Nucleophilic alkyl substitution benzylic halides

An alternative route involves the nucleophilic substitution of an alkyl or benzyl halide with a cyanide ion. Two reactions are possible, leading to an isocyanide (R N=C) or a cyanide (R -ON). 

Benzylic halides that are secondary resemble secondary alkyl halides in that they undergo substitution only when the nucleophile is weakly basic If the nucleophile is a strong base such as sodium ethoxide elimination by the E2 mechanism is faster than substitution... 

A mechanism of this type permits substitution of certain aromatic and ahphatic nitro compounds by a variety of nucleophiles. These reactions were discovered as the result of efforts to explain the mechanistic basis for high-yield carbon alkylation of the 2-nitropropane anion by p-nitrobenzyl chloride. p-Nitrobenzyl bromide and iodide and benzyl halides that do not contain a nitro substituent give mainly the unstable oxygen alkylation product with this ambident anion ... 

The possibility that substitution results from halogen-atom transfer to the nucleophile, thus generating an alkyl radical that could then couple with its reduced or oxidized form, has been mentioned earlier in the reaction of iron(i) and iron(o) porphyrins with aliphatic halides. This mechanism has been extensively investigated in two cases, namely the oxidative addition of various aliphatic and benzylic halides to cobalt(n) and chromiumfn) complexes. 

You have read (Unit 10, Class Xll) that the carbon - halogen bond In alkyl or benzyl haUdes can be easily cleaved by a nucleophile. Hence, an allqrl or ben l haUde on reaction with an ethanollc solution of ammonia undergoes nucleophilic substitution reaction m which the halogen atom Is replaced by an amino (-NHJ group. This process of cleavage of the C-X bond by ammonia molecule Is known as ammonolysis. The reaction Is carried out In a sealed tube at 373 K. The primary amine thus obtained behaves as a nucleophile and can further react with allqrl halide to form secondary and tertiary amines, and finally quaternary ammonium salt. 

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... 

V-Bromosuccinimide (NBS) is a reagent used to substitute benzylic and allylic hydrogens with bromine. The benzylic bromide undergoes SN2 substitution with the nucleophile, methanethiolate. As in part (e), the alkyl halide is more reactive toward substitution than the aryl halide. 

First-Order Reactions First-order nucleophilic substitution requires ionization of the halide to give a carbocation. In the case of a benzylic halide, the carbocation is resonance-stabilized. For example, the 1-phenylethyl cation (2°) is about as stable as a 3° alkyl cation. 

The most important reactions of tetrazolate anions are alkylations in which the anion is used as a nucleophile in substitution reactions mainly with alkyl halides and sulfates. Many such reactions have been reported and a variety of conditions and reagents have been employed. The products are mixtures of iV(l)- and iV(2)-alkyl isomers, the relative proportions of which depend upon the conditions of the alkylation and the influence of the 5-substituent. In general, electron-donating substituents at C-5 tend to favor slightly alkylation at the N(l)-site while electron withdrawing substituents favor 1V(2)-alkylation. The position of alkylation was also influenced by the steric requirements of the alkylating agent and was found to be insensitive to electronic effects of para-substituents on benzyl... 

Like ally lie halides, benzylic halides undergo nucleophilic substitution, both S l and Sn2, faster than simple alkyl halides. 

Among the various carboxylic acid derivatives, acyl chlorides are especially useful because they are readily converted to acid anhydrides, esters, and amides by nucleophilic acyl substitution (Table 19.1). Yields are high and the reaction rates are much greater than the corresponding rates of alkyl halides with the same nucleophiles. Benzoyl chloride, for example, is about 1,000 times more reactive than benzyl chloride toward hydrolysis at 25°C. 

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