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Computational studies to determine the rate constants and thermodynamic properties of the nucleophilic aromatic substitution reactions of 4‐R‐1‐chloro‐2,6‐dinitrobenzenes 1, 6‐R‐1‐chloro‐2,4‐dinitrobenzenes 2 and some of the corresponding 1‐phenoxy derivatives 3 and 4 with aniline in the gas phase, acetonitrile and toluene is reported at the M06‐2x/6‐31g+(d,p) level of theory; R=H, NO2, CF3, CN and ring N. Formation of the Meisenheimer complex intermediate was observed in all cases and its stability was dependent on the number of electron‐withdrawing groups present on the ring and their relative position. The overall reaction was found to be exothermic and exergonic in all cases. From kinetics calculations, the initial attack of the aniline nucleophile on the dinitrobenzene to form the intermediate is rate limiting with the chloride ion as the leaving group in acetonitrile and decomposition of the MC was rate limiting in vacuum and toluene. With the phenoxide ion as the leaving group, the decomposition of the MC intermediate is rate limiting in all cases. The observation of MC and thermodynamic data obtained are suggestive of the prevalence of a multistep SNAr mechanism and ring activation by electron withdrawing group increased the rate of reaction. [ABSTRACT FROM AUTHOR]

In this paper, we present a theoretical study of structure and UV-vis spectra of 11 colored complexes of nucleophiles with nitroaromatic energetic materials. Two different schemes were found to be the most suitable for absorption spectra simulation. In the case of covalently bound Meisenheimer complexes, the time-dependent density functional theory (TD-DFT) approach with the TPSS functional was the most accurate. Meanwhile, for intermolecular charge-transfer complexes, the closest spectral pattern was provided by the time-dependent Hartree-Fock (TD-HF) scheme with modified exchange contribution (40%). It has been found that the binding type is determined predominantly by the steric factors and less by the electronic effects of the nucleophile, which was approved by the quantum theory of atoms in molecules (QTAIM) analysis of the formed bond types and nucleophilicity index calculations. For the charge-transfer complex, an appropriate configuration with the intermolecular separation between the local electrophilic and nucleophilic sites (the C1···N distance) of about 3.1 Å, was revealed using both classical molecular dynamics simulations and geometry optimizations in polar continuum. Absorption energies and intensities of the electronic transitions are generally well-reproduced in all 11 cases and demonstrate a local π–π* excitation in the covalently-bound complexes and pure charge transfer in intermolecular system. The applied computational methods allow reproducing of the sample colors with a high degree of similarity, which may find their application for modeling of new reagents with other expected colorimetric characteristics.

(Het)aryl migration has emerged as a key synthetic tool and has particularly been exploited for the synthesis of α-aryl amides. This method overcomes the existing α-arylation methods, which are not always compatible with the introduction of (het)aryl groups possessing bulky or electrophilic substituents. This review focuses on SO2-extrusive (het)aryl migration in the frame of α-aryl amide synthesis. Anion- and radical-mediated transformations are reported, including the synthesis of polycyclic compounds through cascade reactions. 1 Introduction 2 Anionic Aryl Migration 3 Radical Aryl Migration 4 Conclusion [ABSTRACT FROM AUTHOR]

Electrophilic and nucleophilic substitutions of aromatic substrates share common mechanistic pathways. In both scenarios reacting species attack rings at the unsubstituted (C–H) positions, giving cationic Wheland intermediates or anionic Meisenheimer complexes. However, the following step of rearomatization breaks the intrinsic symmetry, due to different leaving group ability of proton and hydride anion, respectively. In effect, electron-deficient arenes are prone to transformations unparalleled in electrophilic chemistry. In our article, we present transformations of anionic σH-adducts, formed between nitroarenes and carbanions of the Corey–Chaykovsky reagents. Depending on structure of the substrates and reaction conditions, the intermediates undergo cyclization to cyclopropanes (norcaradienes) or base-induced elimination to the alkylated products. Mechanistic studies reveal that order of the carbanions controls competition between the processes, due to steric hindrance developing at the β-elimination step. 1 Introduction 2 Cyclopropanation of Nitronaphthalenes 3 Alkylation of Nitropyridines 4 Mechanistic Studies 5 Summary and Outlook [ABSTRACT FROM AUTHOR]

This paper presents the development and optimization of a cost-effective paper electrochemical sensor for the detection of TNT using Fe 3 O 4 –Au core-shell nanoparticles modified with cysteamine (Fe 3 O 4 @Au/CA). The sensor was constructed by modifying a graphite paste with the aforementioned nanoparticles, which facilitated the formation of a Meisenheimer complex between cysteamine and TNT as an electron donor and an electron acceptor, respectively. The central composite design was employed to optimize four key parameters pH, modifier percentage, contact time, and buffer type to enhance the performance of the sensor. The detection limit was found to be 0.5 nM of TNT, while the linear range of the electrode response spanned from 0.002 μM to 10 μM. The simplicity and low cost of the sensor make it highly attractive for practical applications, particularly in scenarios where rapid and on-site TNT detection is required. [Display omitted] • Fabrication of a paper-based TNT sensor based on the Meisenheimer complexation. • Synergistic effect of Fe 3 O 4 @Au NPs improves the sensor's electrochemical properties. • The RSM-CCD optimization approach was used for the statistical optimization. • The detection limit of the sensor was 0.5 nM in the linear range of 0.002–10 μM. • The developed sensor can detect TNT in aqueous and soil samples, without extraction. [ABSTRACT FROM AUTHOR]

Although it is well-known that nitroaromatic compounds quench the fluorescence of different conjugated polymers and form colored Meisenheimer complexes with proper nucleophiles, the potential of paper as a substrate for those macromolecules can be further developed. This work undertakes this task, impregnating paper strips with a fluorene-phenylene copolymer with quaternary ammonium groups, a bisfluorene-based cationic polyelectrolyte, and poly(2-(dimethylamino)ethyl methacrylate) (polyDMAEMA). Cationic groups make the aforementioned polyfluorenes attachable to paper, whose surface possesses a slightly negative charge and avoid interference from cationic quenchers. While conjugated polymers had their fluorescence quenched with nitroaromatic vapors in a non-selective way, polyDMAEMA-coated papers had a visual response that was selective to 2,4,6-trinitrotoluene (TNT), and that could be easily identified, and even quantified, under natural light. Far from implying that polyfluorenes should be ruled out, it must be taken into account that TNT-filled mines emit vapors from 2,4-dinitrotoluene (DNT) and dinitrobenzene isomers, which are more volatile than TNT itself. Atmospheres with only 790 ppbv TNT or 277 ppbv DNT were enough to trigger a distinguishable response, although the requirement for certain exposure times is an important limitation. [ABSTRACT FROM AUTHOR]

Although it is well-known that nitroaromatic compounds quench the fluorescence of different conjugated polymers and form colored Meisenheimer complexes with proper nucleophiles, the potential of paper as a substrate for those macromolecules can be further developed. This work undertakes this task, impregnating paper strips with a fluorene-phenylene copolymer with quaternary ammonium groups, a bisfluorene-based cationic polyelectrolyte, and poly(2-(dimethylamino)ethyl methacrylate) (polyDMAEMA). Cationic groups make the aforementioned polyfluorenes attachable to paper, whose surface possesses a slightly negative charge and avoid interference from cationic quenchers. While conjugated polymers had their fluorescence quenched with nitroaromatic vapors in a non-selective way, polyDMAEMA-coated papers had a visual response that was selective to 2,4,6-trinitrotoluene (TNT), and that could be easily identified, and even quantified, under natural light. Far from implying that polyfluorenes should be ruled out, it must be taken into account that TNT-filled mines emit vapors from 2,4-dinitrotoluene (DNT) and dinitrobenzene isomers, which are more volatile than TNT itself. Atmospheres with only 790 ppbv TNT or 277 ppbv DNT were enough to trigger a distinguishable response, although the requirement for certain exposure times is an important limitation.

Air pollution by various volatile organic compounds (VOC) is a matter of concern for us. So in this regard, designing real-time VOC responsive materials is gaining attention across the scientific community. In this present work, we have developed an inexpensive VOC sensor based on a Meisenheimer complex derived from picric acid and N,N′-dicyclohexylcarbodiimide. The sensor coated TLC plate was used as a sensor of potentially harmful VOCs. The sensor coated TLC plate looks deep red colored and does not show any fluorescence emission under 366 nm UV light. But in the presence of harmful volatile organic compounds like benzene, toluene, xylene, etc the sensor coated TLC plate becomes orange colored and it also shows strong yellow emission under 366 nm UV light. This property was utilized to detect the VOCs by fluorescence spectroscopy. The detection limit for various VOCs was found to be in the range of 0.7–9 ppm. To make the sensor user friendly, we have demonstrated a method where VOCs can be detected using a smartphone in real-time and also the setup is portable.

The mechanism of SNAr reactions between 2-chloro-5-nitropyrimidine with primary and secondary alicyclic amines, respectively, have been studied by kinetic measurements. The kinetic data obtained in aqueous media opens a controversial discussion based on Brönsted-type plots analysis. The first approach based on the kinetic data reveals a non-catalyzed pathway. Then, the subtlety of the mathematical treatment of the kinetic data is discussed over a concerted or stepwise mechanism, respectively.

Heterocyclic sulfones are relevant in medicinal chemistry, drug design and organic synthesis, and the mechanism of sulfonylation of five‐membered heterocycles is not clear. In this work, it is presented a computational study on the mechanism of sulfonylation of five‐membered heterocycles compounds. Concerted and stepwise mechanisms for the nucleophilic aromatic substitution (SNAr) involved in the reaction were examined. Effect of the neighbouring group (NG), heteroatom in the ring (HT), nucleophile (NU), and leaving group (LG) in fourteen reactions were examined. Analysis of the intrinsic reaction coordinate, reaction force, natural bond orbital (NBO) charges and bond indexes give a reasonable insight about the mechanism for the reactions studied. Results revealed activation free energies ranging from 20.8 kcal/mol up to 38.6 kcal/mol. Reaction force analysis showed that structural changes in the reactant are the most important component associated with the energy of activation with more than 60 % of the contribution. Most sulfonylation reactions in this study proceed through a concerted mechanism; only two occur though a stepwise‐Meisenheimer‐intermediate mechanism. [ABSTRACT FROM AUTHOR]

Recent developments in experimental and computational chemistry have identified a rapidly growing class of nucleophilic aromatic substitutions that proceed by concerted (cSNAr) rather than classical, two‐step, SNAr mechanisms. Whereas traditional SNAr reactions require substantial activation of the aromatic ring by electron‐withdrawing substituents, such activating groups are not mandatory in the concerted pathways. [ABSTRACT FROM AUTHOR]

Electrophilic (het)arenes can undergo reactions with nucleophiles yielding π- or Meisenheimer (σ-) complexes or the products of the SNAr addition/elimination reactions. Such building blocks have only rarely been employed for the design of enzyme inhibitors. Herein, we demonstrate the combination of a peptidic recognition sequence with such electrophilic (het)arenes to generate highly active inhibitors of disease-relevant proteases. We further elucidate an unexpected mode of action for the trypanosomal protease rhodesain using NMR spectroscopy and mass spectrometry, enzyme kinetics and various types of simulations. After hydrolysis of an ester function in the recognition sequence of a weakly active prodrug inhibitor, the liberated carboxylic acid represents a highly potent inhibitor of rhodesain (Ki = 4.0 nM). The simulations indicate that, after the cleavage of the ester, the carboxylic acid leaves the active site and re-binds to the enzyme in an orientation that allows the formation of a very stable π-complex between the catalytic dyad (Cys-25/His-162) of rhodesain and the electrophilic aromatic moiety. The reversible inhibition mode results because the SNAr reaction, which is found in an alkaline solvent containing a low molecular weight thiol, is hindered within the enzyme due to the presence of the positively charged imidazolium ring of His-162. Comparisons between measured and calculated NMR shifts support this interpretation.

Picric acid (2,4,6-Trinitrophenol) is a high-power explosive and a common environmental pollutant found in wastewaters generated from leather, pharmaceutical, and dye industries. It can form a fluorescent Meisenheimer complex with nucleophiles like N , N ’-Diisopropylcarbodiimide (DPC). Based upon this unique Meisenheimer complex, a miniaturized fluorescence sensor has been designed for highly selective and sensitive detection of picric acid from environmental samples and commercial samples. The sensor probe equipped with a portable 532 nm DPSS green laser could detect picric acid concentrations as low as 100 nM (25 ppb) with excellent reproducibility. It shows promise for real time evaluation of picric acid contamination in environmental and commercial samples with excellent discrimination against other structurally related nitroaromatics. The validation results for picric acid concentrations in spiked environmental and commercial samples were in good agreement with high performance liquid chromatography analysis. The fluorescence method is simple, selective, sensitive and amenable to high throughput screening. The design of the portable sensor and its working principle has been discussed. [ABSTRACT FROM AUTHOR]

2,4,6-Trinitrotoluene (TNT) is a widely used nitroaromatic explosive and its detection is important in the public security, environmental protection and human health. We presented a sensitive chemiresistor gas sensor based on modified nanostructured dye-doped polypyrrole (PPy) as anfilm to detection of TNT for the first time. The chemiresistor gas sensors were fabricated via electrosynthesis of PPy on Au interdigital electrodes (Au-IDEs) in the presence of the sulfonated dyes. The films were modified with n -butylamine (nBA), and they could absorb TNT molecules by the formation of the Meisenheimer complex. The role of the sulfonated dyes on the behavior of films was studied. The properties of the polymeric films before and after modification were investigated by scanning electron microscopy, elemental mapping analysis and spectroelectrochemical methods The mechanism of sensing was studied by spectroelectrochemical method and response of modified gas sensor was compared to unmodified sensor. The spectroelectrochemical measurements showed that the potential-dependent of spectra in PPy-Dye films is more than in PPy-ClO 4 film after modification. Thus dye molecule can act as versatile compound in the polymer backbone. It was found that modified chemiresistor gas sensor has a high sensitivity and good selectivity to TNT over other related gases and no response without modification. The detection limit and linear dynamic range for determination of TNT was 0.2 ppb and 9.7–827.8 ppb, respectively. [ABSTRACT FROM AUTHOR]

Stable zwitterionic spirocyclic Meisenheimer compounds were synthesized using a one-step reaction between picric acid and diisopropyl (ZW1) or dicyclohexyl (ZW3) carbodiimide. A solution of these compounds displays intense orange fluorescence upon UV or visible light excitation, which can be quenched or "turned-off" by adding a mole equivalent amount of F- or CN- ions in acetonitrile. Fluorescence is not quenched in the presence of other ions such as Cl-, Br-, I-, NO2-, NO3-, or H2PO4-. These compounds can therefore be utilized as practical colorimetric and fluorescent probes for monitoring the presence of F- or CN- anions. [ABSTRACT FROM AUTHOR]

Detection of trace amounts of 2,4,6-Trinitrotoluene as a widely used explosive in the military and industrial sectors is of vital importance due to security and environmental concerns. The sensitive and selective measurement characteristics of the compound still is considered a challenge for analytical chemists. Unlike conventional optical and electrochemical methods, the electrochemical impedance spectroscopy technique (EIS), has a very high sensitivity, but it faces a significant challenge in that it requires complex and expensive steps to modify the electrode surface with selective agents. We reported the design and construction of an inexpensive, simple, sensitive, and selective impedimetric electrochemical TNT sensor based on the formation of a Meisenheimer complex between magnetic multiwalled carbon nanotubes modified with aminopropyl triethoxysilane (MMWCNTs @ APTES) and TNT. The formation of the mentioned charge transfer complex at the electrode-solution interface blocks the electrode surface and disrupts the charge transfer in [(Fe (CN) 6)] 3−/4- redox probe system. Charge transfer resistance changes (ΔR CT) were used as an analytical response that corresponded to TNT concentration. To investigate the influence of effective parameters on the electrode response, such as pH, contact time, and modifier percentage, the response surface methodology based on central composite design (RSM-CCD) was used. The calibration curve was achieved in the range of 1–500 nM with a detection limit of 0.15 nM under optimal conditions, which included pH of 8.29, contact time of 479 s, and modifier percentage of 12.38% (w/w). The selectivity of the constructed electrode towards several nitroaromatic species was investigated, and no significant interference was found. Finally, the proposed sensor was able to successfully measure TNT in various water samples with satisfactory recovery percentages. [Display omitted] • An impedimetric TNT sensor based on the Meisenheimer complexation was designed. • The electrochemical properties of the sensor were improved using MMWCNTs@APTES. • The sensor was simply prepared with a rapid procedure. • RSM-CCD optimization approach was used for the optimization of variables. • The sensor can detect TNT in aqueous environments without any extraction step. [ABSTRACT FROM AUTHOR]

• LC-MS/MS methods for macozinone, a drug against multi-drug-resistant tuberculosis, and metabolites in plasma and urine. • Allows the quantification of the reduced metabolite H 2 PBTZ obtained by dearomatization of macozinone. • H 2 PBTZ among the first examples of Meisenheimer Complex (MC) metabolites identified in mammals. • Comprehensive stability studies of H 2 PBTZ in plasma and urine. • Application to analyses of samples collected during Phase Ib clinical trials with healthy subjects. Tuberculosis, and especially multidrug-resistant tuberculosis (MDR-TB), is a major global health threat which emphasizes the need to develop new agents to improve and shorten treatment of this difficult-to-manage infectious disease. Among the new agents, macozinone (PBTZ169) is one of the most promising candidates, showing extraordinary potency in vitro and in murine models against drug-susceptible and drug-resistant Mycobacterium tuberculosis. A previous analytical method using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was developed by our group to support phase I clinical trials of PBTZ169. These plasma sample analyses revealed the presence of several additional metabolites among which the most prominent was H 2 PBTZ, a reduced species obtained by dearomatization of macozinone, one of the first examples of Meisenheimer Complex (MC) metabolites identified in mammals. Identification of these new metabolites required the optimization of our original method for enhancing the selectivity between isobaric metabolites as well as for ensuring optimal stability for H 2 PBTZ analyses. Sample preparation methods were also developed for plasma and urine, followed by extensive quantitative validation in accordance with international bioanalytical method recommendations, which include selectivity, linearity, qualitative and quantitative matrix effect, trueness, precision and the establishment of accuracy profiles using β-expectation tolerance intervals for known and newer analytes. The newly optimized methods have been applied in a subsequent Phase Ib clinical trial conducted in our University Hospital with healthy subjects. H 2 PBTZ was found to be the most abundant species circulating in plasma, underscoring the importance of measuring accurately and precisely this unprecedented metabolite. Low concentrations were found in urine for all monitored analytes, suggesting extensive metabolism before renal excretion. [ABSTRACT FROM AUTHOR]

Stable zwitterionic spirocyclic Meisenheimer compounds were synthesized using a one-step reaction between picric acid and diisopropyl (ZW1) or dicyclohexyl (ZW3) carbodiimide. A solution of these compounds displays intense orange fluorescence upon UV or visible light excitation, which can be quenched or “turned-off” by adding a mole equivalent amount of F− or CN− ions in acetonitrile. Fluorescence is not quenched in the presence of other ions such as Cl−, Br−, I−, NO2−, NO3−, or H2PO4−. These compounds can therefore be utilized as practical colorimetric and fluorescent probes for monitoring the presence of F− or CN− anions.

The total stabilization energies (TSEs) and anion stabilization energies (ASEs) of ring-substituted (X-) Meisenheimer complexes featuring two NO2 groups in the ring were determined using appropriate isodesmic reactions. The structures and energies of respective species were calculated at the B3LYP/6-311+G(2d,p) level of theory. Ten series of substituent effects were examined by varying substituent Y, which is connected to the sp3 carbon of the ring. The substituent effects were successfully analyzed using an extended Yukawa-Tsuno equation, . The r− values for the TSEs were identical to those for the ASEs, whereas the s values for the TSEs were significantly different from those for the ASEs. This shows that the effect of neutral species contributes to the s values of the TSEs. The r− and s values for the ASEs of all Meisenheimer complexes were distributed in a narrow range because substituent Y was insulated from the π-conjugation system. The r− values were large and the s values were small. This shows that the r− and s values were independent of each other and that the extended three-term Yukawa-Tsuno equation was intrinsic for substituent-effect analyses of anions. Although the variation was not substantial, the change in the r− values was clearly explained by the orbital interaction between substituent Y and the π-conjugation system. The r− values exhibited a good correlation with the bond lengths between the ring and the 4-NO2 group among all Meisenheimer complexes and benzylic anions. These facts provide a physical meaning: the r− value is a parameter that reveals the degree of the additional π interactions between the electron-withdrawing substituents and the π-conjugation systems of the ring. [ABSTRACT FROM AUTHOR]

We report rapid and ultra-sensitive detection system for 2,4,6-trinitrotoluene (TNT) using unmodified gold nanoparticles and surface-enhanced Raman spectroscopy (SERS). First, Meisenheimer complex has been formed in aqueous solution between TNT and cysteamine in less than 15 min of mixing. The complex formation is confirmed by the development of a pink colour and a new UV–vis absorption band around 520 nm. Second, the developed Meisenheimer complex is spontaneously self-assembled onto unmodified gold nanoparticles through a stable Au–S bond between the cysteamine moiety and the gold surface. The developed mono layer of cysteamine-TNT is then screened by SERS to detect and quantify TNT. Our experimental results demonstrate that the SERS-based assay provide an ultra-sensitive approach for the detection of TNT down to 22.7 ng/L. The unambiguous fingerprint identification of TNT by SERS represents a key advantage for our proposed method. The new method provides high selectivity towards TNT over 2,4 DNT and picric acid. Therefore it satisfies the practical requirements for the rapid screening of TNT in real life samples where the interim 24-h average allowable concentration of TNT in waste water is 0.04 mg/L. [ABSTRACT FROM AUTHOR]

Glutathione transferase (GST) enzymes catalyze the conjugation of glutathione with reactive functional groups of endogenous compounds and xenobiotics, including halonitroaromatics. 1-Chloro-2,4-dinitrobenzene (CDNB) is one of the most commonly used substrates for GST activity assays. We have studied the interactions of dinitronaphthalene analogues of CDNB with recombinant human GST enzymes (Alpha, Mu, and Pi classes) expressed in Escherichia coli . Dinitronaphthalene derivatives were found to be GST inhibitors. The highest potency of inhibition was observed towards Mu-class GSTs, M1-1 and M2-2; IC 50 values for 1-methoxy- and 1-ethoxy-2,4-dinitronaphthalene were in the high nanomolar to low micromolar range. Inhibition accompanies the formation, at the enzyme active site, of very stable Meisenheimer complex intermediates. [ABSTRACT FROM AUTHOR]

The reactivity of the explosive tetryl (N-methyl-N,2,4,6-tetranitroaniline; Mw = 287 u) was studied using electrospray ionization in negative mode. The main species detected in the spectrum corresponds to the ion observed at m/z 318 (previously assumed to be the odd-electron ion [tetryl + HNO]-•, C7H6O9N6). In this study, we show using D-labeling combined with high-resolution mass spectrometry that this species corresponds to an even-electron anion (i.e. C8H8O9N5), resulting from the formation of a Meisenheimer complex between tetryl and the methanol used as the solvent. Fragmentation of this complex under CID conditions revealed an unexpected fragment: the formation of a 2,4,6-trinitrophenoxide anion at m/z 228. 18O-labeling combined with quantum chemical calculations helped us better understand the reaction pathways and mechanisms involved in the formation of this product ion. This occurs via a transition state leading to a SN2-type reaction, consequently evolving toward an ion-dipole complex. The latter finally dissociates into deprotonated picric acid. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]