Nucleophilic Agents Research Articles

Design, Synthesis, and Structure–Activity Relationship of Novel Aniline Derivatives of Chlorothalonil

Chlorothalonil with both low cost and low toxicity is a popularly used fungicide in the agrochemical field. The presence of nucleophilic groups on this compound allows further chemical modifications to obtain novel chlorothalonil derivatives. Fluazinam, another commercially available agent with a broad fungicidal spectrum, has a scaffold of diaryl amine structure. To mimic this backbone structure, a variety of (un)substituted phenyl amines was used as nucleophilic agents to react with chlorothalonil to obtain compounds with a diphenyl amine structure. Via an elegant design, two leads, 2,4,5-trichloro-6-(2,4-dichlorophenylamino)isophthalonitrile (7) and 2,4,5-trichloro-6-(2,4,6-trichlorophenylamino)isophthalonitrile (11), with potential fungicidal activity were discovered after a preliminary bioassay screen. These two leads were further modified to obtain final products by replacing the chlorine groups in the phenyl ring in phenyl amine with other functional groups. These functional groups with various electronic properties and spatial characteristics were considered to explore the relationship between structure and fungicidal activity. The results indicate that the electron-withdrawing group NO2 on the 4 position on the right phenyl ring plays a unique role on enhancing the fungicidal activity. The compounds were identified by proton nuclear magnetic resonance and elemental analysis. Bioassays demonstrated that some of the title compounds exhibited excellent fungicidal activities against cucumber downy mildew at 25 mg/L. Compound 20 has been shown as the optimal structure with 85% control against cucumber downy mildew at 6.25 mg/L concentration. The relationship between structure and fungicidal activity is reported. The present work demonstrates that chlorothalonil derivatives can be used as possible lead compounds for developing novel fungicides.

Electrophilic ipso-substitution in uracil derivatives

Treatment of 5-iodo-1,3,6-trimethyluracil with 50% H2SO4 gives 1,3,6-trimethyluracil; with 5-bromo-1,3,6-trimethyluracil, a mixture of 1,3,6-trimethyluracil and 6-bromomethyl-1,3-dimethyluracil is obtained. 5-Chloro-1,3,6-trimethyluracil remains inert under these conditions. According to the DFT modeling of the reactions of 5-halo-1,3,6-trimethyluracils, a nucleophilic agent can abstract either Hal+ or the methyl proton from the carbocation formed by protonation of the starting halouracil at position 5, which accounts for the formation of two products from the 5-bromo derivative. Under similar conditions, 6-methyluracil dibromohydrin yields N-bromo-5-bromo-6-hydroxymethyluracil. Bromination or chlorination of 5-hydroxymethyl- or 5-formyl-6-methyluracils follows the ipso-substitution scheme leading to 6-methyluracil 5-halo- and 5,5-dihalohydrins.

ChemInform Abstract: A Ring Opening Reaction of 2‐Hetaryl‐2‐(tetrahydro‐2‐furanylidene)acetonitriles with Amino Acids.

The ring opening reactions of 2-hetaryl-2-(tetrahydro-2-furanylidene)acetonitriles with α-, β-, γ-, e-amino acids and alkyl esters of α-amino acids as N-nucleophiles have been investigated. New functionalized amino acid derivatives containing the heterocyclic moiety have been obtained and their reactions with electrophilic and nucleophilic agents have been studied.

Tetra-n-butylammonium Fluoride as an Efficient Transesterification Catalyst for Functionalizing Cyclic Carbonates and Aliphatic Polycarbonates.

We have developed a general method for the functionalization of cyclic carbonate monomers having a pentafluorophenyl ester substituent at the 5-position (MTC-OC6F5), as well as the postpolymerization modification of the subsequent polymer, poly(MTC-OC6F5), with alcohols. The transesterifications are achieved under mild conditions using catalytic tetra-n-butylammonium fluoride (TBAF) as the nucleophilic acyl transfer agent. As an organic-soluble form of fluoride, TBAF loadings as low as 5 mol % were sufficient in bringing about high conversions at room temperature. The mild reaction conditions preserved the integrity of the sensitive carbonate moieties even without the use of Schlenk techniques. In addition to commercial TBAF solutions, we also found solid-supported forms of TBAF to be effective for transesterification, thus enabling facile postreaction workup and purification. More importantly, with only minor adjustments to the reaction conditions, we show that TBAF also promotes the postpolymerization modification of poly(MTC-OC6F5), whereby fluoride-mediated transesterification with various alcohols proceeded quantitatively across the pendant pentafluorophenyl esters. Synthesizing a series of pendant ester-functionalized polycarbonates from a common precursor polymer was previously unattainable with existing methods, an issue that is now resolved by the current work.

Synthesis of β-fluoroenones and their reductive rearrangement in aqueous media

In this paper, a simple and efficient preparation of β-fluoroenones, as a mixture of E/Z isomers with the E-isomer as the main product, from 1,2-allenic ketones by using TBAF·3H2O in water as a nucleophilic fluorination agent has been developed. Moreover, in exploring the synthetic applications of β-fluoroenones, an unprecedented reductive defluorination rearrangement of β-fluoroenones toward enones under mild conditions in aqueous media was also discovered.

Effect of water on product yields of 2-azidobenzoic acid photolysis in aprotic solvents

The effect of water admixtures on the formation of 2-oxo-(3H)-azepine-3-carboxylic acid and 2,1-benzisoxazol-3(1H)-one in the photolysis of 2-azidobenzoic acid in aprotic solvents has been investigated. It has been shown that the addition of nucleophilic agents to the reaction mixture determines the yields of not only 3H-azepines, the products of benzene ring expansion, but also the intramolecular cyclization product 2,1-benzisoxazol-3(1H)-one. Participation of the formed 2,1-benzisoxazol-3(1H)-one in the reaction has been suggested as an explanation of the effect of nucleophilic compounds (water, ethanol, and 2,1-benzisoxazol-3(1H)-one) on the product yield of the monomolecular reaction.

Degradation of poly(ethylene terephthalate) waste with dimethyl tin distanoxane as a catalyst

ABSTRACTIn this article, we report the degradation of poly(ethylene terephthalate) (PET), which occurs through glycolysis in the presence of dimethyl tin distanoxane [(CH3)2Sn(OCOCH3)2] as a catalyst, triethylene glycol (TEG) as a nucleophilic agent, and decaline like a solvent. A number of experiments were executed, which were derived from a factorial experimental design, in which the reaction time was between 40 and 60 min, the amount of TEG was between 3.4 and 5.6 g, and the amount of catalyst was between 0.04 and 0.06% in ratio to PET. The reaction temperature was constant at 175°C in all of the experiments. Once the glycolytic depolymerization occurred, oligomers with a molecular weight around 6000 g/mol were obtained. These oligomers were analyzed through gel permeation chromatography, differential scanning calorimetry, Fourier transform infrared spectroscopy, and 1H‐NMR. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 3482–3488, 2013

The calixarene p-bromodienone route: from a chemical curiosity to an useful synthetic tool

This review gives an account on the development of the calixarene “p-bromodienone route” which include the beginning of the story, the tested and potential applications, and a mention to a different strictly related procedure. The development of this route is due to the serendipitous discovery of calixarene derivatives containing the 4-tert-butyl-4-bromo-2,5-cyclohexadienone moiety (shortly, the p-bromodienone moiety). These derivatives undergo a silver-mediated nucleophilic substitution and a subsequent rearomatization to give products in which a nucleophilic agent is directly linked to the para-position of a calixarene aromatic ring in a sort of “aromatic ring umpolung”. The nucleophiles so far tested are O-nucleophiles (alcohols, phenols, carboxylates) or C-nucleophiles (activated aromatic rings, acetylides) which has led to the corresponding p-substituted derivatives or to unusual m-substituted calixarenes through an intermediate dienone-phenol rearrangement. In this way, a range of additional chemical functionalities can be attached to the calixarene scaffold which include interalia alkyno, carboxy, peptido and glyco substituents. On the basis of literature data, it can be expected that several additional nucleophiles, including S-, N-, and P-nucleophiles, could be used in the calixarene p-bromodienone route thus expanding its scope.

A ring opening reaction of 2-hetaryl-2-(tetrahydro-2-furanylidene)acetonitriles with amino acids

The ring opening reactions of 2-hetaryl-2-(tetrahydro-2-furanylidene)acetonitriles with α-, β-, γ-, e-amino acids and alkyl esters of α-amino acids as N-nucleophiles have been investigated. New functionalized amino acid derivatives containing the heterocyclic moiety have been obtained and their reactions with electrophilic and nucleophilic agents have been studied.

Kinetics and Mechanism of the Alkaline Decomposition of Hexathionate Ion

The alkaline decomposition of hexathionate has been investigated by high-performance liquid chromatography monitoring the concentration of polythionates (such as hexathionate, pentathionate, and tetrathionate) and that of thiosulfate simultaneously in buffered medium at a constant ionic strength. As a major final product, unlike in the case of the alkaline decomposition of tetrathionate and pentathionate, a significant amount of sulfur deposition was also observed. Nevertheless, the chromatograms clearly suggested that heptathionate also appears as a key intermediate in a detectable amount during the course of the reaction. On the basis of these observations an 11-step kinetic model with 9 fitted and 4 fixed rate coefficients is suggested to take all of the most important characteristics of the decomposition into account. The proposed model includes the well-known thiosulfate-assisted sulfur chain, increasing pathways for tetrathionate and pentathionate along with their rate coefficients, but among them that of the thiosulfate-assisted rearrangement of pentathionate has not been reported yet. Having these kinetic parameters in hand reveals a reasonable trend of these rate coefficients against the length of the sulfur chain, suggesting that the attack of the nucleophilic agents like hydroxide, thiosulfate, and sulfite ions is determined by the electron density in the vicinity of the given sulfur atom.

Metabolic fate of combretastatin A-1: LC-DAD-MS/MS investigation and biological evaluation of its reactive metabolites

Combretastatin A-1, an antineoplastic agent characterized by a remarkable cytotoxicity and a strong antitubulinic activity, is currently under investigation in phase I clinical trials. Yet a comprehensive metabolic study of CA-1 in human and animal models has so far not been reported in the literature. We have therefore investigated, through LC–UV and LC–MS analysis the in vitro/in vivo metabolism of CA-1, have synthesized its reactive quinone metabolite Q1, and have evaluated its cytotoxic and antitubulinic activities. In vitro CA-1 metabolism was studied in rat and human liver microsomes in the presence of the nucleophilic trapping agent GSH were performed while urine samples of the CA-1-treated rats were analyzed to establish the in vivo metabolic pathways. The metabolite Q1, that was synthesized in good yield using a polymer supported oxidant, displayed a significant cytotoxicity but was devoid of significant antitubulinic activity. Finally the chemical interaction of Q1 and the other combretastatin quinone metabolites with sulphydryl groups of tubulin was measured by Ellman's method: the results suggested the haptenization of the tubulin through the formation of a covalent bond.

Benzyl alcohol-based synthesis of oxide nanoparticles: the perspective of SN1 reaction mechanism

In this paper, we describe a class of benzyl alcohol-based reactions for the synthesis of a series of inorganic oxide nanoparticles. Benzyl alcohol served as both the solvent and the reagent to interact with various metal chlorides for the synthesis of a series of metal oxides and compound oxides. Typical metal(IV) oxides, like TiO2, metal(III) oxides, like Fe2O3, and metal(II) oxides, like ZnO, with uniform size and special dispersibility, have been prepared through these reactions. The reaction can be illustrated from the perspective of S(N)1 reaction mechanism attributed to the easier formation of benzyl carbocation and unique reactivity of benzyloxy group with nucleophilic agents. By adjusting the experimental conditions, it was found that this type of reaction is available for the synthesis of many inorganic oxides.

Depolymerisation of condensed tannins in ethanol as a gateway to biosourced phenolic synthons

Plant polyphenols are potential sources of substitutes for phenolic petrochemicals, such as bisphenol A. Among them, condensed tannins are the most abundant after lignins in terrestrial plants. They are especially encountered in agro-industrial residues (i.e. fruit marc) and unprocessed biomass (i.e. barks, needles, and leaves). However, this class of biopolymers requires a depolymerisation step prior to their industrial use as fine chemicals. In this work, phenolic synthons were produced by depolymerisation of an industrial grape seed extract of condensed tannins at the multigram scale. The optimization of the depolymerisation reaction through the selection of the most suitable solvent, nucleophilic agent and temperature allowed the reaction to be carried out at mild temperature (40 °C), in two hours, using ethanol as a solvent. The isolation of compounds of interest was performed by precipitation in ethyl acetate followed by a simple adsorption/desorption step on a polyamide cartridge using ethanol as an eluent.

Poly(glycidyl methacrylate): a highly versatile polymeric building block for post-polymerization modifications

The treatment of poly(glycidyl methacrylate) with nucleophilic agents yielded new linear homo/co-polymers. The materials obtained have different physicochemical properties depending upon the nucleophiles utilized and thus, by this way, water soluble polymers are easily accessible. This approach is also very convenient for the synthesis of amphiphilic block copolymers. Additional chemical modifications can further transform the obtained polymers after the post-polymerization treatment. Starting from RAFT pre-synthesized/pre-functionalized polymers, the described procedures allow us to obtain a wide variety of chemically diverse materials characterized by controlled structure and specific functions.

Predicting the reaction mechanism of nucleophilic substitutions at carbonyl and thiocarbonyl centres of esters and thioesters

In nucleophilic substitution reactions at carbonyl centres, there are two possible channels. The first one occurs when the attack of nucleophilic agents takes place simultaneously with the departure of the nucleofuge. This process is named as concerted. The second possibility is the formation of a reaction intermediate, typically a tetrahedral intermediate from which the nucleofuge departs after passing through a second transition state. This second mechanism is defined as stepwise. Whether a concerted or stepwise mechanism is to be expected for a given reaction depends on several factors. Among these determinants are the nucleophilicity of the attacking group, the leaving group ability of the nucleofuge, and the solvent, which affects both the stability of the intermediate or the transition states involved. The role of the electrophilic centre can however become an important factor that can determine the reaction mechanism. In this work we show that the group nucleophilic Fukui function model may be used to rationalize and to predict the reaction mechanism of the title compounds towards alicyclic amines. In general, when the electrophilic carbon centre is attached to the soft sulfur atom, the reaction mechanism is predicted to follow a stepwise route. When the electrophilic carbon atom is attached to a harder oxygen centre, the reaction mechanism is determined by chemical substitution at the nucleofuge moiety. Experimental verification for a set of four substrates is presented. Copyright © 2012 John Wiley & Sons, Ltd.

Methylselenol formed by spontaneous methylation of selenide is a superior selenium substrate to the thioredoxin and glutaredoxin systems.

Naturally occurring selenium compounds like selenite and selenodiglutathione are metabolized to selenide in plants and animals. This highly reactive form of selenium can undergo methylation and form monomethylated and multimethylated species. These redox active selenium metabolites are of particular biological and pharmacological interest since they are potent inducers of apoptosis in cancer cells. The mammalian thioredoxin and glutaredoxin systems efficiently reduce selenite and selenodiglutathione to selenide. The reactions are non-stoichiometric aerobically due to redox cycling of selenide with oxygen and thiols. Using LDI-MS, we identified that the addition of S-adenosylmethionine (SAM) to the reactions formed methylselenol. This metabolite was a superior substrate to both the thioredoxin and glutaredoxin systems increasing the velocities of the nonstoichiometric redox cycles three-fold. In vitro cell experiments demonstrated that the presence of SAM increased the cytotoxicity of selenite and selenodiglutathione, which could neither be explained by altered selenium uptake nor impaired extra-cellular redox environment, previously shown to be highly important to selenite uptake and cytotoxicity. Our data suggest that selenide and SAM react spontaneously forming methylselenol, a highly nucleophilic and cytotoxic agent, with important physiological and pharmacological implications for the highly interesting anticancer effects of selenium.

Nucleophilic substitution reactions promoted by oligoethylene glycols: a mechanistic study of ion-pair SN2 processes facilitated by Lewis base

We present a mechanistic study for nucleophilic substitution (SN2) reactions facilitated by multifunctional n-oligoethylene glycols (n-oligoEGs) using alkali metal salts MX (M+ = Cs+, K+, X– = F–, Br–, I–, CN–) as nucleophilic agents. Density functional theory method is employed to elucidate the underlying mechanism of the SN2 reaction. We found that the nucleophiles react as ion pairs, whose metal cation is ‘coordinated’ by the oxygen atoms in oligoEGs acting as Lewis base to reduce the unfavorable electrostatic effects of M+ on X–. The two terminal hydroxyl (−OH) function as ‘anchors’ to collect the nucleophile and the substrate in an ideal configuration for the reaction. Calculated barriers of the reactions are in excellent agreement with all experimentally observed trends of SN2 yields obtained by using various metal cations, nucleophiles and oligoEGs. The reaction barriers are calculated to decrease from triEG to pentaEG, in agreement with the experimentally observed order of efficiency (triEG CN– > Br– > I–, elucidating the observation that the yield was lowest for F–. It is suggested that the role of oxygen atoms in the promoters is equivalent to that of –OH group in bulky alcohols (tert-butyl or amyl-alcohol) for SN2 fluorination reactions previously studied in our lab. Copyright © 2012 John Wiley & Sons, Ltd.

Characterization of ethanolysis products of poly(dimethylsiloxane) species by electrospray ionization tandem mass spectrometry

The partial and controlled degradation of insoluble cross-linked silicon-based polymers is a promising approach to enable their characterization by mass spectrometry. Providing that the chemolysis reaction specifically proceeds at cross-linking sites, the size of linear poly(dimethylsiloxane)s (PDMS) produced during the treatment should reflect the length of linear segments between branching points in the original network. In this context, the specificity of ethanol to act as a nucleophilic agent towards tri-functional silicon atoms in a D3TD(n)TD3 model was evaluated. Tandem mass spectrometry (MS/MS) combined with accurate mass measurements, MS(3) experiments and collision-induced dissociation of authentic compounds was used for structural characterization of D3TD(n)TD3 ethanolysis products. All MS/MS data were obtained from electrosprayed ammonium adducts, previously reported to provide the most informative data for silicon-based polymers. Since the expected ethanolysis products were hydroxy- and ethoxy-terminated PDMS, the dissociation behavior of such polymeric species was established, using electrosprayed ammonium adducts as the precursor ions. Diagnostic product ions were identified, allowing four main D3TD(n)TD3 ethanolysis products to be structurally characterized. End-group analysis of these polymeric distributions clearly indicated that ethanolysis was mostly occurring on tri-functional silicon atoms but also, to a lesser extent, on those D atoms close to T silicons. The size of the linear skeleton located between two tri-functional silicon atoms could be accurately determined by mass spectrometric analyses of a polymeric model submitted to ethanolysis. This soft and rapid pre-treatment is thus a promising approach for determining the length of linear segments between branching points in the original network of cross-linked silicon-based polymers.

Reactivity of a phosphonate layer grafted onto a surface of dispersed hydroxyapatite

The reactivity of a grafted layer contained on the surface of hydroxyapatite modified with diethyl butylphosphonate is studied. Modified hydroxyapatite is shown to interact with nucleophilic agents. The composition of reaction products depends on the nature of the latter.

Fluorimetric determination of amino acids and photochemical stability of their reaction products with ortho-phthalic aldehyde under irradiation by high-power pulsed laser

The opportunity of the highly sensitive determination of amino acids using the fluorescence of their derivatives that form in the reaction with aqueous solutions of ortho-phthalic aldehyde and nucleophilic agents, potassium cyanide, sodium sulfite, and N-acetyl-L-cysteine was studied as an example. The chemical stability of forming fluorescent compounds (substituted isoindoles) and their photochemical stability under the action of power pulsed laser radiation is higher, and the analytic characteristics of reagents are highly competive with a standard applied reagent for determining amino acids and a mixture ortho-phthalic aldehyde with 2-mercaptoethanol.