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Aromatic nucleophilic substitution reaction of 1-fluoro-2,4-dinitrobenzene with piperidine was kinetically investigated in ethylene glycol-choline chloride and glycerol-choline chloride as 2 deep eutectic solvents (DESs) mixed with dimethyl sulfoxide, in

The nucleophilic aromatic substitution (SNAr) reaction between 1-fluoro-2,4-dinitrobenzene and piperidine (PIP) were studied in two different reverse micellar interfaces: benzene/sodium 1,4-bis(2-ethylhexyl) sulfosuccinate (AOT)/water and benze

The understanding of solvent effects on chemical reaction requires precise knowledge of solute-solvent interactions. Since solute-solvent interactions are much more complex in mixed solvents, the study of chemical kinetics can be valuable because of the p

Fluorine kinetic isotope effects (F KIEs) have been determined using the accelerator-produced short-lived radionuclide 18F in combination with natural 19F. The solvent dependence of the leaving group F KIE was investigated for the nu

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The kinetics of the nucleophilic aromatic substitution (SNAr) reaction between 1-fluoro-2,4-dinitrobenzene (FDNB) and piperidine (PIP) in ethylene glycol (EG)/ sodium bis (2-ethyl-1-hexyl) sulfosuccinate (AOT)/n-heptane and dimethylformamide (D

Solvation effects on the reaction mechanism of the title reactions have been kinetically evaluated in 21 conventional solvents and 17 ionic liquids. Solvent polarity affects the catalyzed and non-catalyzed SNAr pathways differently. The ambiphi

Reaction kinetics of 1-chloro-2,4-dinitrobenzene with piperidine was studied spectrophotometrically in aqueous solutions of methanol, ethanol, and propan-2-ol at 25 °C. The reaction in these solutions is not catalyzed by piperidine. The plots of second-order rate constants of the reaction vs. mole fraction of water show maxima in the all-aqueous solutions. Single-parameter correlations of log k2 vs. π* (dipolarity/polarizability), α (hydrogen-bond donor acidity), and ETN (normalized polarity parameter) are very poor in the all solutions (for example, in aqueous solutions of ethanol, regression coefficients are 0.814, 0.113, and 0.486, respectively). Dual-parameter correlations of log k2 vs. π* and α in all cases represent significant improvement with regard to the single-parameter models (in aqueous solutions of ethanol: n = 11, r = 0.980, and s = 0.034). Dipolarity/polarizability and hydrogen-bond donor acidity (HBD) of media have opposite effects on the reaction rate. The activated complex leading to the zwitterionic intermediate is expected to be favored by increasing the solvent dipolarity/polarizability parameter. Increasing the hydrogen-bond donor acidity of solvent stabilizes piperidine and hence the reaction rate decreases. A dual-parameter equation of log k2 vs. π* and α was obtained in the all-aqueous solutions (n = 31, r = 0.956, s = 0.055) in which π* and α have approximately equal and opposite effects on the reaction rate.

Prodrugs for targeted tumor therapies have been extensively studied in recent years due to not only maximising therapeutic effects on tumor cells but also reducing or eliminating serious side effects on healthy cells. This strategy uses prodrugs which are safe for normal cells and form toxic metabolites (drugs) after selective reduction by enzymes in tumor tissues. In this study, prodrug candidates (1-36) containing nitro were designed, synthesized and characterized within the scope of chemical experiments. Drug-likeness properties of prodrug candidates were analyzed using DS 2018 to investigate undesired toxicity effects. In vitro cytotoxic effects of prodrug canditates were performed with MTT assay for human hepatoma cells (Hep3B) and prostate cancer cells (PC3) and human umbilical vein endothelial cells (HUVEC) as healthy control. Non-toxic compounds (3, 5, 7, 10, 12, 15, 17, 19 and 21–23), and also compounds (1, 2, 5, 6, 9, 11, 14, 16, 20 and 24) which had low toxic effects, were selected to examine their suitability as prodrug canditates. The reduction profiles and kinetic studies of prodrug/Ssap-NtrB combinations were performed with biochemical analyses. Then, selected prodrug/Ssap-NtrB combinations were applied to prostate cancer cells to determine toxicity. The results of theoretical, in vitro cytotoxic and biochemical studies suggest 14/Ssap-NtrB, 22/Ssap-NtrB and 24/Ssap-NtrB may be potential prodrug/enzyme combinations for nitroreductase (Ntr)-based prostate cancer therapy.

A mild, efficient, and eco-friendly method for the synthesis of o-nitroarylamine from o-nitroaryl sulfonic acid via ipso nucleophilic aryl substitution by amine is described. The products have been obtained with good yields at room temperature without the assistance of any metal, activating agent, or toxic oxidant. This method is useful for racemization-free synthesis of N-aryl amino acid esters.

Substitutions such as acylations, arylations, and alkylations are some of the most commonly run reactions for building complex molecules. However, the requirement of a stoichiometric base to scavange acid by-products creates significant challenges when operating in continuous flow due to solid handling issues associated with precipitating base·HX salts. We present a general and simple strategy to overcome these solid handling issues through the use of acid scavenging organic bases that generate low- to moderate-melting ionic liquids upon protonation. The application of these bases towards the most commonly run substitutions are demonstrated, enabling reactions to be run in flow without requiring additional equipment, specific solvents, or dilute reaction conditions to prevent clogging.

Rising concern for environment hazards resulting from the use of volatile organic compounds (VOCs) is prompting many chemists to use “green” solvents like water, polyethylene glycol, ionic liquids and deep eutectic solvents (DES). With a few notable exceptions, many of these processes still need to use volatile organic solvents for the workup and isolation of products. In the present report, we demonstrate a “zero VOC” protocol which eliminates the need to use organic solvents for any stage of the reaction. As a proof of concept, nucleophilic aromatic substitution reactions of 1-halo-2,4-dinitrobenzene with secondary amines were carried out in deep eutectic solvents. The reaction workup involved the addition of water for separating the product from the DES. Evaporation of water led to recovery of the DES, which exhibited good recyclability. The reaction in deep eutectic solvents was much faster than that in many other solvents, as confirmed by the kinetic studies. An attempt was made to elucidate the origin of this rate enhancement based on analysis activation parameters and correlation with the polarity parameters. The results show that use of deep eutectic solvents can take chemists a step closer towards the “zero VOC” synthetic strategy.

Abstract: Deep eutectic solvent (DES)/lipase catalyzed efficient synthesis of N-aryl amines from electron deficient aryl chlorides and amines at ambient temperature is reported. Its significant features include excellent yields of products, use of biodegradable, non-toxic and recyclable catalysts, thereby avoiding toxic metal catalyst/solvents making these protocols environmentally benign. Graphical Abstract: [Figure not available: see fulltext.].

Molecular iodine was found to be an excellent catalyst for reductive redox cyclization of o-nitro-t-anilines 1 into fused tricyclic or 1,2-disubtituted benzimidazoles 2. A range of functional groups such as halides (F, Cl, Br), methoxy, ester, trifluoromethyl, cyano, pyridine and even nitro groups were tolerated using formic acid as a clean, safe, user-friendly and complementary reductant. When iodine was used in a stoichiometric amount (50 mol%), the methodology allowed the direct synthesis of benzimidazole hydroiodides 2·HI in high yields by simple precipitation from the reaction mixture.

Taking advantage of Pd(OAc)2-catalyzed dinitration reactions with Bi(NO3)3·5H2O in trifluoroethanol (TFE) and trifluoroacetic acid (TFA), we have developed an efficient and practical method for the synthesis of secondary dinitro-aromatic amines. The products could be applied to the preparation of 5-amine-N-methyl-benzimidazolone, the azo-dyes, economic advantages. The method has also been expanded to the dinitration reaction of some tertiary aromatic amines.

The reactions of O,O-diethyl 2,4-dinitrophenylphosphate triester (1) with piperidine in ionic liquids and four conventional organic solvents (COS) were subjected to kinetic and product studies. Analytical techniques (UV-vis and NMR) identified two pathways: nucleophilic attack at the phosphoryl center and at the C-1 aromatic carbon. The nucleophilic rate constants (kTN) for these parallel reactions were separated into two terms: kPN and kArN for the corresponding electrophilic centers. Both the rate and the selectivities of the reactions are strongly dependent on the nature of the ionic liquid used, and a good correlation with the solvent acceptor capacity to form hydrogen bonds (β) was observed. Remarkably, an exclusive attack at the phosphoryl center was found using [Bmim]DCA, [Bmpyrr]DCA and [Bmpy]DCA as the reaction solvents. In contrast, with [Bmim]PF6 as the reaction solvent, attack at the C-1 aromatic was the main path (94%). These results suggest that ionic liquids can be considered to be designer solvents because by an appropriate choice of the anion it is possible to steer the selectivity of this reaction. This journal is

A kinetic study is reported for SNAr reactions of 1-(Y-substituted-phenoxy)-2,4-dinitrobenzenes (1a-1h) with amines in MeCN. The plots of pseudo-first-order rate constant versus amine concentration curve upward, indicating that the reactions are catalyzed by a second amine molecule. The Br?nsted-type plots for the reaction of 1-(4-nitrophenyl)-2,4- dinitrobenzene (1a) with secondary amines are linear with βnuc = 1.10 and 0.85 for the uncatalyzed and catalyzed reactions, respectively, while the Yukawa-Tsuno plots for the reactions of 1a-1h with piperidine result in excellent linear correlations with ρY = 1.85 and r = 0.27 for the uncatalyzed reaction and ρY = 0.73 and r = 0.23 for the catalyzed reaction. The catalytic effect decreases with increasing amine basicity or electron-withdrawing ability of the substituent Y in the leaving group. Activation parameters calculated from the rate constants measured at five different temperatures for the catalyzed reaction of 1a with piperidine are ΔH? = 0.38 kcal/mol and ΔS? = -55.4 cal/(mol K). The catalyzed reaction from a Meisenheimer complex (MC ±) is proposed to proceed through a concerted mechanism with a cyclic transition-state rather than via a stepwise pathway with an anionic intermediate, MC-. Deuterium kinetic isotope effects provide further insight into the nature of the concerted transition state.

The reactions of the title compounds with phenoxides, secondary alicyclic (SA) amines, and pyridines, in 44 wt% ethanol-water, at 25°C and an ionic strength of 0.2 M, were subjected to kinetic and product studies. From analytical techniques (HPLC and NMR), two pathways were detected (nucleophilic attack at the phosphoryl center and at the C-1 aromatic carbon) for the reactions of all the nucleophiles with the phosphate (2) and for the pyridinolysis of the thionophosphate (1). Only aromatic nucleophilic substitution was found for the reactions of 1 with phenoxides and SA amines. For the dual reactions, the nucleophilic rate constants (kN) were separated in two terms: documentclass{article}usepackage{amssymb} pagestyle{empty}begin{document}k-{rm N}^{rm P}end{document} and documentclass{article}usepackage{amssymb}pagestyle{empty}begin{document}k-{ rm N}^{{rm Ar}}end{document}, which are the rate constants for the corresponding electrophilic centers. The absence of a break in the Bronsted-type plots for the attack at P is consistent with concerted mechanisms. The Bronsted slopes, βAr 0.32-0.71, for the attack at the aromatic C-1, are in agreement with stepwise mechanisms where formation of a Meisenheimer complex is the rate-determining step. 2013 Wiley Periodicals, Inc. Int J Chem Kinet 45: 202-211, 2013 Copyright

Pseudo-first-order rate constants (kobsd) have been measured spectrophotometrically for nucleophilic substitution reactions of 1-X-2,4-dinitrobenzenes (1a-d, X = F, Cl, Br, I) with various primary and secondary amines in MeCN and H2O

This report discloses proof of concept and experimental results from a project involving design, development, and investigation of a novel approach for flow chemistry and the realization of equipment operating according to this new approach. This device is named multijet oscillating disk (MJOD) reactor and is dedicated to continuous flow organic synthesis in milliscale. Characteristics such as the importance of the multijet disk unit, with or without oscillating, and possible limitations, such as back-mixing, have been explored, and the flow system is benchmarked with other technologies. Several well-known reactions and syntheses usefully both in the chemical industry as well as in the research laboratory have been conducted using the new system, which have been benchmarked with batch- and microreactor protocols. In particular the Haloform reaction, the Nef reaction, nucleophilic aromatic substitution, the Paal-Knorr pyrrole synthesis, sodium borohydride reduction, O-allylation, the Suzuki cross-coupling reaction, the Hofmann rearrangement and N-acylation were performed during the study of the MJOD reactor performance. Our investigations revealed that the MJOD millireactor system can produce various organic compounds at a high rate concomitant with an excellent selectivity. A Hofmann rearrangement was conducted, a reaction that involves handling of a slurry of the substrate. This reaction was successfully conducted, achieving a quantitative conversion into the target molecule.

Rate constants are reported for the reactions of a series of 4-substituted-1-phenoxy-2,6-dinitrobenzenes 1 and 6-substituted-1-phenoxy-2,4- dinitrobenzenes 2 activated by CF3, COOCH3, CN, NO 2 groups or by ring-nitrogen wi

This work presents a new approach using ionic liquids, namely ethylammonium nitrate. The aim was to analyze how the addition of small amounts of a protic ionic liquid to a pure molecular solvent, modifies the microscopic characteristics of a reaction medium. In order to achieve this, a kinetic study of nucleophilic aromatic substitution reactions between 1-fluoro-2, 4-dinitrobenzene and 1-butylamine or piperidine was developed in this type of binary mixtures. We have detected nucleophiles competition originated by the presence of the ionic solvent at very low concentrations, observing the ethylamine derivative as the main substitution product. Moreover, in the light of previous results we have confirmed that the protic ionic liquid can act as both Broensted acid and/or nucleophile. In this connection, we have selected the nucleophilic addition of amines to carbonyl compounds as reaction model. The protic ionic liquid in the presence of aromatic aldehydes substituted by electron-donating groups makes possible the formation of the corresponding imines with good yields. The results demonstrated that the influence of the protic ionic liquid is very important in the course of both reaction systems. Copyright

Rate constants are reported for the reactions of a series of 1-chloro-, 1-fluoro- and 1-phenoxy-nitrobenzenes activated by CF3 or CN groups or by ring-nitrogen with n-butylamine, pyrrolidine or piperidine in acetonitrile. The results are compar

(Chemical Equation Presented) A kinetic study is reported for nucleophilic substitution reactions of 2,4-dinitro-1-fluorobenzene (DNFB) with a series of secondary amines in MeCN and H2O at 25.0°C. The reaction in MeCN results in an upward curva

Kinetics of the reactions of the title compound with some amines as nucleophiles in aprotic solvents have been investigated at the λmax of the aminolysis product at 35 ± 0.1 °C under pseudo-first order conditions. The reaction is overall second order, first with respect to each reactant. The second order rate coefficients decreased with increase in [amine] in all cases. Formation of an electron donor-acceptor complex is indicated. The temperature effect on the reaction rate has been studied in the range (293-318 K). The entropy of activation parameters are large and negative in all cases indicating formation of a crowded transition state. Mechanistic interpretation is given.

Rate constants are reported for reaction of 4-substituted 1-chloro-2,6-dinitrobenzenes 1, 6-substituted 1-chloro-2,4-dinitrobenzenes 2, and some of the corresponding 1-phenoxy derivatives, 3 and 4, with n-butylamine, pyrrolidine and pi-peridine in acetoni

Three series of benzimidazole N-oxide derivatives were developed and were examined for their activity against trypanosomatid parasites (Trypanosoma cruzi and Leishmania spp.). 2H-Benzimidazole 1,3-dioxides displayed remarkable in vitro activities against

Effect of nucleophile on the reactions of o-(2,4-dinitrophenyl) indanone oxime (DNPIO) has been studied with cyclohexylamine (CHA), ethanolamine (ETA) and piperidine (PIP) in acetonitrile at 35±0.1°C. Reactions of DNPIO with CHA and ETA are kinetically of second order. However, the reactions with PIP are wholly base catalyzed and a third order dependence on PIP has been observed.

The kinetics of the reactions of O-(2′,4′ -dinitrophenyl)-4-phenyl-3-buten-2-one oxime have been studied with piperidine, cyclohexylamine, n-butylamine and pyrrolidine in acetonitrile at 35 ± 0.1°. Base catalysis has been observed with piperidine and pyrrolidine. Mechanistic interpretation is given.

Reaction kinetics of 1-fluoro-2,4-dinitrobenzene with piperidine has been studied spectrophotometrically in aqueous solutions of methanol, ethanol, propan-2-ol and 2-methylpropan-2-ol at 10 deg C. The reaction in the aqueous solutions is not catalyzed by

Twenty-two 2,4-dinitroanilines were synthesised and their pK(a) values were determined. The 2,4-dinitroanilines and their protonated forms were studied by 15N NMR spectroscopy. The relations between the 15N NMR chemical shifts and the pK(a) values of the 2,4-dinitroanilines and their salts were found to be linear. The deprotonation reaction of N-methyl-2,4- dinitroanilines and N-methyl-2,4,6-trinitroaniline by MTBD was successful only for the latter and yielded protonated MTBD molecule and the anion in which the electrons are strongly delocalised. The kinetic parameters of the 2,4-dinitroanilines in reactions with hydroxide ions in mixed solvent DMSO:water (95:5, v/v) were determinated and discussed. (C) 2000 Elsevier Science B.V.

Useful yields are achieved in the regioselective direct formation of anilines and aromatic amides through hydrogen nucleophilic aromatic photosubstitution of m-dinitrobenzene with primary amines and amides, promoted by fluoride anion.

The kinetics of the reactions of 1-fluoro-2,4-dinitrobenzene with morpholine and piperidine were studied at 25°C in several binary solvent mixtures of the polar aprotic hydrogen bond acceptor solvent + chloroform or dichloromethane type, which, in some ca

The use of chemical probes for the characterization of chemical properties was explored for completely non-aqueous aprotic binary solvent mixtures. The Dimroth-Reichardt ET(30) betaine dye, 4-nitrophenol, 4-nitroanisole, 4-nitroaniline and N,N-

The nucleophilic aromatic substitution SNAr reaction of 1-fluoro-2,4-dinitrobenzene with n-butylamine and piperidine was studied in n-hexane and AOT/n-hexane/water reverse micelle media. The kinetic profile of the reactions was investigated as

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The reactivity of some dinitro-benzene and -thiophene derivatives with piperidine and sodium benzenethiolate has been examined giving evidence that benzenes show large and thiophenes show small kinetic secondary steric effects, respectively. The acid diss

A detailed study of piperidinolysis and hexylaminolysis of O-(2,4-dinitrophenyl) benzophenone oxime, O-(2,4-dinitrophenyl)-p-chlorobenzophenone oxime and O-(2,4-dmitrophenyl)-p-bromobenzo-phenone oxime in cyclohexane at different temperatures has been undertaken. The piperidinolysis reactions show a third order dependence on amine and inverse temperature effect. The analysis of data indicates that the reactions proceed through two routes; the rate of first route increases and of the second route decreases with temperature. The overall rate kA shows inverse temperature effect due to predominating effect of the second route. The results support the Jack Hirst's concept of reaction mechanism in nonpolar solvents. In contrast to piperidinolysis, n-hexylaminolysis reactions show only a second order dependence on amine which has been explained to be due to lesser stability of hydrogen bonded homoconjugate acid BH+B involving long chain hexylamine molecules.

The reactions of O-(2,4-dinitropnenyl)-substituted p,p′-dimethoxybenzophenone oxime, p,p′-fluorobenzophenone oxime and p,p×-dichlorobenzophenone oxime with pyrrolidine and piperidine in benzene were found to be third order in amine, with no uncatalytic ro

The kinetics of the reaction between 1-chloro-2,4-dinitrobenzene and piperidine was studied in several completely non-aqueous binary solvent mixtures where the preferential solvation is the rule at 15, 25 and 40 °C. The reaction was chosen as the simplest

Reactions of N-(2,4-dinitrophenyl)-4-dimethylaminopyridinium salts with piperidine in acetonitrile are catalyzed by anions. The catalytic activity of anions increases with increase in their basicity in the series F- > C6H5SO2O- > Cl- = Br- > I- ? (C6H5)4B-. Unlike monofunctional organic bases (piperidine and triphenylphosphine oxide) that do not affect the reaction rate, the anions favor abstraction of hydrogen atom and dimethylaminopyridine in the cyclic transition state. 1996 MAEe Cyrillic signΚ Hayκa/Interperiodica Publishing.

The reactions of n-butylamine, pyrrolidine and piperidine with phenyl 2,4,6-trinitrophenyl ether, 3, in DMSO result in the rapid reversible formation of adducts by reaction at the 3-position followed by attack at the 1-position leading to substitution of

Aromatic amines can be obtained from 2,4-dinitrobenzenesulfonic acid sodium-salt and aliphatic amides in excess at 170-180 deg C, for 6-7 hours.The steric hindrances have an important role in this reaction.

Kinetics of aminolysis of N-(2,4-dinitrophenyl)-camphor oxime has been carried out with cyclohexylamine (CHA) and piperidine (PIP) in 1:4 aqueous-acetonitrile (v/v) at 35 +/- 0.1deg C.N-(2,4-dinitrophenyl) piperidine and N-(2,4-dinitrophenyl) cyclohexylamine have been obtained in quantitative yield.Evidence for base catalysis has been obtained in the case of piperidine.Mechanistic interpretation is given.

The reactions of 2,6-dinitrophenyl phenyl ether and of 6-methyl-2,4-dinitrophenyl phenyl ether with piperidine, morpholine, butylamine and benzylamine are base catalysed in both dimethyl sulfoxide and acetonitrile.The reaction of 2-phenoxy-3,5-dinitropyridine with aniline is base catalysed in acetonitrile, but not in dimethyl sulfoxide, and its reactions with piperidine, morpholine, butylamine and benzylamine in acetonitrile are also base catalysed.The results are discussed in terms of the prevailing theories of aromatic nucleophilic substitution reactions.Increasein activation of the substrate increases the k2/k-1 and k3/k-1 ratios.For ortho substituents, steric/stereoelectronic effects in the transition state reduce both k-1, the rate constant for the decomposition of the zwitterionic intermediate to reactants, and k2 and k3, the rate constants for its decomposition to products.When the substrate has two ortho groups the different behaviour of primary and secondary amines found with substrates containing only one ortho-nitro group is not observed.

The reaction of 2,3-(cyclopenten-endo-3',5'-diyl)-N-(2",4"-dinitrophenoxy)succinimide (1) with hydroxide ion and piperidine in aq. acetonitrile is base-catalysed.The exo-isomer (2) reacts at a faster rate than the endo-isomer (1).The rate of the reaction in various acetonitrile-water media decreases with a decrease in water concentration for both hydroxide ion and piperidine in the case of endo-isomer and only in respect of hydroxide ion in the case of exo-isomer.The reaction rate with piperidine in the case of exo-isomer, however, increases with a decrease in the percentage of water.The mechanistic interpretation is given.

The kinetics of reactions between 1-halogeno-2,4-dinitrobenzene (halogen = F, Cl) and butylamine and piperidine were re-investigated in cyclohexane.The kobs values (s-1 mol-1 dm3) increased with increases in the initial concentration of the reacting amine.Investigation of the reaction mixtures at zero reaction time, indicated the presence of an interaction between the substrate and the amine which occurred in a rapidly established equilibrium and which preceded the substitution process.The nature of the molecular complexes observed is discussed.Present and previous data indicate that the kobs increase was difficult to explain with the traditional hypotesis of proton and leaving group departure as a rate determining step.A better rationalisation of the experimental data may be obtained by involving the molecular complexes on the substitution reaction pathway.

Aminolysis of O-(2,4-dinitrophenyl) derivatives of benzophenone oxime and 4'-bromobenzophenone oxime with piperidine and morpholine has been studied in benzene at 35 +/- 0.1 deg C.These reactions show inverse temperature effect and third order dependence on amine.The results have been explained on the basis of electrophilic catalysis by homoconjugated acids.It has been concluded from these results that third order dependence on cyclic amines and second order on noncyclic amine is usually noted for aminolysis reactions in benzene.

Rate constants for nucleophilic aromatic substitution reactions of picryl chloride, I, with acetate ion and a series of amine nucleophiles, including primary, secondary, tertiary (quinuclidines), and amines which show the α-effect, in aqueous and methanol

The rate of reactions between 1-fluoro-2,4-dinitrobenzene and aliphatic amines is enhanced by the presence of cyclic (or non-cyclic) amidic systems.This kinetic behaviour is explained by the presence of some equilibria involving the catalyst and both subs