We disclose herein a strategy for the rapid synthesis of versatile organoselenium compounds under mild conditions. In this work, magnesium-based selenium nucleophiles are formed in situ from easily available organic halides, magnesium metal, and elemental selenium via mechanical stimulation. This process occurs under liquid-assisted grinding (LAG) conditions, requires no complicated pre-activation procedures, and operates broadly across a diverse range of aryl, heteroaryl, and alkyl substrates. In this work, symmetrical diselenides are efficiently obtained after work-up in the air, while one-pot nucleophilic addition reactions with various electrophiles allow the comprehensive synthesis of unsymmetrical monoselenides with high functional group tolerance. Notably, the method is applied to regioselective selenylation reactions of diiodoarenes and polyaromatic aryl halides that are difficult to operate via solution approaches. Besides selenium, elemental sulfur and tellurium are also competent in this process, which showcases the potential of the methodology for the facile synthesis of organochalcogen compounds.

Acetamide Electrosynthesis from CO2 and Nitrite in Water.

Renewable electricity driven electrocatalytic CO2 reduction reaction (CO2 RR) is a promising solution to carbon neutralization, which mainly generate simple carbon products. It is of great importance to produce more valuable C-N chemicals from CO2 and nitrogen species. However, it is challenging to co-reduce CO2 and NO3 - /NO2 - to generate aldoxime an important intermediate in the electrocatalytic C-N coupling process. Herein, we report the successful electrochemical conversion of CO2 and NO2 - to acetamide for the first time over copper catalysts under alkaline condition through a gas diffusion electrode. Operando spectroelectrochemical characterizations and DFT calculations, suggest acetaldehyde and hydroxylamine identified as key intermediates undergo a nucleophilic addition reaction to produce acetaldoxime, which is then dehydrated to acetonitrile and followed by hydrolysis to give acetamide under highly local alkaline environment and electric field. Moreover, the above mechanism was successfully extended to the formation of phenylacetamide. This study provides a new strategy to synthesize highly valued amides from CO2 and wastewater.

Acetamide Electrosynthesis from CO2 and Nitrite in Water

AbstractRenewable electricity driven electrocatalytic CO2 reduction reaction (CO2RR) is a promising solution to carbon neutralization, which mainly generate simple carbon products. It is of great importance to produce more valuable C−N chemicals from CO2 and nitrogen species. However, it is challenging to co‐reduce CO2 and NO3−/NO2− to generate aldoxime an important intermediate in the electrocatalytic C−N coupling process. Herein, we report the successful electrochemical conversion of CO2 and NO2− to acetamide for the first time over copper catalysts under alkaline condition through a gas diffusion electrode. Operando spectroelectrochemical characterizations and DFT calculations, suggest acetaldehyde and hydroxylamine identified as key intermediates undergo a nucleophilic addition reaction to produce acetaldoxime, which is then dehydrated to acetonitrile and followed by hydrolysis to give acetamide under highly local alkaline environment and electric field. Moreover, the above mechanism was successfully extended to the formation of phenylacetamide. This study provides a new strategy to synthesize highly valued amides from CO2 and wastewater.

Microwave-assisted synthesis of crosslinked ureido chitosan for hemostatic applications

In this study, we present a facile method for introducing hydrophilic ureido groups (NH2-CO-NH-) into chitosan using a microwave-assisted reaction with molten urea, with the aim of enhancing chitosan's interaction with blood components for improved hemostasis. The formation of the ureido groups through nucleophilic addition reaction between the amine groups in chitosan and in situ generated isocyanic acid was confirmed by FTIR, CP/TOSS 13C NMR, and CP/MAS 15N NMR spectroscopic techniques. However, in stark contrast to the glucans, the said modification introduced extensive crosslinking in chitosan. Spectroscopic studies identified these crosslinks as carbamate bridges (-NH-COO-), which were likely formed by the reaction between the ureido groups and hydroxyl groups of adjacent chains through an isocyanate intermediate. These carbamate bridges improved ureido chitosan's environmental stability, making it particularly resistant to changes in pH and temperature. In comparison to chitosan, the crosslinked ureido chitosan synthesized here exhibited good biocompatibility and cell adhesion, rapidly arrested the bleeding in a punctured artery with minimal hemolysis, and induced early activation and aggregation of platelets. These properties render it an invaluable material for applications in hemostasis, particularly in scenarios that necessitate stability against pH variations and degradation.