Nitro groups nucleophilic addition, substitution

The generally accepted mechanism for nucleophilic aromatic substitution m nitro substituted aryl halides illustrated for the reaction of p fluoromtrobenzene with sodium methoxide is outlined m Figure 23 3 It is a two step addition-elimination mechanism, m which addition of the nucleophile to the aryl halide is followed by elimination of the halide leaving group Figure 23 4 shows the structure of the key intermediate The mech anism is consistent with the following experimental observations... 

S909). First, an addition of the cyano group takes place to give intermediate 127, in which nucleophilic substitution of aliphatic nitro group provides the final product 128 (Scheme 20). 

The majority of analgesics can be classified as either central or peripheral on the basis of their mode of action. Structural characteristics usually follow the same divisions the former show some relation to the opioids while the latter can be recognized as NSAlD s. The triamino pyridine 17 is an analgesic which does not seem to belong stmcturally to either class. Reaction of substituted pyridine 13 (obtainable from 12 by nitration ) with benzylamine 14 leads to the product from replacement of the methoxyl group (15). The reaction probably proceeds by the addition elimination sequence characteristic of heterocyclic nucleophilic displacements. Reduction of the nitro group with Raney nickel gives triamine 16. Acylation of the product with ethyl chlorofor-mate produces flupirtine (17) [4]. 

Such nucleophilic displacements are likely to be addition-elimination reactions, whether or not radical anions are also interposed as intermediates. The addition of methoxide ion to 2-nitrofuran in methanol or dimethyl sulfoxide affords a deep red salt of the anion 69 PMR shows the 5-proton has the greatest upfield shift, the 3- and 4-protons remaining vinylic in type.18 7 The similar additions in the thiophene series are less complete, presumably because oxygen is relatively electronegative and the furan aromaticity relatively low. Additional electronegative substituents increase the rate of addition and a second nitro group makes it necessary to use stopped flow techniques of rate measurement.141 In contrast, one acyl group (benzoyl or carboxy) does not stabilize an addition product and seldom promotes nucleophilic substitution by weaker nucleophiles such as ammonia. Whereas... 

Diazophenol formation is most competitive when a nitramine substrate contains an electron-withdrawing nitro group ortho to the nitro group being displaced and hence meta to the nitramine functionality, assumedly because that site is then activated towards nucleophilic aromatic substitution. Heating nitramines in inert chlorinated solvents also favours diazophenol formation but this is suppressed by using urea or sulfamic acid as additives. 

Predictably, the ir-electron-excessive character of pyrrole and its benzologues renders them relatively inert to nucleophilic addition or substitution reactions. Consequently, such reactions are rare and are promoted only by the presence of electron-withdrawing substituents. ipso-Substitution of the 2-nitro group of 2,5-dinitropyrrole by methoxide ions... 

The most common preparations of amines on insoluble supports include nucleophilic aliphatic and aromatic substitutions, Michael-type additions, and the reduction of imines, amides, nitro groups, and azides (Figure 10.1). Further methods include the addition of carbon nucleophiles to imines (e.g. the Mannich reaction) and oxidative degradation of carboxylic acids or amides. Linkers for primary, secondary, and tertiary amines are discussed in Sections 3.6, 3.7, and 3.8. 

Two of three nitrofluorobenzene isomers react with methoxide, but the third is unreactive. Obtain energies of methoxide anion (at left), ortho, meta and para-nitrofluorobenzene, and the corresponding ortho, meta and para-methoxide anion adducts (so-called Meisenheimer complexes). Calculate the energy of methoxide addition to each of the three substrates. Which substrate is probably unreactive What is the apparent directing effect of a nitro group Does a nitro group have the same effect on nucleophilic aromatic substitution that it has on electrophilic aromatic substitution (see Chapter 13, Problem 4) Examine the structures and electrostatic potential maps of the Meisenheimer complexes. Use resonance arguments to rationalize what you observe. 

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