Nature Of Nucleophile Research Articles

Conjugate Additions of Organolithiums to Electron-poor Olefins: A Simple and Useful Approach to the Synthesis of Complex Molecules

Conjugate addition reactions of organometallic compounds to electron-poor olefins is a versatile synthetic methodology for the formation of new carbon–carbon bonds. However, a careful control of the regioselectivity of the process is needed because of the presence of two electrophilic sites in the activated olefin. This issue is often overcome by employing "soft" nucleophiles such as organocopper and organozinc reagents, because of their high selectivity towards the 1,4-addition. In contrast, organolithium compounds, which are "hard" nucleophiles, generally give access to 1,2-adducts, 1,4-conjugate addition being sometimes observed according to the nature of nucleophiles and/or electrophiles, or to the presence of additives. In this Minireview, we have described some peculiar examples to get an outline of the recent acquisitions in the field of the conjugate additions of functionalized organolithiums to electron-poor olefins. Particular attention is paid to the synthesis of complex structures starting from simple substrates by means of cascade reactions promoted by conjugate addition reactions with organolithiums. Keywords: Organolithiums, conjugate addition, alkenes, heterocycles, stereoselectivity, cascade reactions.

Redox-based chemiluminescence assay of aminothiols in human urine: A fundamental study

The biological importance of aminothiols is well recognized with the concentration of these compounds within biological fluids such as plasma and urine functioning as valuable biomarkers in a number of clinical circumstances and a wide variety of diseases. Herein, for the first time, chromatographic coupled chemiluminescent assay was used for simultaneous determination of aminothiols in human urine. The method exploits nucleophilic nature of aminothiols to form adducts in the existence of quinones. The released adducts retain the redox-cycling capability of parent quinones and able to liberate reactive oxygen species (ROS) when come in contact with dithiothreitol (DTT). Strong glow is released upon reaction of ROS with luminol. The method succeeded to determine aminothiols in human urine after solid phase extraction achieving good linearity and high sensitivity shown by low limit of detection (LOD) ranged from 3.8 to 16 (fmol per injection).

Revealing a nucleophilic addition reaction between aza-BODIPY and cyanide anion

In this work, a new nucleophilic addition reaction between the aza-BODIPY construct and cyanide anion is investigated and confirmed. Interestingly, CN− is verified to attack one of the pyrrole rings on the boron-dipyrromethene construct, which is different from the present CN− detection systems. The reaction mechanism is proposed based on NMR results and the photophysical spectra changes. In addition, when the electron-rich substituents are introduced to the aza-BODIPY structure, the reaction with CN− will become slow, thus confirming the nucleophilic addition reaction nature. More importantly, the mass spectra and single crystal structure of the aza-BODIPY-CN adduct could well support the proposed reaction mechanism. The reaction between CN− and aza-BODIPY is very fast (in 5min at room temperature) and results in significant absorption and emission changes of the aza-BODIPY compound. This work, as far as we know, is the first attempt to systematically reveal the reaction between CN− and the aza-BODIPY compound.

ChemInform Abstract: Ring‐Opening Reactions of Oxetanes: A Review of Methodology Development and Synthetic Applications

AbstractReview: 53 refs.

Theoretical investigation of loratadine reactivity in order to understand its degradation properties: DFT and MD study.

Antihistamines are frequently used pharmaceuticals that treat the symptoms of allergic reactions. Loratadine (LOR) is an active component of the second generation of selective antihistaminic pharmaceutical usually known as Claritin. Frequent usage of this type of pharmaceuticals imposes the need for understanding their fundamental reactive properties. In this study we have theoretically investigated reactive properties of LOR using both density functional theory (DFT) calculations and molecular dynamics (MD) simulations. DFT study is used for collecting information related to the molecule stability, structure, frontier molecular orbitals, quantum molecular descriptors, charge distribution, molecular electrostatic potential surfaces, charge polarization, and local reactivity properties according to average local ionization energy surfaces. Based on these results, N24 atom of pyridine ring and oxygen atom O1 were identified with nucleophilic nature. In order to collect the information necessary for the proposition of degradation compounds we also calculated bond dissociation energies (BDE) for hydrogen abstraction and single acyclic bonds as well. According to BDE, the oxidation is likely to occur in the piperidine and cycloheptane rings. MD simulations were used in order to understand the interactions with water through radial distribution functions (RDF). Based on RDFs the most important interactions with solvent are determined for carbon atom C5, chlorine atom Cl15, and oxygen atom O1. Collected results based on DFT calculations and MD simulations provided information important for suggestion of possible degradation compounds. Covalent and noncovalent interactions between LOR and (•)OH have also been investigated.

Synthesis and some chemical characteristics of 4″-nitro-3,3′:4′,3″-ter-1,2,5-oxadiazol-4-amine

A convenient preparation method was developed for 4″-nitro-3,3′:4′,3″-ter-1,2,5-oxadiazol-4-amine by substituting one nitro group of 4,4″-dinitro-3,3′:4′,3″-ter-1,2,5-oxadiazole at treating with equivalent quantity of ammonia in solvents of low polarity. In the reaction of the obtained amino-nitro derivative with N- and О- nucleophiles depending on the reaction conditions and the nucleophile nature either substitution of the nitro group occurs for the nucleophile residue to form 4″-alkoxy-, azido-, hydraznyl- or mono- and dialkylamino-[3,3′;4′,3″]-ter(1,2,5-oxadiazol)-4-ylamines, or the compound suffers an intramolecular cyclization affording 7Н-tri-1,2,5-oxadiazolo[3,4-b:3′,4′-d:3″,4″-f]azepines.

Dehydrogenative Allylic Aminations of But-3-enoic Acid Derivatives

Two complementary Pd-catalyzed protocols enabling the γ-selective intermolecular allylic amination of but-3-enoic acid derivatives are reported. These transformations can be successfully achieved via either­ a direct Pd(II)-catalyzed protocol or by way of a one-pot Pd(II)/Pd(0)-catalyzed sequence, depending on the nature of the nitrogen nucleophile used.

5,6-dihydro-[1,2,4]triazolo[1,5-с]quinazolines. Message 3. Synthesis of 2-aryl-5-trichloromethyl-5,6-dihydro[1,2,4]triazolo[1,5-с]quinazolines and their reactivity towards n-nucleophiles

Features of 5-trichloromethyl-2-aryl-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolines formation as result of [5+1]-cyclocondensation of the corresponding [2-(3-aryl-1H-1,2,4-triazole-5-yl)phenyl]amines with chloral hydrate are described in the article. It has been shown that this transformation is regioselective, occurs by refluxing of the initial compounds in acetic acid with formation of 2-aryl-5-trichloromethyl-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolines. The possible mechanism of 5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolines has been proposed and substantiated. It has been shown that the reaction proceeds as step-by-step transformation that includes ANE and AN processes. The 2-phenyl-5-trichloromethyl-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazoline obtained was studied in reactions with N-nucleophiles. It has been found that regardless of the nature of nucleophile the reaction mentioned above leads to formation of 2-phenyl5-(dichloromethyl)-[1,2,4]triazolo[1,5-c]qinazoline. The mechanism of the transformation mentioned above is given; it is β-elimination on the E1cb-mechanism followed by isomerisation. The structure of the compounds synthesized has been confirmed by the complex of physicochemical methods, including 1H-, 13C-NMR-spectrometry, chromato-massspectrometry, mass-spectrometry and X-ray structural study. A detailed analysis of 1H and 13C-NMR spectral data of the compounds synthesized has been conducted. It has been found that the signals of the carbon atom in position 5 at 79.25-77.95 ppm were characteristic for 2-aryl-5-trichloromethyl-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolines, whereas aromatization of the molecule leads to significant deshielding of this carbon atom (163.41 ppm). The prospects of further chemical modification of 2-aryl-5-(dichloromethyl)-[1,2,4]triazolo[1,5-c]quinazolines has been discussed.

Chemical Functionalization of N-Doped Graphene

Due to its unique physical and chemical properties, graphene is currently considered an ideal material for applications in electronic devices,[1] however, the lack of a band gap limits its application in the semiconducting field. Breaking the symmetry of graphene through the introduction of electron donor or acceptor heteroatoms into the graphene lattice has been proposed as a mean to controllably shift the electronic bands of graphene.[2] In this regard, nitrogen doping has been intensively studied, due to the facile doping process and the effective modulation of the electronic properties while maintaining high electrical conductivity. Because of the electron-rich nature of nitrogen, it leads to n-type electronic doping and the Fermi level is shifted above the Dirac point,[3] modifying the band gap in the material. Doped graphene could also be modified by specific reactions at the dopant heteroatom through different routes, depending on the nucleophilic or electrophilic nature of the dopant element.[4] In the particular case of graphene doped with nitrogen, N atoms could act as anchoring sites for N-alkylation reactions.[5]In this lecture we present recent advances carried out in our group, concerning the chemical modification of N-doped graphene with different electron donor and electron acceptor moieties, as well as the influence in the electronic properties of the starting material. [1] Z. Yang, J. Ren, Z. Zhang, X. Chen, G. Guan, L. Qiu, Y. Zhang and H. Peng, Chem. Rev., 2015, 115, 5159. [2] H. Wang, T. Maiyalagan and X. Wang, ACS Catal., 2012, 2, 781. [3] M. Wu, C. Cao and J. Jiang, Nanotechnology, 2010, 21, 505202. [4] S. Navalón, A. Dhakshinamoorthy, M. Álvaro and H. García, Chem. Rev., 2014, 114, 6179. [5] M. Barrejón, A. Primo, M. J. Gómez-Escalonilla, José Luis G. Fierro, H. García and F. Langa, Chem. Commun., 2015, 51, 16916.

Novel methodology for facile fabrication of nanofiltration membranes based on nucleophilic nature of polydopamine

Novel methodology for facilely fabricating nanofiltration (NF) composite membrane has been successfully developed by employing nucleophilic nature of polydopamine (PDA) chemistry. The self-polymerized PDA coating over polysulfone (PSf) substrate was utilized as a key intermediate layer for trimesoyl chloride (TMC) grafting followed by poly(ethyleneimine) (PEI) deposition to construct the hierarchically structured separation layer of NF membrane. In contrast to the electrophilic quinone moieties of PDA layer usually involved in the Michael addition and Schiff base reactions with polymeric amines for membrane preparation in previous reports, the phenolic hydroxyl groups of catechol moieties as well as amine groups at the PDA layer possess nucleophilic nature, which are capable of quickly coupling with the highly reactive acyl chlorides to form ester and amide bonds in the step of TMC grafting, resulting in TMC moieties covalently anchored at the PDA layer with free acyl chloride groups. Such created acyl chlorides are further coupled with the amine groups of branched PEI polymer in the PEI deposition procedure to form the stable amide bonds linking the PDA base layer and PEI upper layer in the resulting hierarchical separation layer. The properties of membranes prepared at different stages were characterized with respect to surface chemistry, pore properties, and separation performances to understand deeply the newly developed methodology for membrane preparation. Further studies focusing on NF properties and stability of the developed NF membrane revealed that such membrane shows high efficiencies in retention of divalent cations, small organic molecules as well as heavy metal ions, and exhibits desirable thermal stability and long-term performance stability.

Investigation of phosphate adsorption by a polyethersulfone-type affinity membrane using experimental and DFT methods

A fabricated polyethersulfone (PES)-type affinity membrane was employed for the removal of phosphate from the aqueous solution. Influences of pH, contact time, temperature, and initial phosphate concentration, as well as the coexistent Cl−, SO42-, Ca(II), and Mg(II) on the phosphate adsorption were evaluated. The adsorption kinetics and the adsorption isotherms of this membrane toward phosphate were investigated. In addition, the insight into the phosphate uptake at an atomic-scale was revealed by the density functional theory calculations. The coexistent Cl– and SO42- showed a disturbance on the uptake of phosphate; conversely, the presence of Ca(II) and Mg(II) increased the uptake of phosphate. The negative influence of SO42- was more remarkable than that of Cl– due to the notably nucleophilic nature of this anion. The accelerating role of Ca(II) was stronger than that of Mg(II), because the Ca(II)-loaded membrane exhibited a more stronger affinity to phosphate than the Mg(II)-loaded form. Lagergren second-order and Langmuir models were suitable for describing the adsorption kinetics and adsorption isotherms, and the phosphate adsorption onto the membrane was a spontaneous and endothermic process.

Electrochemical and Spin-Trapping Properties of para-substituted α-Phenyl-N-tert-butyl Nitrones

Nitrones are known both as therapeutic antioxidants and efficient spin-traps. In this work, the redox behavior of various para-substituted α-phenyl-N-tert-butyl nitrones (PBN) was studied by cyclic voltammetry. The polar effect of the substituents was found to correlate with the electrochemical properties of the nitronyl function. Compounds bearing an electron-withdrawing group were more easily reduced than those having an electron-donating group and an opposite trend was observed for the oxidation. Ease of oxidation was also computationally rationalized using DFT approach showing increased ease of oxidation with electron donating functionalities. Since electrochemical properties of nitrones are known to correlate with biological properties, this work provides insights in the design of potent nitrone antioxidants. Using cyclic voltammetry the relative rate of superoxide trapping by nitrones was investigated and compared to the classical antioxidant BHT. The determination of the relative rate of phenyl radical trapping was also carried out but showed no clear correlation with the nature of the substituents. This indicates the absence of a polar effect in agreement with previous data and further supports the intermediate nature, that is, non- or weakly nucleophile, of phenyl radical. On the contrary kinetics of hydroxymethyl radical trapping was found to correlate with the nature of the substituents, demonstrating the nucleophilic nature of its addition onto nitrones.

Synthetic Studies on Tricyclic Diterpenoids: Direct Allylic Amination Reaction of Isopimaric Acid Derivatives.

A selective synthesis of 7‐ or 14‐nitrogen containing tricyclic diterpenoids was completed according to a strategy in which the key step was the catalyzed direct allylic amination of methyl 14α‐hydroxy‐15,16‐dihydroisopimarate with a wide variety of nitrogenated nucleophiles. It was revealed that the selectivity of the reaction depends on the nature of nucleophile. The catalyzed reaction of the mentioned diterpenoid allylic alcohol with 3‐nitroaniline, 3‐(trifluoromethyl)aniline, and 4‐(trifluoromethyl)aniline yield the subsequent 7α‐, 7β‐ and 14αnitrogen‐containing diterpenoids. The reaction with 2‐nitroaniline, 4‐nitro‐2‐chloroaniline, 4‐methoxy‐2‐nitroaniline, phenylsulfamide, or tert‐butyl carbamate proceeds with the formation of 7α‐nitrogen‐substituted diterpenoids as the main products.

Kinetic Analysis of Haloacetonitrile Stability in Drinking Waters.

Haloacetonitriles (HANs) are an important class of drinking water disinfection byproducts (DBPs) that are reactive and can undergo considerable transformation on time scales relevant to system distribution (i.e., from a few hours to a week or more). The stability of seven mono-, di-, and trihaloacetonitriles was examined under a variety of conditions including different pH levels and disinfectant doses that are typical of drinking water distribution systems. Results indicated that hydroxide, hypochlorite, and their protonated forms could react with HANs via nucleophilic attack on the nitrile carbon, forming the corresponding haloacetamides (HAMs) and haloacetic acids (HAAs) as major reaction intermediates and end products. Other stable intermediate products, such as the N-chloro-haloacetamides (N-chloro-HAMs), may form during the course of HAN chlorination. A scheme of pathways for the HAN reactions was proposed, and the rate constants for individual reactions were estimated. Under slightly basic conditions, hydroxide and hypochlorite are primary reactants and their associated second-order reaction rate constants were estimated to be 6 to 9 orders of magnitude higher than those of their protonated conjugates (i.e., neutral water and hypochlorous acid), which are much weaker but more predominant nucleophiles at neutral and acidic pHs. Developed using the estimated reaction rate constants, the linear free energy relationships (LFERs) summarized the nucleophilic nature of HAN reactions and demonstrated an activating effect of the electron withdrawing halogens on nitrile reactivity, leading to decreasing HAN stability with increasing degree of halogenation of the substituents, while subsequent shift from chlorine to bromine atoms has a contrary stabilizing effect on HANs. The chemical kinetic model together with the reaction rate constants that were determined in this work can be used for quantitative predictions of HAN concentrations depending on pH and free chlorine contact times (CTs), which can be applied as an informative tool by drinking water treatment and system management engineers to better control these emerging nitrogenous DBPs, and can also be significant in making regulatory decisions.

Copolymers of acrylonitrile with quaternizable thiazole and triazole side-chain methacrylates as potent antimicrobial and hemocompatible systems

A series of six copolymeric families, P(AN-co-MTAs) with various molar fractions of acrylonitrile (fAN) and methacrylates (fMTA) based on 1,3-thiazole and 1,2,3-triazole pendant groups with several spacers of different length and nature (alkyl or succinic), have been synthesized by conventional radical polymerization. The molar fraction of acrylonitrile in the copolymers (FAN) was determined by CHNS elemental analysis. The copolymers were also characterized by ATR-FTIR and molecular weights were determined by size exclusion chromatography (SEC). Due to the nucleophilic nature of the azole heterocycles the copolymers have been easily modified by N-alkylation reaction with butyl iodide leading to polyelectrolytes of diverse amphiphilic balance, P(AN-co-MTAs-BuI). The degree of quaternization (DQ) was quantitative in all instances and was determined by 1H NMR spectroscopy. Dynamic light scattering (DLS) measurements were performed in order to determine the particle size and the charge density of the systems. The antimicrobial activity of the copolymers was studied in terms of minimal inhibitory concentration (MIC) against the Gram-positive bacteria Staphylococcus aureus, the Gram-negative Pseudomonas aeruginosa and the yeast Candida parapsilosis, as well as the cytotoxic activity toward human red blood cells (RBCs). These types of amphiphilic copolycations presented high selectivity (>300) maintaining moderate to good antimicrobial activity (MIC=4–64μg/mL) and being non-hemolytic even at high molar fractions of AN in the copolymers compared to PMTAs-BuI homopolymers. Moreover, two examples of acrylonitrile-enriched copolymers (FAN=0.6) presented an excellent time-killing efficiency against microorganisms with 99.9% of killing ranging from 5 to 30min. Besides, important changes in the morphology of the cell envelop of the microorganisms after treatment with P(AN-co-MTAs) were observed by Field Emission Scanning Electron Microscopy (FE-SEM) compared to untreated samples. These results indicate that these quaternized copolymers (QUATs) behave like the corresponding PMTAs-BuI homopolymers, being microbiostatic and also highly effective microbiocidal agents.

Dual Behavior of Bromine Atoms in Supramolecular Chemistry: The Crystal Structure and Magnetic Properties of Two Copper(II) Coordination Polymers

The crystal structures of two copper(II) chloride coordination polymers, (Cu2(2bp)2Cl4)n, henceforth “polydimer”, and (Cu3(2bp)2Cl6)n, henceforth “polytrimer”, where 2bp = 2-bromopyridine, and the temperature dependence of their magnetic susceptibilities are reported. Also, the temperature dependence of the magnetic susceptibility of the monomeric complex, Cu(2bp)2Cl2, is reported. The magnetic data were measured in the range 2–310 K. The organic bromine atom of the 2bp ligand shows electrophilic and nucleophilic character: an electrophilic nature via C–Br···Cl interactions and a nucleophilic nature via Cu···(π)Br interactions. The Cu···(π)Br interactions, previously underestimated in the literature, turn the 2bp ligand to a bidentate rather than monodentate ligand via the N–Cu coordination bond and the Cu···(π)Br noncovalent interactions. Thus, the 2bp ligand behaves as a molecular bender; the Cu···(π)Br interactions result in the bending of the (CuCl2)n infinite linear extended chains at specific locati...

Synthesis and biological evaluation of (acyl)hydrazones and thiosemicarbazones obtained via in situ condensation of iminium salts with nitrogen-containing nucleophiles.

An unprecedented, highly convergent, high-yielding, one-pot synthesis of (acyl)hydrazones and thiosemicarbazones was carried out by the in situ condensation of isolable iminium chlorides of imidazolidin-2-(thio)one, tetrahydropyrimidin-2-thione and indole derivatives with nitrogen nucleophiles in the presence of a base. The developed reaction procedure is largely advantageous. It is highly parallelizable, no intermediates need to be isolated and minimal sample handling is required during the purification steps. Some relevant reaction parameters including reaction temperature and p[Formula: see text] of the base are discussed. NMR analysis was carried out to assess the stereochemistry of the obtained compounds. The stereochemical outcome of the reaction was found to be affected by the nature of the nitrogen-containing nucleophile being the majority of the derivatives isolated as single geometric isomers. The cytotoxicity and antiviral activities of the prepared compounds have been preliminary assessed. In cell-based screenings some of the derivatives proved to be cytotoxic at low micromolar concentrations and interesting anti-Reo-1 properties have been detected.

Electrophilic alkylation of pseudotetrahedral nickel(II) arylthiolate complexes.

A kinetic study is reported for reactions of pseudotetrahedral nickel(II) arylthiolate complexes [(Tp(R,Me))Ni-SAr] (Tp(R,Me) = hydrotris{3-R-5-methyl-1-pyrazolyl}borate, R = Me, Ph, and Ar = C6H5, C6H4-4-Cl, C6H4-4-Me, C6H4-4-OMe, 2,4,6-Me3C6H2, 2,4,6-(i)Pr3C6H2) with organic electrophiles R'X (i.e., MeI, EtI, BzBr) in low-polarity organic solvents (toluene, THF, chloroform, dichloromethane, or 1,2-dichloroethane), yielding a pseudotetrahedral halide complex [(Tp(R,Me))Ni-X] (X = Cl, Br, I) and the corresponding organosulfide R'SAr. Competitive reactions with halogenated solvents and adventitious air were also examined. Akin to reactions of analogous and biomimetic zinc complexes, a pertinent mechanistic question is the nature of the reactive nucleophile, either an intact thiolate complex or a free arylthiolate resulting from a dissociative pre-equilibrium. The observed kinetics conformed to a second-order rate law, first order with respect to the complex and electrophile, and no intermediate complexes were observed. In the absence of a mechanistically diagnostic rate law, a variety of mechanistic probes were examined, including kinetic effects of varying the metal, solvent, electrophile, and temperature, as well as the 3-pyrazolyl and arylthiolate substituents. Compared to zinc analogues, the effect of Ni-SAr covalency is also of interest herein. The results are broadly interpreted with respect to the disparate mechanistic pathways.

A diruthenium μ-carbido complex that shows singlet-carbene-like reactivity.

Low-temperature deprotonation of the cationic μ-methylidyne complex [(Cp*Ru)2(μ-NPh)(μ-CH)][BF4] (Cp* = η(5)-C5Me5) with KN(SiMe3)2 affords a thermally unstable μ-carbido complex [(Cp*Ru)2(μ-NPh)(μ-C)] (2), as evidenced by trapping experiments with elemental S or Se and (13)C NMR spectroscopic observation. The reactivity of 2 toward CO2, Ph2S(+)CH2(-), EtOH, and an intramolecular C-H bond indicates that the μ-carbido carbon in 2 has an ambiphilic (nucleophilic and electrophilic) nature consistent with the formulation of 2 as the first example of a transition-metal-substituted singlet carbene. DFT study suggests that the Ru substituents in 2 are stronger σ-donor and weaker π-donor to the carbene center than amino substituents in N-heterocyclic carbenes.

Preparation and properties of 2-methyl-4-tosyl-1,3-thiazole-5-sulfonyl chloride

Chlorination of readily available 2-methyl-5-methylsulfanyl-4-tosyl-1,3-thiazole has afforded 2-methyl-4-tosyl-1,3-thiazole-5-sulfonyl chloride. The latter can react with amines to build sulfonamides, efficient electrophilic reagents capable of undergoing nucleophilic substitution reactions. Regiochemistry of the described reactions depends strongly on the nature of nucleophiles, used for regioselective synthesis of some previously unknown trisubstituted 1,3-thiazoles.