Nitrobenzene nucleophilic substitution reactions

C-Methylation products, o-nitrotoluene and p-nitrotoluene, were obtained when nitrobenzene was treated with dimethylsulfoxonium methylide (I)." The ratio for the ortho and para-methylation products was about 10-15 1 for the aromatic nucleophilic substitution reaction. The reaction appeared to proceed via the single-electron transfer (SET) mechanism according to ESR studies. 

The yields of reaction products from thermal nucleophilic substitution reactions in DMSO of 0- and p-nitrohalobenzenes (Zhang et al. 1993) or p-dinitrobenzene (Liu et al. 2002) with the sodium salt of ethyl a-cyanoacetate were found to be markedly diminished from the addition of small amounts of strong electron acceptors such as nitrobenzenes. At the same time, little or no diminution effects on the yields of the reaction products were observed from the addition of radical traps such as nitroxyls. These results are consistent with the conclusion that such reactions proceed via a nonchain radical nucleophilic substitution mechanism (Scheme 4.26). 

Cyclopropylphosphine oxides (140) react with the sodium salts of amides, presumably via cyclopropane ring-opening and intramolecular olefination, to give dihydropyrrole derivatives in moderate to good yield. Vicarious nucleophilic substitution reactions of a variety of substituted nitrobenzene derivatives with the carbanion of chloromethyldiphenylphosphine oxide to give o-(141) and p-(142)-nitrobenzyldiphenylphosphine oxides have been investigated. ... 

Angrish et al. (2005) reported a rapid and efficient method for aromatic nucleophilic substitution reaction of chloronitrobenzene with number of substituted amines in presence of l-butyl-3-methylimidazolium tetrafluoroborate ionic liquid (green reaction media) to give N-substituted nitrobenzene under microwave irradiation. 

The solvent dependence of the reaction rate is also consistent with this mechanistic scheme. Comparison of the rate constants for isomerizations of PCMT in chloroform and in nitrobenzene shows a small (ca. 40%) rate enhancement in the latter solvent. Simple electrostatic theory predicts that nucleophilic substitutions in which neutral reactants are converted to ionic products should be accelerated in polar solvents (23), so that a rate increase in nitrobenzene is to be expected. In fact, this effect is often very small (24). For example, Parker and co-workers (25) report that the S 2 reaction of methyl bromide and dimethyl sulfide is accelerated by only 50% on changing the solvent from 88% (w/w) methanol-water to N,N-dimethylacetamide (DMAc) at low ionic strength this is a far greater change in solvent properties than that investigated in the present work. Thus a small, positive dependence of reaction rate on solvent polarity is implicit in the sulfonium ion mechanism. 

Arylations of nitro compounds can be achieved by aromatic nucleophilic substitution using aromatic nitro compounds, as discussed in Chapter 9.100 Komblum and coworkers reported displacement of the nitro group of nitrobenzenes by the anion of nitroalkanes. The reactions are usually carried out in dipolar aprotic solvents such as DMSO or HMPA, and nitroaromatic rings are substituted by a variety of electron-withdrawing groups (see Eq. 5.63).101... 

An alternate and more controlled approach to the synthesis of phenothiazines involves sequential aromatic nucleophilic displacement reactions. This alternate scheme avoids the formation of the isomeric products that are sometimes observed to form from the sulfuration reaction when using substituted aryl rings. The first step in this sequence consists of the displacement of the activated chlorine in nitrobenzene (30-1) by the salt from orf/io-bromothiophenol (30-2) to give the thioether (30-3). The nitro group is then reduced to form aniline (30-4). Heating that compound in a solvent such as DMF leads to the internal displacement of bromine by amino nitrogen and the formation of the chlorophenothiazine (30-4). Alkylation of the anion from that intermediate with 3-chloro-l-dimethylaminopropane affords chlorpromazine (30-5) [31]. 

An SN1 reaction on the carbon atom next to the ring has a large negative p value. In this example, a tertiary benzylic cation is the intermediate and the rate-determining step is, of course, the formation of the cation. The cation is next to the ring but delocalized round it and the p value is -4.5, about the same value, though negative, as that for the nucleophilic substitution on nitrobenzenes by the addition-elimination mechanism that we saw in the last section. 

Sometimes a cathodic substitution reaction takes place during the reduction of ortho-substituted nitrobenzenes thus the reduction of 2-nitrophenoxyacetic acid (21) in 2 N hydrochloric acid (50% ethanol) yielded 5-chloro-2H-l,4-benzoxazin-3(4H)-one (22), Y = C1) rather than the expected cyclic hydroxamic acids02 in the presence of another nucleophile Y (e.g., thiocyanate) ring substitution with this reagent occurs. 

Nucleophilic substitution of chlorine is a key feature of a synthetic approach to a series of indole-6-carboxylic acids. For example, conversion of the starting nitrobenzene 392 using an SnAc reaction followed by reductive cyclization into the indole 393 was concluded by treatment with base to afford the final product 394 (Scheme 46) <2004SL883>. 

Interesting cases of reactions of metal salts of secondary amines with nitrobenzene have also been recorded. Thus MontmoUin [142] reacted potassium salt of carbazol with nitrobenzene. The nucleophilic substitution of nitrobenzene occurred in para position to the nitro groups. A similar reaction with diphenyl- mine [143] has also been described. 

Predictions based on Abboud-Kamlet-Taft parameters lead to better results, since the anion s basicity (0-value) and the cation s hydrogen bond donor ability (a-value) are assessed separately. For example, in the nucleophilic substitution of methyl-p-nitrobenzene sulfonate and a halide (Fig. 11) the hydrogen bond donor ability of the cation should be reduced in order to eliminate strong interactions with the halide. This was impressively demonstrated for the rates of reaction, which decreased according to [C4mpyr][BTA] > [C4dmim][BTA] > [C4mim][BTA] [149,150],... 

More recently DDT-dehydrochlorinase has been isolated and purified ( 660-fold) to apparent homogeneity from houseflies (49). In contrast to that described in earlier studies, this enzyme was found to be a dimer with subunits of molecular weights of 23,000 and 25,000. It was also found to possess substantial GSH-S-transferase activity towards 2,4-dinitrochlorobenzene and 3,4-dichloro-nitrobenzene. Based on its structure, catalytic activity and chromatographic behavior it was concluded that the purified heterodimeric DDT-dehydrochlorinase was indeed a GSH-S-transferase isozyme (49). It was proposed that instead of the nucleophilic substitution usually observed in GSH-S-transferase activity, DDT-dehydrochlorination by this enzyme involves an E2 elimination reaction in which the GS thiolate anion abstracts the hydrogen on the C-2 of DDT and this initiates the departure of the chlorine atom from C-1 ( 9) (Figure 9). 

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