Aromatic nucleophilic substitution in nonionic alkylglucoside micelles

The kinetics and mechanism of the aromatic nucleophilic substitution reaction of 2,4-dinitrochlorobenzene (DNCB) with OH- in nonionic sugar-derived micelles were investigated and compared with those for reaction in polyoxyethylene glycol surfactants. Hydroxyl groups on the sugar headgroups of micellized n-nonyl beta-D-glucopyranoside (C9G1), n-dodecyl beta-D-maltoside (C12G2), and n-dodecyl beta-D-maltotrioside (C12G3) are partially deprotonated by OH- and the alkoxide ions react with DNCB, forming an arene ether. Observation of more than one isosbestic point indicates that more than one intermediate ether is formed, largely at C3 or C4 with micellar stereocontrol. Over time the ethers react with OH- giving 2,4-dinitrophenoxide ion.     

Iron-assisted nucleophilic aromatic substitution on solid phase

Iron-assisted S(N)Ar reactions were performed for the first time on solid phase, and a library of 36 unsymmetrically substituted phenylpiperazines and phenyl-1,4-diazepanes was synthesized with this novel strategy. The scope of iron-assisted S(N)Ar reactions on solid phase was investigated, and reactions of representative nucleophiles from groups VI (O, S, and Se) and V (N and P) of the periodic table were examined. Decomplexation of resin-bound iron complexes was achieved with 1,10-phenanthroline under irradiation, thereby overcoming the notorious disadvantages of decomplexation observed in solution-phase chemistry.     

Predicting regioselectivity in nucleophilic aromatic substitution

We have investigated practical and computationally efficient methods for the quantitative prediction of regioisomer distribution in kinetically controlled nucleophilic aromatic substitution reactions. One of the methods is based on calculating the relative stabilities of the isomeric σ-complex intermediates using DFT. We show that predictions from this method can be used quantitatively both for anionic nucleophiles with F(-) as leaving group, as well as for neutral nucleophiles with HF as leaving group. The σ-complex approach failed when the leaving group was Cl/HCl or Br/HBr, both for anionic and neutral nucleophiles, because of difficulties in finding relevant σ-complex structures. An approach where we assumed a concerted substitution step and used such transition state structures gave quantitatively useful results. Our results are consistent with other theoretical works, where a stable σ-complex has been identified in some cases, whereas others have been indicated to proceed via a concerted substitution step.     

Influence of anionic and cationic reverse micelles on nucleophilic aromatic substitution reaction between 1-fluoro-2,4-dinitrobenzene and piperidine

The nucleophilic aromatic substitution (S(N)Ar) 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 benzene/benzyl-n-hexadecyl dimethylammonium chloride (BHDC)/water reverse micellar media. The kinetic profiles of the reactions were investigated as a function of variables such as surfactant and amine concentration and the amount of water dispersed in the reverse micelles, W0 = [H2O]/[surfactant]. In the AOT system at W0 = 0, no micellar effect was observed and the reaction takes place almost entirely in the benzene pseudophase, at every AOT and PIP concentration. At W0 = 10, a slight increment of the reaction rate was observed at low [PIP] with AOT concentration, probably due to the increase of micropolarity of the medium. However, at [PIP] > or = 0.07 M the reaction rates are always higher in pure benzene than in the micellar medium because the catalytic effect of the amine predominates in the organic solvent. In the BHDC system the reaction is faster in the micellar medium than in the pure solvent. Increasing the BHDC concentration accelerates the overall reaction, and the saturation of the micellar interface is never reached. In addition, the reaction is not base-catalyzed in this micellar medium. Thus, despite the partition of the reactants in both pseudophases the reactions effectively take place at the interface of the aggregates. The kinetic behavior can be quantitatively explained taking into account the distribution of the substrate and the nucleophile between the bulk solvent and the micelle interface. The results were used to evaluate the amine distribution constant between the micellar pseudophase and organic solvent and the second-order rate coefficient of S(N)Ar reaction in the interface. A mechanism to rationalize the kinetic results in both interfaces is proposed.     

Solvent-controlled leaving-group selectivity in aromatic nucleophilic substitution

A solvent-controlled inversion of leaving group ability allows selective access to either of two internal substitution products in S(N)Ar reactions of substrates with competing leaving groups. Application of this principle in a selective synthesis of the highly functionalized xanthone core of the antibiotic FD-594 is presented.     

Unusual dealkylations and rearrangements in aromatic nucleophilic substitution

The reaction of 2,4-dinitrohalobenzenes with di-isopropylamine produces mainly N-(2,4-dinitrophenyl)-isopropylamine and N-(2,4-dinitrophenyl)-n-propylamine instead of the expected straightforward substitution product. Dealkylations are also observed in the reactions with isopropylcyclohexylamine and dicyclohexylamine. A carbanionic mechanism is proposed.     

First nucleophilic aromatic substitution of annelated pyrazole.

3-Chloropyrazolo[3,4-c]quinoline 5, 3-chloropyrazolo[3,4-c]isoquinoline 6, 1,2-dihydro-1,2-dimethylpyrazolo[3,4-c]quinolin-3-one 8, and 1,2-dihydro-1,2-dimethylpyrazolo[3,4-c]isoquinolin-3-one 10 were obtained by acid-induced nucleophilic aromatic substitution (S(N)H) of H-3 in N-hydroxypyrazolo[3,4-c]quinoline 1b and in N-hydroxy pyrazolo[3,4-c]isoquinoline 3b. In the acid-induced chlorination, 3b was far more reactive than 1b, whereas the related N-hydroxypyrazolo[4,3-c]quinoline 2b and N-hydroxypyrazolo[4,3-c]isoquinoline 4b were completely unreactive toward S(N)H under identical conditions.     

Efficient nucleophilic aromatic substitution between aryl nitrofluorides and alkynes

The nucleophilic aromatic substitution reaction between electron-deficient aryl fluorides and terminal alkynes is shown to be efficiently promoted by sodium bis(trimethylsilyl)amide as a base. Moderate to excellent yields of 2-ethynylnitrobenzene products can be obtained under mild conditions.     

Novel gas-phase ion-molecule aromatic nucleophilic substitution in beta-carbolines

We report a novel gas-phase ion-molecule aromatic-nucleophilic substitution reaction between beta-carbolines and water vapour, that accounts for the observation of ions with higher masses than the precursor ion in the MS/MS spectra.     

Intramolecular aromatic nucleophilic substitution of the benzimidazole-activated nitro group

A wide range of 2-(2-nitrophenyl)-1H-benzimidazoles undergo high-yielding intramolecular S(N)Ar of nitrite with N-pendant alkoxides under mild conditions (DMF, rt). When this operationally simple process is carried out at elevated temperatures in the presence of excess NaH, the initially formed S(N)Ar products are converted to the corresponding N-vinyl-substituted 2-(2-hydroxyphenyl)-1H-benzimidazoles via base-catalyzed isomerization. [reaction: see text]     

Electrophilic and nucleophilic aromatic substitution: Analogous and complementary processes

Analysis of many variants of nucleophilic aromatic substitution of hydrogen proceeding according to an addition—elimination pattern reveals that this is the major reaction pathway, whereas nucleophilic replacement of halogen or another nucleofugal group is the secondary process, i.e.,ipso-substitution. In this respect electrophilic and nucleophilic aromatic substitution can be considered as analogous processes.This account is published in connection awarding Prof. M. Mgkosza the degree ofDoctor Honoris causa by the Russian Academy of Sciences for his investigations in the fields of physical organic chemistry and fine organic synthesis.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3. pp. 531–544, March, 1996.     

Head-to-backbone cyclization of peptides on solid support by nucleophilic aromatic substitution

A new versatile synthetic route is presented for the cyclization of tripeptides on solid support using nucleophilic aromatic substitution in the cyclization step. Identification of all conformers within a limit of 3 kcal/mol from the identified global minimum conformations by Monte Carlo conformational searching reveals that five out of six synthesized compounds have well-defined peptide backbone conformational properties. This was determined by clustering the identified conformers against a filter of seven to nine torsion angles in the peptide backbone. Thus, the results meet our goal to find synthetic routes to peptides that are conformationally sufficiently locked to serve as convenient leads for further development of pharmacophoric models. The strategy is based on Fmoc-peptide chemistry on a N-aminoethyl-substituted glycine bound to the commercially available Rink amide PS-resin. After deprotection of the N-terminus of the tripeptide, it is acylated with a fluoronitrobenzoic acid. Subsequently, a Boc group on the N-bound aminoethyl substituent is selectively deprotected allowing cyclization from the head (N-terminus) to the backbone substituent, thereby leading to the desired cyclized tripeptides. A number of representative examples of peptides cyclized by this method have been synthesized and characterized by NMR. Protecting groups that allow the incorporation of side chain functionalized amino acids have been found. Thus, the route provides access to generic libraries of conformationally restricted peptide sequences expressing a range of proteinogenic pharmacophores.