Crown ethers have the ability of solubilizing inorganic salts in apolar solvents and to promote chemical reactions by phase-transfer catalysis. However, details on how crown ethers catalyze ionic S(N)2 reactions and control selectivity are not well understood. In this work, we have used high level theoretical calculations to shed light on the details of phase-transfer catalysis mechanism of KF reaction with alkyl halides promoted by 18-crown-6. A complete analysis of the of the model reaction between KF(18-crown-6) and ethyl bromide reveals that the calculations can accurately predict the product ratio and the overall kinetics. Our results point out the importance of the K* ion and of the crown ether ring in determining product selectivity. While the K* ion favors the S(N)2 over the E2 anti pathway, the crown ether ring favors the S(N)2 over E2 syn route. The combination effects lead to a predicted 94% for the S(N)2 pathway in excellent agreement with the experimental value of 92%. A detailed analysis of the overall mechanism of the reaction under phase-transfer conditions also reveals that the KBr product generated in the nucleophilic fluorination acts as an inhibitor of the 18-crown-6 catalyst and it is responsible for the observed slow reaction rate. (C) 2012 Elsevier B.V. All rights reserved.; Brazilian Research Council (CNPq); Brazilian Research Council (CNPq); Brazilian Office of Higher Education (CAPES); Brazilian Office of Higher Education (CAPES); Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG); Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG); Institute for Science and Technology of Materials (INOMAT); Institute for Science and Technology of Materials (INOMAT)
Preparation of the title compounds are described as an alternative nucleophilic aromatic substitution for practices in the graduate laboratory. The low toxicity and disponibility of the reagents make a suitable procedure approach to experiments regarding this aromatic reaction.
In this work the theoretical study of the gas-phase bimolecular nucleophilic substitution reaction, CH3Cl + OH-→ CH3OH + Cl-, is introduced aiming the description of the reaction path and the calculation of rate coefficients with the canonical variational transition state (CVTST) method. The calculations were performed at the MP2/6-31+G(d) level. The calculated enthalpy difference for the reaction at 298.15 K (-49.93 kcal mol-1) is in good agreement with the literature value: -50.4 kcal mol-1. The calculated rate coefficient, 1.94 × 10-9 cm³ molecule-1 s-1 at 298.15 K, also shows good agreement with the experimental data: 1.3-1.6 × 10-9 cm³ molecule-1 s-1. Moreover, the rate coefficients show non-Arrhenius behavior, decreasing as the temperature increases, which is consistent with the experimental expectation. In this way, the performance of the variational transition state theory for this reaction can be considered satisfactory.
2-Aryl-6-cyano-7-methyl-5-indolizinones were successfully converted into 2-aryl-5-chloro-6-cyano-7-methylindolizines. The obtained 5-chloroindolizines readily underwent nucleophilic substitution at position 5 leading in high yields to novel 5-functionalised indolizines.
The meta-halo-3-methylbenzonitrile derivatives (-F, -Cl, -Br, -I) were synthesized as model compounds to study reactivity towards aromatic nucleophilic substitution. A single-mode microwave system was incorporated into a commercial radiochemical synthetic module for F-18 labeling. Labeling yields of 64% for fluoro-, 13% for bromo- and 9% for chloro-precursors were achieved in DMSO in < 3 min. The observed order of reactivity of the leaving groups toward aromatic nucleophilic substitution was F>>Br>Cl>>>I.
An effective Hamiltonian mixed molecular orbital and valence bond (EH-MOVB) method is described to obtain an accurate potential energy surface for chemical reactions. Building upon previous results on the construction of diabatic and adiabatic potential surfaces using ab initio MOVB theory, we introduce a diabatic-coupling scaling factor to uniformly scale the ab initio off-diagonal matrix element H12 such that the computed energy of reaction from the EH-MOVB method is in agreement with the target value. The scaling factor is very close to unity, resulting in minimal alteration of the potential energy surface of the original MOVB model. Furthermore, the relative energy between the reactant and product diabatic states in the EH-MOVB method can be improved to match the experimental energy of reaction. A key ingredient in the EH-MOVB theory is that the off-diagonal matrix elements are functions of all degrees of freedom of the system and the overlap matrix is explicitly evaluated. The EH-MOVB method has been applied to the nucleophilic substitution reaction between hydrosulfide and chloromethane to illustrate the methodology and the results were matched to reproduce the results from ab initio valence bond self-consistent valence bond (VBSCF) calculations. The diabatic coupling (the off-diagonal matrix element in the generalized secular equation) has small variations along the minimum energy reaction path in the EH-MOVB model...
The kinetics of aromatic nucleophilic substitution of the nitric oxide generating diazeniumdiolate ion, DEA/NO, by thiols, (L-glutathione, L-cysteine, DL-homocysteine, 1-propanethiol, 2-mercaptoethanol and sodium thioglycolate) from the prodrug, DNP-DEA/NO, has been examined in aqueous solution and in solutions of cationic DOTAP vesicles. Second-order rate constants in buffered aqueous solutions (kRS- = 3.48 – 30.9 M-1s-1; 30 °C) gave a linear Brønsted plot (βnuc = 0.414 ± 0.068) consistent with rate-limiting SNAr nucleophilic attack by thiolate ions. Cationic DOTAP vesicles catalyze the thiolysis reactions with rate enhancements between 11 and 486-fold in Tris-HCl buffered solutions at pH 7.4. The maximum rate increase was obtained with thioglycolate ion. Thiolysis data are compared to data for nucleophilic displacement by phenolate (kPhO- = 0.114 M-1s-1) and hydroxide (kOH- = 1.82 × 10-2 M-1s-1, 37 °C) ions. The base hydrolysis reaction is accelerated by CTAB micelles and DODAC vesicles with vesicles being ca 3-fold more effective as catalysts. Analysis of the data using pseudophase ion-exchange formalism implies that the rate enhancement of the thiolysis and base hydrolysis reactions is due primarily to reactant concentration in the surfactant pseudophase.
A computational approach using density functional theory to compute the energies of the possible σ-complex reaction intermediates, the “σ-complex approach”, has been shown to be very useful in predicting regioselectivity, in electrophilic as well as nucleophilic aromatic substitution. In this article we give a short overview of the background for these investigations and the general requirements for predictive reactivity models for the pharmaceutical industry. We also present new results regarding the reaction rates and regioselectivities in nucleophilic substitution of fluorinated aromatics. They were rationalized by investigating linear correlations between experimental rate constants (k) from the literature with a theoretical quantity, which we call the sigma stability (SS). The SS is the energy change associated with formation of the intermediate σ-complex by attachment of the nucleophile to the aromatic ring. The correlations, which include both neutral (NH3) and anionic (MeO−) nucleophiles are quite satisfactory (r = 0.93 to r = 0.99), and SS is thus useful for quantifying both global (substrate) and local (positional) reactivity in SNAr reactions of fluorinated aromatic substrates. A mechanistic analysis shows that the geometric structure of the σ-complex resembles the rate-limiting transition state and that this provides a rationale for the observed correlations between the SS and the reaction rate.
The design, synthesis, properties, and cell imaging applications of a series of pyridine-disulfide based fluorescent probes (WSP1, WSP2, WSP3, WSP4 and WSP5) for hydrogen sulfide detection are reported. The strategy is based on the dual-nucleophilicity of hydrogen sulfide. A hydrogen sulfide mediated tandem nucleophilic substitution-cyclization reaction is used to release the fluorophores and turn on the fluorescence. The probes showed high sensitivity and selectivity for hydrogen sulfide over other reactive sulfur species including cysteine and glutathione.
Seven reactive dyes judiciously selected based on chemical structures and fixation mechanisms were applied at 2% owf of shade on amidoximated acrylic fabrics. Amidoximated acrylic fabric has been obtained by a viable amidoximation process. The dyeability of these fabrics was evaluated with respect to the dye exhaustion, fixation, and colour strength under different conditions of temperature and dyeing time. Nucleophilic addition type reactive dyes show higher colour data compared to nucleophilic substitution ones. FTIR studies further implicate the binding of reactive dyes on these fabrics. A tentative mechanism is proposed to rationalize the high fixation yield obtained using nucleophilic addition type reactive dyes. Also, the levelling and fastness properties were evaluated for all dyes used. Excellent to good fastness and levelling properties were obtained for all samples irrespective of the dye used. The result of investigation offers a new method for a viable reactive dyeing of amidoximated acrylic fabrics.
Die vorliegende Arbeit befasst sich mit dem Einbau von Substituenten X in 2-Position von Imidazolium-Verbindungen; dieser ist durch nukleophile Substitution in 2-Chloroimidazolium-Ionen (a) und durch elektrophilen Angriff an 2,3-Dihydroimidazol-2-ylidene möglich (b). Das unter (a) genannte Verfahren startet vom 2-Chloroimidazolium-Kation; von den hierdurch erhaltenen Produkten sind besonders erwähnenswert der Aufbau des SO3-Addukts (1,3-Diisopropyl-4,5-dimethylimidazolium-2-sulfonat), das in die kationische Supersäure (1,3-Diisopropyl-4,5-dimethyl-2-sulfoimidazolium-hexafluoroantimonat)überführt werden kann, sowie die Synthese des Cyanoimidazolium-Kations und dessen Folgechemie. Die Verwendung des Imidazol-2-ylidens als nukleophiler Reaktionspartner erreicht in (b) einen weiteren Höhepunkt mit der Synthese des lange gesuchten kationischen Phosphonsäurechlorids (2-(Dichlorophosphoryl)-1,3-diisopropyl-4,5-dimethylimidazolium-chlorid) und dessen Hydrolyse zur neuartigen Organophosphonsäure (1,3-Diisopropyl-4,5-dimethylimidazoliophosphonsäure). Auch die unerwartete Bildung des dikationischen Ketons (2-[(1,3-Diisopropyl-4,5-dimethylimidazolium-2-yl)carbonyl]-1,3-Diisopropyl-4,5-dimethylimidazolium-dichlorid) eröffnet neue Möglichkeiten auf dem Wege in die Chemie elementorganischer Imidazol-Derivate.; The presented work is dealing with the insertation of X substituents in 2-position of imidazolium compounds; this route is possible through nucleophilic substitution on 2-chloroimidazolium ions (a) and through the electrophilic attack on 2...
The objective of this study was to investigate the nucleophilic aromatic substitution using [18F]fluoride as nucleophile. Therefore, structures ranging from simple monosubstituted aromatic systems to complicated multi-substituted aromatic systems were tested, and several effects were studied in detail, including the following:
1. Structural effects (positions and number of groups on the ring, type of activation or deactivation, type of possible leaving groups and type of protection of OH groups).
2. Solvent effects (was studied using a variety of dipolar aprotic solvents)
3. Concentration effects (was studied using concentrations 1-50 mg/mL).
4. Temperature effects (was studied using temperatures 60-180 °C).
Two types of reactions were studied. These are:
1. Fluorodenitration reactions: Ar-NO2 --> Ar-18F
2. Fluorodehalogenation reactions: Ar-X --> Ar-18F (X= F, Br, Cl)
The study was divided into 3 parts. In the first part, aryl systems (including haloaryls, nitroaryls, benzaldehydes, acetophenones and benzophenones) were tested. In the second part, the focus was on optimising the conditions for the production of [18F]FDOPA precursors for path A (chapter 2). In the last part, model systems for producing [18F]FDOPA via path B (chapter 2) were tested in the nucleophilic aromatic substitution by [18F]fluoride. The RCYs obtained from some precursors were used further to calculate the rate constants and the energy of activation for this process.
The main results can be summarised in the following points:
1. Fluorodenitration reactions can be used efficiently to produce nca [18F]arylfluorides. DMF is the best solvent but DMSO and DMAc can be used also. For very activated systems...
In der vorliegenden Arbeit wurde ein neues Konzept zur Darstellung von [18F]markierten aromatischen Aminosäuren entwickelt und evaluiert.
Hierzu wurden als Modellverbindungen verschiedene Benzole, substituiert mit Methoxy-, Methylgruppen sowie mit einer oder zwei Formyl-Gruppen in nukleophilen Substitionsreaktionen mit [18F]Fluorid umgesetzt. Dabei wurde der Einfluss verschiedener Abgangsgruppen (-F, -Cl, -Br, -NO2) unter verschiedenartigen Reaktionsbedingungen untersucht. Zur schnellen und effizienten Decarbonylierung mit Wilkinson-Katalysator wurde der Effekte von Temperatur, Zeit und Katalysator-Konzentration ermittelt. Die Darstellung von 2-[18F]Fluortyrosin durch das neue Synthesekonzept zur 18F-Markierung in Gegenwart der (geschützten) Aminosäurefunktion wurde erfolgreich durchgeführt.; In this work a new synthetic strategy aiming at the synthesis of [18F] labeled aromatic amino acids was developed and evaluated.
As model compounds, methoxy- and methyl- substituted benzenes, with one or two formyl-groups as activating auxiliary, were labeled by nucleophilic substitution with [18F]fluoride. The influence of different leaving groups (-F, -Cl, -Br, -NO2) and different reaction parameters on the radiochemical yield was examined. For the fast and efficient decarbonylation of these model compounds by Wilkinson’s Catalyst...
The objective of this work was to develop a new strategy aiming at the syntheses of n.c.a. 18F-labeled aromatic amino acids via three steps, i.e. nucleophilic 18F-labeling, decarbonylation and hydrolysis. First, systematic investigations on nucleophilic aromatic 18F-fluorination was performed by using a variety of model compounds exhibiting different substitution patterns with both +M (-MeO or -Me) and -M substituents (leaving group (-LG) or -CHO). Secondly, the optimized decarbonylation condition was determined by decarbonylating the 18F-labeled model compounds. In overall synthesis, a proof-of-principle study on the synthesis of [18F]fluoro-p-tyrosine proved the three-step synthetic strategy to be suitable for syntheses of 18F-labeled aromatic amino acids. However, in the case of the precursor with low reactivity toward SNAr ([18F]fluoro-m-tyrosine and [18F]FDOPA), further optimization of the organic synthesis of precursors is in progress. In the last part, an automated synthesis of [18F]FDOPA over four steps (fluorination, reductive iodination, alkylation and hydrolysis), as described in the literature, was brought into routine application for the first time. 9064 ± 3076 MBq of [18F]FDOPA could be produced within 120 min of production time from EOB (n = 5). The radiochemical purity and enantiomeric purity were both 95 %. The specific activity was ca. 50 GBq/µmol at EOS.; Das Ziel dieser Arbeit ist die Entwicklung einer neuen Strategie für die Synthese von n.c.a. 18F-markierten aromatischen Aminosäuren in drei Schritten...
Halogenation of poly(isobutylene-co-isoprene) (IIR) increases its reactivity towards sulphur and other nucleophiles. Currently brominated (BIIR) and chlorinated (CIIR) derivatives are commercially available; however, an iodinated derivative has been briefly investigated. The effects of leaving group ability and microstructure on the reactivity of halogenated poly(isobutylene-co-isoprene) were studied to put iodobutyl rubber reactivity into context and to compare existing commercial products to their isomeric derivatives.
Polymers containing halomethyl (r-CIIR, r-BIIR, r-IIIR) isomers of butyl rubber were prepared from as-received BIIR to compare the effect of leaving group on thermal stability and reactivity towards nucleophilic substitution. The polymer containing (E,Z)-endo-iodomethyl isomers (r-IIIR) readily underwent nucleophilic substitution at low temperatures; however, it was sensitive towards dehydrohalogenation at temperatures above 65⁰C. At temperatures between 100⁰C and 135⁰C, the bromomethyl derivative (r-BIIR) demonstrated the best balance between reactivity toward nucleophilic substitution and dehydrohalogenation. Exceptional thermal stability at temperatures up to 190⁰C was displayed by the chloromethyl derivative (r-CIIR); however...
The allylic bromide functionality within brominated poly(isobutylene-co-isoprene), or BIIR, is amenable to substitution by a wide range of nucleophiles. The objective of this work was to gain insight into the dynamics of these substitution reactions, and to develop methods for accelerating these processes. Of particular interest was the reactivity of exomethylene (Exo-Br) and bromomethyl (BrMe) isomers found within BIIR toward various nucleophiles, and catalytic techniques for affecting the proportion of these isomers.
BIIR isomerization can be catalyzed through ionic chemistry involving soluble Lewis acids such as zinc stearate and through a nucleophilic SN2’ rearrangement with soluble bromide salts such as tetrabuylammonium bromide (TBAB). The compatibility of TBAB with other nucleophiles makes it a preferable choice, but further rate enhancements can be realized using the corresponding iodide salt (TBAI). TBAI serves not only as nucleophilic isomerization catalyst, but also accelerates halide displacement from BIIR by an in-situ formation of an allylic iodide intermediate.
Studies of BIIR isomerization and substitution reactions involved solvent-borne reactions of tetrabutylammonium acetate (TBAAc) and solvent-free reactions with PPh3 and 2-[2-(dimethylaminoethoxy)ethanol]. In all cases...
Un objectif majeur en chimie organique est le développement de méthodes de synthèses générales, simples et peu coûteuses permettant la modification efficace des ressources naturelles en différents produits d’intérêt public. En particulier, la recherche de méthodes chimiosélectives et de méthodes dites « vertes » représente un intérêt croissant pour le secteur industriel (dont le domaine pharmaceutique). En fait, l’application en synthèse sur grande échelle de procédés catalytiques, sélectifs et utilisant des conditions douces permet de réduire le volume de déchets et la demande énergétique, minimisant ainsi les coûts de production et les effets néfastes sur l’environnement. Dans ce contexte, le groupe de recherche du Professeur André B. Charette de l’Université de Montréal s’intéresse au développement de méthodes générales et chimiosélectives permettant la transformation de fonctionnalités aisément accessibles tels que les amides et les alcools. La fonction amide, aussi appelée liaison peptidique dans les protéines, est présente dans diverses familles de molécules naturelles et est couramment employée comme intermédiaire synthétique dans la synthèse de produits d’intérêt pharmaceutique. Le groupement alcool est...
We propose and test an empirical nucleofugality index to rank the leaving group ability of a series of molecular fragments present in nucleophilic substitution reactions of carbonyl and thiocarbonyl derivatives. The nucleofugality index is defined as the group electrophilicity of the leaving group embedded in the substrate that undergoes the nucleophilic attack. The reliability and usefulness of this new reactivity index is tested against experimental kinetic data.
Ten α-cyclodextrin -rotaxanes have been prepared with alkane-, stilbene- and azobenzene-based axles, capped through nucleophilic substitution of either 2-chloro-4,6-dimethoxy-1,3,5-triazine or 2,4-dichloro-6-methoxy-1,3,5- triazine in aqueous solution
Synthesis of methyl substituted phenols (via various diazonium salts), to be used as a monomer in the synthesis of ordered polyesters and to study the liquid crystal continuum from monomer-to-oligomer-to-polymer, was attempted.
Deblocking of di(methoxyphenyl) terephthalates with sodium ethanethiolate in dimethylformamide resulted in the preferential cleavage of the ester linkage over the alkyl -aromatic ether linkage. A number of cleavage products resulted, depending upon the reaction conditions.
4,4'[sulfonyl bis(ρ-phenylene ether)] dianisole was prepared as a model compound to be used in the ordered poly(ester-sulfone) study. Deblocking with hydrobromic and hydrobromic acid-acetic acid cosolvents was successful. However, deblocking wtih sodium ethanethiolate in dimethylformamide resulted in preferential cleavage of the aryl-aryl ether linkage over the alkyl-aromatic ether linkage.
Attempts to synthesize 4,4'-[sulfonyl bis(p-phenylene ether)] dianisole by the Ullmann sythesis of diaryl ethers was unsuccessful.
The effect of para-substituents on aromatic-nucleophic substitution reactions, in cleavage reactions of diaryl ethers by sodium ethanethiolate in diamethylformamide, was studied. Electron-withdrawing groups were found to facilitate the cleavage reaction.