Meisenheimer intermediate

Since the decomposition of the Meisenheimer intermediate is not the ratedetermining step, the trends for the leaving groups are quite different from common nucleophilic substitution. The leaving group trends for SnAt substitutions were reported to have the following order F > N02 > SOPh > Cl > Br I > OAr > OR > SR52 53. 

Aprotic polar solvents have to be used for several reasons. They are often good solvents for both monomers (including phenolates) and amorphous polymers. In addition, they can also stabilize the Meisenheimer intermediates. Common aprotic polar solvents, such as DMSO, /V,/V-dimcthyl acetamide (DMAc), DMF, N-methyl pyrrolidone (NMP), and cyclohexylpyrrolidone (CHP) can be used. Under some circumstances, very high reaction temperature and boiling point solvents such as sulfolane and diphenyl sulfone (DPS) have to be used due to the poor reactivity of the monomers or poor solubility of the resulting, possibly semicrystalline polymers, as in the PEEK systems. 

By comparing CPK models of the Meisenheimer intermediates which should be formed in each case, steric hindrance for substitution of the nitro group (intermediate 30) should be larger than for substitution of any of the chlorine atoms (intermediates 31, 32). This is in accordance with the observed results where bulkiness of the butylamine leads to a diminution of the corresponding nitro-substitution product. Nevertheless, as we have... 

In an unusual reaction, involving a Meisenheimer intermediate, 3,5-dinitrobenzophenone reacted with A/.A-dimethylphenylacetamidine to give either a quinoline (519) or an isoquinoline (520) (77JOC435). Enamines (521) react with diethyl maleate and aluminum chloride at room temperature to give good yields of the unusual 3,6-dihydropyrid-2-ones (522)... 

Nucleophilic displacement of an a- or y-halogen atom by the classical SAE mechanism of nucleophilic displacement via a Meisenheimer intermediate (e.g. 900) is facilitated by mesomeric stabilization of the transition state. However, the mechanistic balance is fine whereas 4-bromopyridine 1-oxide reacts with potassium amide by the A-E mechanism, the 2-bromo analogue prefers the E-A route. Again, nucleophilic displacement in chloropyrazines can involve the ANRORC mechanism. 

The rate of fluorination using potassium fluoride alone follows the reverse order dimethyl sulfoxide > sulfolane > Af-methylpyrrolid-2-one > acetonitrile > 1,2-dimcthoxyethane. This can be explained by considering the different abilities of the solvents to stabilize the anionic (Meisenheimer) intermediate in the reaction. Therefore, the use of bromo(tetraphenyl)-A -phos-phane results not only in an increase in the concentration of fluoride in the media, but also helps to stabilize the anionic Meisenheimer intermediate when the solvent itself is too poor at realizing this function. 

Kinetic measurements gave evidence for deprotonation of the spiro-Meisenheimer intermediate 35 as the rate-limiting step during the rearrangement of 2-(4-nitrophenoxy)ethylamine 32 into 33 in aqueous alkah [23] (Scheme 14, R = H). The kinetic effect of N-alkyl substitution [24-26] (Scheme 14, R = Me, Et, f-Pr) has also been investigated. 

Hitherto we have concentrated on electrophilic aromatic substitution. However, certain n-deficient aromatic rings are deactivated towards electrophilic attack but are susceptible to nucleophilic addition and a subsequent elimination. A particular example is 2,4-dinitrochloroben-zene. The electron-withdrawing nitro groups facilitate a Michael-type addition of a nucleophile to give a so-called Meisenheimer intermediate (Scheme 4.8). Collapse of the Meisenheimer intermediate and reversion to the aromatic system may lead to expulsion of the halide ion, as exemplified by the preparation of 2,4-dinitrophenylhydrazine. 2,4-Dinitrofluorobenzene is known as Sanger s reagent and is used for the detection of the N-terminal amino acids in peptides. 

An interesting reaction of converting nitrobenzene into p nitrosophenol [48] was now rationalized in terms of the formation of Jackson-Meisenheimer intermediate, according to scheme (4) ... 

Knipe, A. C., Lound-Keast, J., Sridhar, N. interpretation of the kinetics of generai-base-cataiyzed Smiies rearrangement of 2-(p-nitrophenoxy)ethyiamine into 2-(p-nitroaniiino)ethanoi rate-iimiting deprotonation of a spiro-Meisenheimer intermediate. J. Chem. Soc., Perkin Trans. 21984, 1885-1891. 

Nitro substituents activate the displacement of leaving groups like halide, as in benzene chemistry, and extensive use of this has been made in thiophene work. Such nucleophilic displacements proceed at least 10 times faster than for benzenoid counterparts, and this may be accounted for by participation of the sulfur in the delocalisation of charge in the Meisenheimer intermediate. Nitrogroups also permit the operation of VNS processes (3.3.3), as illustrated below. ... 

Substrate binding and activation are followed by attack of the carboxylate side chain of Asp-145 at the benzoyl C-4 atom to give an enzyme-stabilized Meisenheimer intermediate (EMc) (Figure 8). Indeed, a site-directed mutant in which Asp-145 has been replaced by an alanine is catalytically inactive." Ketonization of the EMc results in rearomatization of the benzoyl ring and expulsion of the chloride. This nucleophilic addition-elimination mechanism (SNAr-type reaction) results in a second covalent (aryl-enzyme) intermediate, which is subsequently hydrolyzed by a water molecule that is activated by His-90 to give the free enzyme and the product. The existence of a covalent aryl-enzyme intermediate has been inferred from 0-labeling studies (similar to those described for haloalkane and haloalcohol dehalogenase) and from the direct measurement of the aryl-enzyme... 

Figure 8 A schematic representation of the cataiytic mechanism of 4-chiorobenzoyi-CoA dehaiogenase. The cataiytic residues functioning in the enzyme-substrate compiex (E S), Meisenheimer intermediate (EMc), aryiated enzyme intermediate (EAr), and enzyme-product compiex (E P Cr H ) are shown. The direction of the cataiytic steps is asfoiiows from E S to EMc to EAr and finaiiy to E P Ci H+.

Nucleophilic aromatic substitution reactions follow the well-established two-step addition-elimination mechanism via a Meisenheimer intermediate (Fig. 8.3). Indeed, reaction of fluoride ion with trifluoro- -triazine, gives the corresponding perfluorocarbanion system that has been directly observed by NMR spectroscopy, supporting this mechanistic rationale. This reactivity has been termed mirror-image chemistry, which contrasts the very well-known chemistry of... 

The carbanion is stabilized by electron-mthdramng groups in the positions ortho and para to the halogen atom. If we examine the following resonance structures for a Meisenheimer intermediate, we can see how ... 

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