Addition-elimination Reaction Research Articles

Visible-Light Induced Radical Addition-Elimination Reaction for Constructing Allylic Sulfones from Sulfonyl Chlorides and Allyl Bromides.

Allyl sulfones are commonly present in bioactive compounds and organic building blocks. This work introduces a photocatalytic radical addition-elimination reaction involving readily accessible sulfonyl chlorides and allyl bromides. It delivers structurally diverse allylic sulfones in moderate to excellent yields, showcasing a high tolerance to functional groups. Notably, this method operates under mild reaction conditions without the need for oxidants, stoichiometric reducing metals, or additives.

Covalent organic polymers based on special dithioureas for efficient removal of Hg2+ from aqueous solutions

The damage caused by mercury ions (Hg2+) to human beings motivates the development of highly efficient technologies for the removal of Hg2+ from water. Here, based on the coordination theory between functional groups and Hg2+, two covalent organic polymers (COPs) materials were successfully prepared by a more environmentally friendly Michael addition elimination reaction, and the thiourea structure, which has a particularly strong affinity for Hg2+, was successfully introduced into the material framework. The introduction of the special dithiourea structure created a rich environment of S and N atoms within the COPs structure, which exhibited high adsorption performance for Hg2+. Adsorption experiments showed that the dithiourea-functionalized COPs exhibited high adsorption capacities for Hg2+, with the maximum adsorption capacities of 840.9 and 880 mg g−1 for the two materials, respectively. The adsorption performance remained relatively good after four adsorption-desorption cycles, and the adsorption selectivity for Hg2+ was intense. Mechanistic studies by X-ray photoelectron spectroscopy and density flooding theory calculations suggest that it is the S atoms within the structure that chelate with the Hg2+ and contribute to the adsorption capacity of the Hg2+. Therefore, this study provides a new strategy for the development of COP adsorbents for efficient removal of Hg2+ in aqueous solutions during remediation activities.

2,3-Dichloronaphthoquinone derivatives: Synthesis, antimicrobial activity, molecular modelling and ADMET studies

In the present study, an intermediate namely 2-(3-bromopropylamino)-3-chloronaphthalene-1,4-dione was initially synthesized via the nucleophilic addition–elimination reaction between 2,3-dichloro-1,4-naphthoquinone and 3-bromo-1-aminopropane. Then a coupling reaction between the intermediate and piperazine derivatives yielded a number of 1,4-naphthoquinone derivatives. Spectroscopic analysis successfully characterized the products that were obtained in good yields. In vitro antibacterial properties of the compounds were examined against different bacterial strains. In vitro antibacterial properties of the compounds were examined against the bacterial strains S. Aureus, E. Faecalis, E. Coli and P. Aeruginosa. While compound 9 was found to be effective against all bacterial strains used, compound 12 was active against three strains and compounds 10 and 11 were effective against the two. None of the compounds are effective against C. albicans strain. In silico molecular docking studies revealed that all compounds had docking scores comparable to the antibacterial drugs ciprofloxacin and gentamicin and might be considered as DNA gyrase B inhibitors. Molecular dynamics simulations were also conducted for a better understanding of the stability and the selected docked complexes. Additionally, the drug similarity of the synthesized compounds and ADMET characteristics were examined in conjunction with the antibiotic ciprofloxacin, and drug potentials were then evaluated. Compatible predictions were found with the drug similarity and ADMET parameters.

Construction of Diverse Pyrrolidine-Based Skeletons through the Ag-Catalyzed Stereoselective Addition-Elimination Reaction of Azomethine Ylides with Nitroallyl Acetates.

Because scaffold diversity has a pronounced impact on biological screening, the efficient and expedient construction of skeletally diverse compound collections is a fundamental demand in drug discovery. In this regard, we report here an asymmetric tandem conjugate addition-elimination reaction of pyrroline esters with nitroallyl acetates and its application to the construction of various types of fused or spirocyclic pyrrolidines. A AgOAc/(R,Sp)-ThioClickFerrophos (TCF) catalyst efficiently promotes the addition-elimination reaction, setting vicinal chiral stereocenters featuring a tetrasubstituted carbon with excellent enantio- and diastereoselectivity while leaving the versatile nitroolefin moiety. The broad substrate scope of this reaction and the transformability of the resulting nitroolefin, imine, and ester moieties allow for the construction of diverse pyrrolidine-based fused or spiro bicyclic skeletons in optically active forms by various intramolecular cyclization processes.

Adventures in CH-Arylation Chemistry

AbstractThe present article provides a personalized account on CH-arylation reactions employed for the synthesis of heterocycles. The presence of a nitro group allowed for direct and regioselective CH-arylations of pyrazoles, imidazoles, indoles and a variety of purine analogues. Direct CH-arylations without the presence of an activating nitro-group were employed for inter- and intramolecular reactions of purine derivatives, which allowed for the synthesis of a great variety of polycyclic systems. Domino C–N coupling / hydroamination / CH-activation reactions of diarylacetylenes with anilines allowed for the synthesis of polycondensated N-heterocycles. Products include indolo- and azaindolo[1,2-f]phenanthridines, quinolino[3′,4′:4,5]pyrrolo[1,2-f]phenanthridines, pyrimido[5′,4′:4,5]pyrrolo[1,2-f]phenanthridines, and benzothieno[2′,3′:4,5]pyrrolo[1,2-f]phenanthridines. The reaction of N-heterocycles, such as indoles, with 1,1-difluoroalkenes resulted in a twofold addition-elimination reaction to give 1,1-diaminoalkenes, which were transformed by CH-arylation into various polycondensated heterocycles, such as indoloisoquinolines, thienoindolizines, oxepines and helicenes. Pyridofluoranthenes, diindenopyrene and azadiindenopyrenes were prepared by a combination of Pd-catalyzed cross-coupling reactions with acid-mediated cycloisomerizations and Pd-catalyzed intramolecular CH-arylations. Bis(carbazoles), benzodithiazoles, benzodithiophenes and 2,5-diarylpyrroles were prepared by inter- and intramolecular CH-arylation reactions.

Base catalyzed one-pot thia-Michael addition-oxidation reaction of hetero-aromatic thiols to 2-aryl-3-nitro-2H-chromenes and their antibacterial evaluation

A thia-Michael addition reaction was developed for the synthesis of heteroaromatic thiol-based 2H-chromenes and the antibacterial activity was studied against two pathogenic bacterial strains, E. coli, and S. aureus.

Addition-elimination reactions of 2,2-disubstituted malononitriles and α-aryl nitriles. Subsequent transformations.

Addition-elimination reactions of 2,2-disubstituted malononitriles and α-aryl nitriles. Subsequent transformations.

Density functional theory investigation of mechanisms of degradation reactions of sulfonated PEEK membranes with OH radicals in fuel cells: addition–elimination reactions and acid catalyzed water elimination

Sulfonated polyether (ether) ketone or sulfonated PEEK (sPEEK) membranes are one possible candidate for proton-transfer membranes in hydrogen fuel cells. Reaction with hydroxy radicals is expected to be a significant source of degradation of these membranes during fuel cell operation. In this work, the reactivity of the sPEEK polymer molecule with OH radicals is studied by M062X hybrid density functional calculations of the energetics of several reaction paths in a water environment as modeled by polarized continuum model calculations. Reactants, products, encounter minima and transition states are optimized for a reaction pathway in which OH addition is followed by acid-catalyzed water elimination which cationizes the polymer, degradation is expected to follow this reaction as the unstable cation then undergoes bond-breaking or other reactions. Two pathways for this acid-catalyzed cationization, one in which a water molecule plays the role of an additional co-catalyst, are reported. Further calculations explore reaction pathways in which addition of OH to the polymer is followed by bond breaking reactions which would break the polymer chain or the bond between the polymer and sulfonyl groups. Examination of the free energy barriers to all these reactions, relative to reactants, suggests that these direct bond-breaking reactions may compete somewhat with acid-catalyzed water elimination following OH addition.

Ultrasound-Assisted Efficient Synthesis of Azomethine Derivatives of 1-Phenylimidazo[1,5-a]Pyridine

In the present research work, ultrasound-assisted synthesis of a series of novel azomethine derivatives of 1-phenylimidazo[1,5-a]pyridine has been achieved. The synthetic route involves the conversion of ethyl-1-phenylimidazo-[1,5-a]pyridine-3-carboxylate to 1-phenylimidazo[1,5-a]pyridine-3-carbohydrazide followed by nucleophilic addition-elimination reaction with diverse aromatic aldehydes. The developed clean and simple protocol offers a set of advantages such as mild reaction conditions, environment friendliness, and high atom economy apart from excellent yields (70–92%). All compounds were found to be stable in atmospheric conditions for a long period of time and were soluble in polar solvents.

An unexplored representative of gem-difluoroalkenes`, 1,1,4,4,4-Pentafluorobut-1-ene CF3[sbnd]CH2[sbnd]CH[dbnd]CF2 (HFO-1345czf): Reactivity and functionalization possibilities

A new, simple one-pot synthesis of 1,1,4,4,4-pentafluorobut-1-ene CF3CH2CHCF2 (HFO-1345czf) (1) was developed. Reactivity of 1 was evaluated in copper(I)-catalyzed defluoroborylation with the following Suzuki-Miyaura cross-coupling of boryl(monofluoro)alkene and addition-elimination reactions with nucleophiles and electrophiles. Features of the chemical behavior of 1 are discussed.

Mercapto-pyrimidines are reversible covalent inhibitors of the papain-like protease (PLpro) and inhibit SARS-CoV-2 (SCoV-2) replication.

The papain-like protease (PLpro) plays a critical role in SARS-CoV-2 (SCoV-2) pathogenesis and is essential for viral replication and for allowing the virus to evade the host immune response. Inhibitors of PLpro have great therapeutic potential, however, developing them has been challenging due to PLpro's restricted substrate binding pocket. In this report, we screened a 115 000-compound library for PLpro inhibitors and identified a new pharmacophore, based on a mercapto-pyrimidine fragment that is a reversible covalent inhibitor (RCI) of PLpro and inhibits viral replication in cells. Compound 5 had an IC50 of 5.1 μM for PLpro inhibition and hit optimization yielded a derivative with increased potency (IC50 0.85 μM, 6-fold higher). Activity based profiling of compound 5 demonstrated that it reacts with PLpro cysteines. We show here that compound 5 represents a new class of RCIs, which undergo an addition elimination reaction with cysteines in their target proteins. We further show that their reversibility is catalyzed by exogenous thiols and is dependent on the size of the incoming thiol. In contrast, traditional RCIs are all based upon the Michael addition reaction mechanism and their reversibility is base-catalyzed. We identify a new class of RCIs that introduces a more reactive warhead with a pronounced selectivity profile based on thiol ligand size. This could allow the expansion of RCI modality use towards a larger group of proteins important for human disease.

Cationic 31-pyridylation of a chlorophyll-a derivative using Barluenga reagents

The 3-vinyl group in methyl pyropheophorbide-a was transformed into the cationic 1-pyridinioethenyl group by the action of a commercially available Barluenga reagent, bis(pyridine)iodonium(I) tetrafluoroborate, via the dehydroiodation of the 1-pyridinio-2-iodoethenyl adduct. Similar addition–elimination reactions with synthetic Barluenga reagent analogs possessing p-methyl, methoxy, and amino groups on the pyridine ligand afforded the 31-(p-substituted pyridinio) counterparts. Using another Barluenga reagent analog comprised of sterically demanded 2,4,6-collidine, the above chlorophyll-a derivative was reacted with p-(un)substituted pyridines to give the corresponding 31-pyridinio substitutes.

Synthesis of CF3-Substituted Alkylamines, 1,2-Bisazoles, and 1,4,5,6-Tetrahydro-1,2,4-triazines from Newly Designed Tetrazole-Activated Trifluoromethyl Alkenes

A new class of Michael acceptor, tetrazolyl-trifluoromethyl alkenes, has been discovered. They readily undergo Michael-type addition instead of addition-elimination reaction with aliphatic amines and azoles to furnish β-trifluoromethyl alkylamines and CF3-substituted 1,2-bisazole derivatives, respectively. Additionally, some of the products are capable of engaging in microwave-assisted intramolecular denitrogenative annulation, leading to the formation of CF3-substituted 1,4,5,6-tetrahydro-1,2,4-triazines that are otherwise difficult to access by other methodologies.

Discovery of N-methylbenzo[d]oxazol-2-amine as new anthelmintic agent through scalable protocol for the synthesis of N-alkylbenzo[d]oxazol-2-amine and N-alkylbenzo[d]thiazol-2-amine derivatives

We discovered a lead compound, N-methylbenzo[d]oxazol-2-amine (2a), which had comparable potency to albendazole, an orally administered anthelminticdrug, against Gnathostoma spinigerum, Caenorhabditis elegans and Trichinella spiralis. Compound 2a showed about 10 times lower cytotoxicity towards normal human cell line (HEK293) than albendazole. Moreover, we have developed new processes for the synthesis of N-alkylbenzo[d]oxazol-2-amine and N-alkylbenzo[d]thiazol-2-amine derivatives via metal-free conditions. This protocol could serve as a robust and scalable method, especially, to synthesize N-methylbenzo[d]oxazol-2-amine and N-methylbenzo[d]thiazol-2-amine derivatives which were difficult to prepare using other metal-free conditions. The method employed benzoxazole-2-thiol or benzothiazole-2-thiol as the substrate. The reaction was triggered by methylation of the thiol functional group to form the methyl sulfide intermediate, a crucial tactic, which facilitated in a smooth nucleophilic addition–elimination reaction with gaseous methylamine generated in situ from N-methylformamide. In addition, the proteomic analysis of compound 2a was also studied in this work.

Kinetics of Ring Closure Thiazole Cyclization Using 3-Chloroacetylacetone with Thioamides

Background: Thiazoles are an important heterocycle which exhibits various bioactivities. Thiazole ring is found in core structure of various medicinally useful compounds. It shows biological activities like anti-inflammatory, antibacterial, antifungal, antioxidant, cytotoxicity, anticonvulsant, insecticidal, anticancer and antitumor. Thioamides are reported to show bioactivities like antibacterial, antileukemia, antifungal, anti-arthritic, antimalarial and cytotoxic. Hantzsch synthesis is one of the most efficient reactions for thiazole formation which is a cyclization reaction between thioamides and α-halo carbonyl compounds. A very few reports on kinetic investigation of thiazole formation are available. Previously we have studied thiazole formation using 3-chloroacetylacetone and substituted thioureas by pH metric study. The reaction between 3-chloroacetylacetone and Thioamides is not reported yet. The present work deals with kinetics and mechanistic study of ring closure of thiazole using thioamides and 3-chloroacetylacetone. The reaction has been carried out in water-ethanol system at 303K. The kinetic investigations are carried out pH metrically. Nature of reaction is explained on the basis of thermodynamic parameters. Reaction products are isolated and characterized on the basis of spectral data. The effect of temperature on reaction rate is studied at 30°C to 50°C. Thermodynamic parameters are evaluated. Objective/s: To determine the order of reaction. • To determine the rate of reaction. • To evaluate the rate of reaction at various temperatures. • To determine the rate of reaction in different media. • To study the effect of dielectric constant, ionic strength etc. • To observe calculation of energy of activation, enthalpy of activation, entropy of activation and free energy of activation. • To propose reaction mechanism considering various thermodynamic parameters. Method: Measuring the change in pH, the concentration of H+ ion will be determined and accordingly rate of reaction will be calculated. Result: Van’t Hoff’s differential method and the stoichiometric study suggested that one mole of Thioamides reacts with one mole of 3-chloroacetylacetone. The rates of reaction are measured at different concentration of Thioamides at constant concentration of 3-chloroacetylacetone. The plot of log (dc / dt) against log [3-chloroacetylacetone] and log [ Thioamides] is also straight line and slope of the plot is nearly one with respect to both. At five different temperatures second order rate constants are determined. The energy of activation (Ea) is determined by plotting graph of logk versus 1/T and other thermodynamic parameters are calculated. The negative entropy of activation (∆S*) of this reaction specifies rigid nature of the transition state. The entropy of activation (∆S*) is negative value and it specifies that less stable noncyclic reactants convert into stable cyclic product. Free energy of activation (∆G*) is calculated [Table 1], Graph 1. Reacting species are oppositely charged according to salt effect [Graph 2]. In water-isopropyl alcohol system reaction is fast than water-ethanol system [Graph 3]. Conclusion: • Using Van’t Hoff’s differential method the rate of reaction between 3-chloroacetylacetone and Thioamides is found to be one with respect to both components. • The proposed rate law also shows that the order of reaction is two. • Negative entropy (∆S*) shows that from open chain compound cyclic compound is formed. Nucleophilic addition and addition–elimination reaction take place. • Oppositely charge species are present in reaction. • Rate increases with increase in dielectric constant. Isopropyl alcohol-water system shows high-rate constant as compared to Ethanol-water system.

Molecular beam mass spectrometry study on plasma-assisted low-temperature oxidation of ethylene

The chemical kinetics of plasma-assisted low-temperature oxidation of ethylene (C2H4) is explored by molecular beam mass spectrometry and kinetic modeling. In the experiments, a dielectric barrier discharge (DBD) flow reactor coupled with photoionization and electron ionization molecular beam mass spectrometry (PI-MBMS/EI-MBMS) is employed to provide detailed speciation information, including ions, radicals, and molecules in C2H4/O2/Ar systems (∼340 K, 30 Torr). A series of hydrocarbons and oxygenated intermediates including ethenol, methyl hydroperoxide, ethyl hydroperoxide, diacetylene, vinylacetylene, and hydroxyacetaldehyde is detected for the first time in this system. A kinetic mechanism that contains both combustion and plasma reaction networks is developed. The path fluxes of fuel consumption and oxygenates formation are obtained based on the rate of production analysis. Based on our experimental observations and modeling analysis, new insights into the kinetics of C2H4/O2/Ar plasmas are provided. The fuel is mainly consumed through OH addition, dissociation after e/Ar* collision, reactions with O/O(1D), and dissociative ionization. H abstraction reactions that are favored in alkane plasmas contribute little to the fuel consumption of ethylene. Formation pathways of C1 oxygenates are mainly initiated by CH3 produced by O/O(1D) reactions with fuel, and the subsequent pathways of OH/H addition to the fuel are responsible for the formation of most C2 oxygenates. Oxygen addition-elimination reactions of C2H4OH isomers are the sources of ethenol formation. The concentration profiles for some of the species under different oxygen mole fractions are measured. The two distinct patterns of species mole fraction profiles with increasing oxygen concentrations indicate the different dominating formation pathways, namely oxidation pathways and non-oxidation pathways. And the competition between oxidation effects and plasma effects is displayed by the non-monotonic mole fractions profiles of oxidation products.

A functional-group-based approach to modeling real-fuel combustion chemistry – III: Application to biodiesels

Real biodiesel fuels are mixtures comprising many high molecular weight components, making it a challenge to predict their combustion chemistry with detailed kinetic models. Our group previously proposed a functional-group approach (FGMech) to model the combustion chemistry of real gasoline and jet fuels; this approach has now been extended to model real biodiesel combustion and mixtures with petroleum fuels. As in our previous work, a decoupling philosophy is adopted for construction of the model. A lumped reaction mechanism describes the (oxidative) pyrolysis of fuels, while a detailed base chemistry model represents the oxidation of key pyrolysis intermediates. However, due to the presence of the ester group, several oxygenated species are identified as additional primary products and incorporated into the lumped reaction steps. In addition to the lumped reactions initiated by unimolecular decomposition and H-atom abstraction reactions, a lumped H-atom addition-elimination reaction is also incorporated as a new reaction class to account for the presence of double bonds. Stoichiometric parameters are obtained based on a multiple linear regression (MLR) model, which establishes relationships between the fuel's functional group distributions and the stoichiometric parameters of the lumped reactions. Global rate constants are developed from consistent rate rules obtained from pure fuels. New pyrolysis experimental data for methyl pentanoate/methyl nonanoate and methyl heptanoate/n-heptane mixtures (50%/50% in mol) are obtained in a jet-stirred reactor at atmospheric pressure. In general, kinetic models developed using the FGMech approach can reasonably reproduce all the validation targets obtained in this work, as well as those in the literature, confirming that functional-group-modeling is a promising approach to simulate combustion behavior of diesel/biodiesel surrogate fuels and real biodiesels.

Synthesis and Study of the Crystal Structure of 2-[(Dipyrrolidin-1-yl) methylene] malononitrile

This study aims to synthesis 2-[(dipyrrolidin-1-yl)methylene] malononitrile 2 and identify its crystal structure by X-ray diffraction analysis. 2-[(dipyrrolidin-1-yl)methylene] malononitrile was prepared by a direct displacement of the methylthio group (SMe) in the 2-[bis(methylthio)methylene] malononitrile 1 with pyrrolidine as cyclic secondary amine by conjugating addition-elimination reaction under reflux conditions for two hours. The compound was obtained in high yield (80%). The structure of compound 2-[(dipyrrolidin-1-yl)methylene] malononitrile2 was identified by performing X-ray diffraction analysis. Suitable crystals of compound 2 were grown by slow evaporation of methanol solution of the compound. The compound 2 crystallized in an orthorhombic crystal system with a space group of Pbcn. In the title compound, the two cyanide groups and the two pyrrolidine rings adopted trans configurations across the C2=C3 bond. The bond lengths and angles of the two pyrrolidinyl rings in the compound are within the normal range. The maximum deviation of N5/C2/C3/C4/N5a/C4a is 0.002(1) around C4, and no deviation has been recorded for the fragment N1/N1a/C2/C3 (0.000 (1)°). The dihedral angle between the pyrrolidine ring and N1/N1a/C2/C3 is 33.06(8)°, and the dihedral angle between the pyrrolidine ring and N5/C2/C3/C4/N5a/C4a is 50.57(7)°. The crystal packing is stabilized by two intermolecular and one intramolecular C---H…N hydrogen bonds, which form a one-dimensional polymeric chain along the axis.

Aqueous Chlorination of D-Limonene.

Limonene (1-methyl-4-(1-methylethenyl)-cyclohexene) is one of the most widespread monocyclic terpenes, being both a natural and industrial compound. It is widely present in the environment, including in water supplies. Therefore, it may be subjected to aqueous chlorination at water treatment stations during drinking water preparation. Besides, being a component of numerous body care and cosmetic products, it may present at high levels in swimming pool waters and could also be subjected to aqueous chlorination. Laboratory experiments with aqueous chlorination of D-limonene demonstrated the prevalence of the conjugated electrophilic addition of HOCl molecule to the double bonds of the parent molecule as the primary reaction. The reaction obeys the Markovnikov rule, as the levels of the corresponding products were higher than those of the alternative ones. Fragmentation pattern in conditions of electron ionization enabled the assigning of the structures for four primary products. The major products of the chlorination are formed by the addition of two HOCl molecules to limonene. The reactions of electrophilic addition are usually accompanied by the reactions of elimination. Thus, the loss of water molecules from the products of various generations results in the reproduction of the double bond, which immediately reacts further. Thus, a cascade of addition-elimination reactions brings the most various isomeric polychlorinated species. At a ratio of limonene/active chlorine higher than 1:10, the final products of aqueous chlorination (haloforms) start forming, while brominated haloforms represent a notable portion of these products due to the presence of bromine impurities in the used NaOCl. It is worth mentioning that the bulk products of aqueous chlorination are less toxic in the bioluminescence test on V. fischeri than the parent limonene.

Design, synthesis, and evaluation of new vanin-1 inhibitors based on RR6

Fourteen novel vanin-1 inhibitors coded OMP-# were designed from RR6 and successfully synthesized by a nucleophilic addition–elimination reaction of the pantetheinic acid-derived Weinreb amide as a key step under Barbier conditions. The synthesized OMP compounds exhibited inhibitory activity against human serum vanin-1 in vitro. Among the synthesized compounds, OMP-7, which possesses a trifluoromethoxy group at the para-position on the phenyl ring, exhibited the most potent activity, approximately 20 times that of the mother compound RR6. OMP-7 was further subjected to an in vivo assay using a normal hamster. More potent activity was observed than that of RR6 against both serum and renal vanin-1. The activity lasted for 4 h after injection against serum vanin-1 and 1 h after injection against renal vanin-1, whereas RR6 did not show the desired activity.