From Alkyl Halides via Nitriles

Primary or secondary alkyl halides can be converted into nitriles (alkyl cyanide) by nucleophilic substitution. The nitriles formed can in turn be converted to carboxylic acids by hydrolysis. 

The cyanide ion is negatively charged and the negatively charged carbon atom has nucleophilic character. The reaction usually occurs via 8, 2 mechanism. The nitrile formed can be hydrolyzed to a carboxylic acid. 

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Many other examples of synthetic equivalent groups have been developed. For example, in Chapter 6 we discussed the use of diene and dienophiles with masked functionality in the Diels-Alder reaction. It should be recognized that there is no absolute difference between what is termed a reagent and a synthetic equivalent group. For example, we think of potassium cyanide as a reagent, but the cyanide ion is a nucleophilic equivalent of a carboxy group. This reactivity is evident in the classical preparation of carboxylic acids from alkyl halides via nitrile intermediates. 

Sandmeyer s synthesis of aromatic nitriles is far more elegant than the removal of water from the ammonium salts of carboxylic acids, which latter reaction is also applicable to benzene derivatives. In particular, the former synthesis permits of the preparation of carboxylic acids via the nitriles, and so provides a complete substitute for Kolbe s synthesis (alkyl halide and potassium cyanide), which is inapplicable to aromatic compounds. The simplest example is the conversion of aniline into benzoic add. The converse transformation is Hofmann s degradation (benzamide aniline, see p. 152). 

Ketenimines are usually prepared from carboxylic acid derivatives such as amides and imino chlorides via elimination and from nitriles via alkylation with alkyl halides under strong basic conditions (21,64). 

Alkyl halides are used to make some higher alkylamines, just as in the laboratory (Sec. 22.10). The acids obtained from fats (Sec. 33.4) can be converted into long-chain 1-aminoalkanes of even carbon number via reduction of nitriles (Sec. 22.8). 

N-Pentylamine Synthesis N-Pentylamine s structure (CH3CH2CH2CH2CH2NH2) indicates it is composed of 5 carbon atoms. Since the starting material cannot have over 4 carbon atoms, the synthesis of the amine must include an increase in the carbon skeleton of the starting material. Synthesis via reduction of nitriles (-CHN) has the special feature of increasing the length of a carbon chain, producing a primary amine that has one more carbon atom than the alkyl halide from which the nitrile was made. 

There is one more way for conversion of ort/to-nitroarylacetonitriles into indoles. Alkylation of such nitriles with allyl or benzyl halides followed by treatment of the compounds obtained with basic agents results in a multistep transformation, which is likely to proceed via intermediate nitrosoarenes, to produce 1-hydroxyindoles. For instance, alkylation of ort/io-nitroarylacetonitriles with 3-phenylallyl bromide gives the compounds that in the presence of chlorotri-methylsilane and triethylamine undergo cyclization into 3-cyano-l-hydroxy-2-vinylindoles (Scheme 70) [188]. Presumably, this reaction proceeds via 0-silylation of the nitronate anion and 1,5-elimination of trimethylsilanol from the intermediate trimethylsilyl nitronate, followed by cyclization and a hydrogen shift. 

Reactions.—The use of NaBH, in polar aprotic solvents as a convenient and effective source of nucleophilic hydrogen for the reduction of alkyl halides (and tosylates) to alkanes has been reported in full this year. This reagent is selective and does not affect other functional groups such as ester or nitrile (contrast LiAlH4). Sodium trimethoxyborohydride is an alternative, especially for reduction in the presence of alkene functions this report also includes details of a one-pot sequence from alcohols via the iodides to alkanes (Scheme 46). ... 

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