Hydrolysis of a nitrile

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. 

Among the methods for preparing carboxylic acids carboxylation of a Grignard reagent and preparation and hydrolysis of a nitrile convert RBr to RCO2H The malonic ester synthesis converts RBr to RCH2CO2H... 

JCS(C)2613) systems, and in many cases the starting materials are available via oxazine intermediates (e.g. 113), or by in situ hydrolysis of a nitrile (74GEP2365302). 

Active Figure 20.4 MECHANISM Mechanism of the basic hydrolysis of a nitrile to yield an amide, which is subsequently... 

Acid-catalyzed hydrolysis of a nitrile to give a carboxylic acid occurs by initial protonation of the nitrogen atom, followed by nucleophilic addition of water. Review the mechanism of base-catalyzed nitrile hydrolysis in Section 20.7, and then write all the steps involved in the acicl-catalyzed reaction, using curved arrows to represent electron flow in each step. 

Some companies are successfully integrating chemo- and biocatalytic transformations in multi-step syntheses. An elegant example is the Lonza nicotinamide process mentioned earlier (.see Fig. 2.34). The raw material, 2-methylpentane-1,5-diamine, is produced by hydrogenation of 2-methylglutaronitrile, a byproduct of the manufacture of nylon-6,6 intermediates by hydrocyanation of butadiene. The process involves a zeolite-catalysed cyciization in the vapour phase, followed by palladium-catalysed dehydrogenation, vapour-pha.se ammoxidation with NH3/O2 over an oxide catalyst, and, finally, enzymatic hydrolysis of a nitrile to an amide. 

A paper concerning the synthesis of miharamycin analogues modified in the sugar moiety demonstrated the hydrolysis of a nitrile upon treatment with silica gel in the presence of water (Scheme 37).174 The cyanide 197 resulting from the opening of epoxide... 

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. 

Formation of carboxylic acid from alkyl halide using the hydrolysis of a nitrile. 

The first reaction is a nucleophilic addition of HCN to a ketone, the second is a dehydration of an alcohol and hydrolysis of a nitrile, and the third is esterification by methanol. 

Racemic pipecolic acid (6) is obtained by ring closure of TV-alkylglycines by ionic 203 or radical 204 mechanisms. It also may be obtained by conversion of suitable substituents at the C2 of piperidine into the 2-carboxy group, e.g. hydrolysis of a nitrile group 205 or oxidation of a 1,2-dihydroxyethyl group. 206 Resolution of the racemic mixture can be carried out by fractional crystallization. 207-209 Enzymatic resolution of racemic pipecolic acid 210-213 or of synthetic intermediates 214 has been reported. 

Of the two procedures just described, preparation and carboxy-lation of a Grignard reagent or formation and hydrolysis of a nitrile, only one is appropriate to each of the following RX RC02H conversions. Identify the correct procedure in each case, and specify why the other will fail. 

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. 

The interruption of the hydrolysis of a nitrile at the amide stage can often be achieved in a preparative manner, as for example in the preparation of phenyl-acetamide (Expt 5.156), where the nitrile is dissolved in concentrated hydrochloric acid at 40 °C and subsequently poured into water. The use of hot polyphosphoric acid has also been recommended.166... 

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). 

Figure 4-7. The hydrolysis of a nitrile to generate a carboxylic acid.

A special example of the hydrolysis of a nitrile is seen in the copper-promoted addition of water (or an alcohol) to 3-cyano-2-azamaleodinitrile (4.5). It is of interest that the nitrile is specifically attacked in preference to the imine (Fig. 4-12). 

Carboxylic acids are prepared by at least four methods (1) by oxidation of primary alcohols or aldehydes, (2) by oxidation of an aromatic side chain, (3) from a Grignard reagent and carbon dioxide, or (4) by hydrolysis of a nitrile, RC=N. 

Given a carboxylic acid, write an equation for its synthesis by hydrolysis of a nitrile (cyanide) or by the Grignard method. 

Fig. 7.8. Partial hydrolysis of a nitrile to a primary carboxylic acid amide under acidic conditions initiating the two-step total hydrolysis of acetone cyanohydrin (B). Grey background overall reaction above the grey area competing reactions with inappropriate choice of pH below the grey area mechanistic details.

Answer Procedure VI1-1 involving the carbonation of a Grignard reagent procedure VIS-2 whicli is the hydrolysis of a nitrile and procedure VII1-3, which is the oxidation of an alky benzene. 

Many of the reactions of a CN triple bond resemble those of a CO double bond, and the mechanisms have many similarities also. The mechanism for the hydrolysis of a nitrile to an amide under basic conditions is shown in Figure 19.6. 

Mechanism of the hydrolysis of a nitrile to an amide under basic conditions. 

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