Alkyl halides nitrile synthesis

Both methods of nitrile synthesis—SN2 displacement by CN- on an alkyl halide and amide dehydration—are useful, but the synthesis from amides is more general because it is not limited by steric hindrance. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Annwer We should need keto-ester (17) for this, and even then alkylation with secondary halide (18) is iikely to be poor. Alternatively we could use nitrile (19) but this requires the same alkyl halide (IS). The Michael synthesis on page 133 is best. 

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). 

Problem 18.8 Prepare ethylamine by (a) Gabriel synthesis, (6) alkyl halide amination, (c) nitrile reduction, (d) reductive amination, (e) Hofmann degradation. ... 

Nitriles are most commonly prepared via the conversion of carboxylic acids to primary amides, followed by dehydration with boiling acetic anhydride, or other commonly employed dehydration reagents, e.g. SOCI2 or POCI3. This is a useful synthesis for amide, because it is not limited by steric hindrance. Alkyl nitriles can be prepared by the action of metal cyanides on alkyl halides (see Section 5.5.2). 

Reactions at o -Position. Many studies have been concerned with the reactions of alkyl halides with cyanide in the presence of various metal ions, and with the direct alkylation of cyanide complexes. The classic synthesis of isonitriles was accomplished by the use of silver cyanide, whereas the corresponding reaction of organic halogen compounds with alkali cyanides yields nitriles (Equations 40 and 41) (34,36). 

Nitriles may be prepared by several methods (1). The first nitrile to be prepared was propionitrile, which was obtained in 1834 by distilling barium ethyl sulfate with potassium cyanide. This is a general preparation of nitriles from sulfonate salts and is referred to as the Pelouze reaction (2). Although not commonly practiced today, dehydration of amides has been widely used to produce nitriles and was the first commercial synthesis of a nitrile. The reaction of alkyl halides with sodium cyanide to produce nitriles (eq. 1) also is a general reaction with wide applicability ... 

An ester is formed when a nitrile is heated with an alcohol in the presence of concentrated sulphuric acid, thus providing a two-step synthesis of an ester from an alkyl halide. Examples are to be found in Expt 5.152. The reaction proceeds by way of an intermediate imino-ester (7) which is not usually isolated, but may be if so required.163... 

Nitriles can be prepared by the SN2 reaction of a cyanide ion with a primary alkyl halide. However, this limits the nitriles that can be synthesised to those having the following general formula RCH2CN. A more general synthesis of nitriles involves the dehydration of primary-amides with reagents such as thionyl chloride or phosphorus pentoxide ... 

The simplest method of nitrile preparation is S, -2 reaction of CN withs primary alkyl halide, as discus in Section 20.6. Hus method is Itocled by the usual Sx2 steric oonstrauiu to the synthesis of u-umidiKiUitRl nitriles. RCKjCN. 

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