Aryl halides and nucleophilic aromatic substitution

Chlorobenzene, for example, can be boiled with sodium hydroxide for days without producing a detectable amount of phenol (or sodium phenoxide). Similarly, when vinyl chloride is heated with sodium hydroxide, no substimiion occurs  

We can understand this lack of reactivity on the basis of several factors. The benzene ring of an aryl halide prevents back-side attack in an Sn2 reaction  

Phenyl cations are very unstable thns SnI reactions do not occnr. The carbon-halogen bonds of aryl (and vinylic) halides are shorter and stronger than those of alkyl, allylic, and benzylic halides. Stronger carbon-halogen bonds mean that bond breaking by either an S l or Sn2 mechanism will require more energy. 

Two effects make the carbon-halogen bonds of aryl and vinylic halides shorter and stronger (1) The carbon of either type of halide is sp hybridized, and therefore the electrons of the carbon orbital are closer to the nucleus than those of an -hybridized carbon. (2) Resonance of the type shown here strengthens the carbon-halogen bond by giving it double-bond character  

Having said all this, we shall find in the next two subsections that aryl halides can be remarkably reactive toward nucleophiles if they bear certain substituents or when we allow them to react under the proper conditions. 

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An aryl halide can also be coupled to an amine using metal catalysis. The reaction represents an alternative to the classical methods for the synthesis of aryl amines, such as reduction of nitro groups and nucleophilic aromatic substitution (see Chapter 8). 

We have seen that the aryl halides are characterized by very low reactivity toward the nucleophilic reagents like OH , OR, NH3, and CN" that play such an important part in the chemistry of the alkyl halides. Consequently, nucleophilic aromatic substitution is much less important in synthesis than either nucleophilic aliphatic substitution or electrophilic aromatic substitution. 

Other aryl halides that give stabilized anions can undergo nucleophilic aromatic substitution by the addition-elimination mechanism Two exam pies are hexafluorobenzene and 2 chloropyridme... 

The reaction between an alkoxide ion and an aryl halide can be used to prepare alkyl aryl ethers only when the aryl halide is one that reacts rapidly by the addition-elim mation mechanism of nucleophilic aromatic substitution (Section 23 6)... 

How- does this reaction take place Although it appears superficially similar to the SN1 and S 2 nucleophilic substitution reactions of alkyl halides discussed in Chapter 11, it must be different because aryl halides are inert to both SN1 and Sj 2 conditions. S l reactions don t occur wdth aryl halides because dissociation of the halide is energetically unfavorable due to tire instability of the potential aryl cation product. S]sj2 reactions don t occur with aryl halides because the halo-substituted carbon of the aromatic ring is sterically shielded from backside approach. For a nucleophile to react with an aryl halide, it would have to approach directly through the aromatic ring and invert the stereochemistry of the aromatic ring carbon—a geometric impossibility. 

Synthetically important substitutions of aromatic compounds can also be done by nucleophilic reagents. There are several general mechanism for substitution by nucleophiles. Unlike nucleophilic substitution at saturated carbon, aromatic nucleophilic substitution does not occur by a single-step mechanism. The broad mechanistic classes that can be recognized include addition-elimination, elimination-addition, and metal-catalyzed processes. (See Section 9.5 of Part A to review these mechanisms.) We first discuss diazonium ions, which can react by several mechanisms. Depending on the substitution pattern, aryl halides can react by either addition-elimination or elimination-addition. Aryl halides and sulfonates also react with nucleophiles by metal-catalyzed mechanisms and these are discussed in Section 11.3. 

For model reactions, we chose the aromatic substitution of aryl halides with nucleophiles such as phenolates or amines. The reaction parameters particularly focused upon were reaction time, selectivity, work-up procedure, and overall processing time. 

Nucleophilic substitution of halogen atom in aromatic and heteroaromatic halides with a hydroxyamino group proceeds only in substrates that are activated by a strong electron-withdrawing substituent in the benzene ring (e.g. 27, equation 17). Despite this limitation this reaction is useful for synthesis of arylhydroxylamines and usually provides good yields of products. Along with activated aryl halides and sulfonates, activated methyl aryl ethers such as 28 can be used (equation 18). 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

Aryl halides bearing strong electron-withdrawing groups and thus allowing nucleophilic aromatic substitution can be used for the arylation of azinone anions. 4-(4-Hydroxy-3-methylphenyl)phthalazin-l(2//)-one has been arylated simultaneously at N-2 and at the phenolic OH with 4-chlorobenzonitrile and potassium carbonate in dimethyl-acetamide (DMA) <2005CHJ200>. 

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>. 

Organic molten salts such as tris-n-butyl-dodecylphosphonium halides (melting point below 40°C) have been used as reaction media for nucleophilic aromatic substitution of aryl tosylates by halide ions (Fry and Pienta, 1985). 

As mentioned earlier, Ding et al.15 captured a number of dichlorohetero-cyclic scaffolds where one chloro atom is prone to nucleophilic aromatic substitution onto resin-bound amine nucleophiles (Fig. 1). Even though it was demonstrated that in many cases the second chlorine may be substituted with SNAr reactions, it was pointed out that palladium-catalyzed reactions offer the most versatility in terms of substrate structure. When introducing amino, aryloxy, and aryl groups, Ding et al.15 reported Pd-catalyzed reactions as a way to overcome the lack of reactivity of chlorine at the purine C2 position and poorly reactive halides on other heterocycles (Fig. 10). 

Iron sulfate [82] and iron chloride [83] have also been reported as catalysts for the nucleophilic aromatic substitution of unactivated aryl halides. As solvents, liquid ammonia and DMSO at room temperature are used (Scheme 6.17). 

Reaction of a nitro-substituted aryl halide with a good nucleophile leads to nucleophilic aromatic substitution. Methoxide will displace fluoride from the ring, preferentially at the positions ortho and... 

The reason this reaction is suitable is that it involves nucleophilic aromatic substitution by the addition-elimination mechanism on a p-nitro-substituted aryl halide. Indeed, this reaction has been carried out and gives an 80-82% yield. A reasonable synthesis would therefore begin with the preparation of p -ch I oron itrobenzene. 

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