Nucleophilic Substitution in Nitro-Substituted Aryl Halides

5 NUCLEOPHILIC SUBSTITUTION IN NITRO-SUBSTITUTED ARYL HALIDES 

One group of aryl halides that do undergo nucleophilic substitution readily consists of those that bear a nitro group ortho or para to the halogen. 

An ortho-nitio group exerts a comparable rate-enhancing effect. m-Chloronitrobenzene, although much more reactive than chlorobenzene itself, is thousands of times less reactive than either 0- or p-chloronitrobenzene. 

The effect of 0- and p-nitro substituents is cumulative, as the following rate data demonstrate  

PROBLEM 23.2 Write the structure of the expected product from the reaction of 1-chloro-2,4-dinitrobenzene with each of the following reagents  

20 Nucleophilic Substitution in Nitro-Substituted Aryl Halides 

Chlorobenzene is inert to aqueous sodium hydroxide at room temperature. Reaction temperatures of over 300°C are required for nucleophilic substitution of chlorobenzene to proceed at a reasonable rate. 

One group of aryl halides that do undergo nucleophilic substitution readily consists of those that bear a nitro group ortho or para to the halogen. p-Chloronitrobenzene reacts with sodium methoxide at 85°C to give p-nitroanisole. The position of the nitro group on the ring is important. 

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The generally accepted mechanism for nucleophilic aromatic substitution in nitro-substituted aryl halides, illustrated for the reaction of p-fluoronitrobenzene with sodium methoxide, is outlined in Figure 23.3. It is a two-step addition-elimination mechanism, in 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 mechanism is consistent with the following experimental observations ... 

In contrast to nucleophilic substitution m alkyl halides where alkyl fluorides are exceedingly unreactive aryl fluorides undergo nucleophilic substitution readily when the ring bears an o or a p nitro group... 

The most common types of aryl halides in nucleophilic aromatic substitutions are those that bear- o- or p-nitro substituents. Among other classes of reactive aryl halides, a few merit special consideration. One class includes highly fluorinated aromatic compounds such as hexafluorobenzene, which undergoes substitution of one of its fluorines on reaction with nucleophiles such as sodium methoxide. 

Similarly, 3-oxo-6-nitrobenzoxazine, which is also a lactam, has been N-arylated using sodium hydride and 4-nitrochlorobenzene in dimethylformamide (DMF) <1985IJB1263>. The reaction is a nucleophilic aromatic substitution assisted by the 4-nitro group and is therefore not general to all aryl halides. However, there is a route to N-arylated benzoxazines 148-151 through a catalyzed tandem cyclization-arylation reaction of 147, shown in Scheme 9 <2004S2527>. 

Alkyl halides are often used as substrates instead of alcohols. In such cases the salt of the inorganic acid is usually used and the mechanism is nucleophilic substitution at the carbon atom. An important example is the treatment of alkyl halides with silver nitrate to form alkyl nitrates. This is used as a test for alkyl halides. In some cases there is competition from the central atom. Thus nitrite ion is an ambident nucleophile that can give nitrites or nitro compounds (see 0-60).731 Dialkyl or aryl alkyl ethers can be cleaved with anhydrous sulfonic acids.732... 

Alkyl halides with an electron-withdrawing group on the halogen-bearing carbon can be dimerized to olefins by treatment with bases. Z may be nitro, aryl, etc. It is likely that in most cases the mechanism451 involves nucleophilic substitution followed by elimination452 (illustrated for benzyl chloride) ... 

Aryl- and heteroaryl halides can undergo thermal or transition metal catalyzed substitution reactions with amines. These reactions proceed on insoluble supports under conditions similar to those used in solution. Not only halides, but also thiolates [76], nitro groups [76], sulfinates [77,78], and alcoholates [79] can serve as leaving groups for aromatic nucleophilic substitution. 

Substitutions by the SRn 1 mechanism (substitution, radical-nucleophilic, unimolecular) are a well-studied group of reactions which involve SET steps and radical anion intermediates (see Scheme 10.4). They have been elucidated for a range of precursors which include aryl, vinyl and bridgehead halides (i.e. halides which cannot undergo SN1 or SN2 mechanisms), and substituted nitro compounds. Studies of aryl halide reactions are discussed in Chapter 2. The methods used to determine the mechanisms of these reactions include inhibition and trapping studies, ESR spectroscopy, variation of the functional group and nucleophile reactivity coupled with product analysis, and the effect of solvent. We exemplify SRN1 mechanistic studies with the reactions of o -substituted nitroalkanes (Scheme 10.29) [23,24]. 

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