Hydrolysis of a nitrile to an acid

Hydrolysis of a nitrile to an acid. Reflux 1 g. of the nitrile with 6 ml. of 30-40 per cent, sodium hydroxide solution until ammonia ceases to be evolved (2-3 hours). Dilute with 5 ml. of water and add, with coohng, 7 ml. of 50 per cent, sulphuric acid. Isolate the acid by ether extraction, and examine its solubility and other properties. 

Hydrolysis of a nitrile to an amide. Warm a solution of 1 g. of the nitrile benzyl cyanide) in 4 ml. of concentrated sulphuric acid to 80-90°, and allow the solution to stand for 5 minutes. Cool and pour the solution cautiously into 40 ml. of cold water. Filter oflT the precipitate stir it with 20 ml. of cold 5 per cent, sodium hydroxide solution and filter again. RecrystaUise the amide from dilute alcohol, and determine its m.p. Examine the solubility behaviour and also the action of warm sodium hydroxide solution upon the amide. 

The reaction conditions required for acid-catalyzed hydrolysis of a cyano group are typically more vigorous than those required for hydrolysis of an amide, and in the presence of excess water, a cyano group is hydrolyzed first to an amide and then to a carboxylic acid. It is possible to stop at the amide by using sulfuric acid as a catalyst and one mole of water per mole of nitrile. Selective hydrolysis of a nitrile to an amide, however, is not a good method for the preparation of amides. They are better prepared from acid chlorides, acid anhydrides, or esters. 

Nitrilase [EC 3.5.5.1], also known as nitrile aminohy-drolase and nitrile hydratase, catalyzes the hydrolysis of a nitrile to produce a carboxylate and ammonia. The enzyme acts on a wide range of aromatic nitriles. Nitrile hydratase [EC 4.2.1.84], also known as nitrilase, catalyzes the hydrolysis of a nitrile to produce an aliphatic amide. The enzyme acts on short-chain aliphatic nitriles, converting them into the corresponding acid amides. However, this particular enzyme does not further hydrolyze these amide products nor does the enzyme act on aromatic nitriles. 

Active Figure 20.4 MECHANISM Mechanism of the basic hydrolysis of a nitrile to yield an amide, which is subsequently hydrolyzed further to a carboxylic acid anion. Sign in at www.thomsonedu.com to see a simulation based on this figure and to take a short quiz. 

Mechanism of the basic hydrolysis of a nitrile to yield an amide, which is subsequently hydrolyzed further to a carboxylic acid. 

The sodium salt of succinimide reacts with a,o)-dibromide such as 4.93 to give 4.94. In a second step, the enolate of a-phenyl nitrile displaced the bromide moiety in 4.94 to give 4.95. Acid hydrolysis converted the nitrile to an acid and the imide to an amine, leading to 4.96. Reaction of 4.94 (n = 4) with the indicated nitrile (R = H) led to a 57% yield of 2-phenyl-6-aminohexanoic acid (4.96a). Similarly prepared were 2-phenyl-7-aminoheptanoic acid 4.96b) in 68% yield 2-phenyl-8-amino-octanoic acid 4.96c) in 68% yield 2-phenyl-10-aminodecanoic acid 4.96d) in 44% yield and, 2-phenyl-12-aminododecanoic acid 4.96e) in 26% yield, all with R = H.45 Many other nitriles were used in this sequence to give a wide variety of phenyl... 

Figure 5.5 Degradation routes for nitriles. The first route is a two-step reaction involving a nitrile hydratase, which converts the nitrile to the amide, and an amidase, which converts the amide to the corresponding acid. The second pathway involves direct hydrolysis of the nitrile to the carboxylic acid and ammonia by a nitrilase.

The presence of the propionamide fragment in the stmcture of the anti-inflammatory agent broperamole (125-1) is reminiscent of the heterocycle-based NSAID propionic acids. The activity of this agent may trace back to the acid that would result on hydrolysis of the amide. Tetrazoles are virtually always prepared by reaction of a nitrile with hydrazoic acid or, more commonly, sodium azide in the presence of acid in a reaction very analogous to a 1,3-dipolar cycloaddition. A more recent (and safer) version of the reaction noted later (see losartan, 77-4) uses tributyltin azide. In the case at hand, reaction of the anion of mefa-bromobenzonitrile (125-1) with sodium azide and an acid affords the tetrazole (125-2). Condensation of the anion from that intermediate with ethyl acrylate leads to the product from Michael addition saponiflcation gives the corresponding carboxylic acid (125-3). This is then converted to the acid chloride reaction with piperidine affords broperamole (125-4) [136]. 

The individual steps are (a) the anodically formed nickel oxide hydroxide dehydrogenates the amine to an imine (b) the imine is further dehydrogenated to the nitrile (c) competing with the second dehydrogenation are the hydrolysis of the imine to an aldehyde and its further oxidation to an acid or (d) the condensation with the starting amine to form an azomethine. 

Amides are also available from nitriles, which have the same oxidation level. Direct acid or base hydrolysis of a nitrile usually requires fairly severe conditions and often does not stop at the amide stage but goes on the carboxylic acid. Treatment of nitriles with a solution of HC1 in ethanol furnishes an imidate ester which is hydrolyzed in aqueous acid to the amide. Because a nitrile is the starting material, only primary amides can be produced by this process. 

In the case of water as a nucleophile, the initially produced hydroxyimine may tauto-merise to an amide, which in turn generates a carboxylic acid upon further hydrolysis. Hydrolysis of a nitrile is, of course, one of the standard classical methods for the synthesis of carboxylic acids (Fig. 4-7). 

This reaction proceeds by initial reaction of ammonium chloride with the aldehyde to form an imine (see Section 18.8). Then cyanide adds to the imine in a reaction that is exactly analogous to the addition of cyanide to an aldehyde to form a cyanohydrin (see Section 18.4). The final step in the Strecker synthesis is the hydrolysis of the nitrile to a carboxylic acid (see Section 19.5). 

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