Acidic hydrolysis of a nitrile

In basic hydrolysis, a hydroxide ion attacks the nitrile carbon atom, and subsequent protonation leads to the amide tautomer. Further attack by the hydroxide ion leads to hydrolysis in a manner analogous to that for the basic hydrolysis of an amide (Section 17.8F). (Under the appropriate conditions, amides can be isolated when nitriles are hydrolyzed.) 

Cyclic amides are called lactams. The size of the lactam ring is designated by Greek letters in a way that is analogons to lactone nomenclature (Section 17.7C)  

The penicillin antibiotics (see the following structures) contain a j8-lactam ring  

The penicillins apparently act by interfering with the synthesis of bacterial cell walls. It is thought that they do this by reacting with an amino group of an essential enzyme of the cell wall biosynthetic pathway. This reaction involves ring opening of the j8-lactam and acylation of the enzyme, inactivating it. 

Bacterial resistance to the penicillin antibiotics is a serious problem for the treatment of infections. Bacteria that have developed resistance to penicillin produce an enzyme called penicillinase. Penicillinase hydrolyzes the /3-lactam ring of penicillin, resulting in penicilloic acid. Because penicilloic acid cannot act as an acylating agent, it is incapable of blocking bacterial cell wall synthesis by the mechanism shown above. 

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The mechanism for acidic hydrolysis of a nitrile resembles the basic hydrolysis, except that the nitrile is first protonated, activating it toward attack by a weak nucleophile (water). Under acidic conditions, the proton transfer (tautomerism) involves protonation on nitrogen followed by deprotonation on oxygen. Propose a mechanism for the acid-catalyzed hydrolysis of benzonitrile to benzamide. 

Acid-catalyzed nitrile hydrolysis is similar to amide hydrolysis and occurs by initial protonation of the nitrogen atom, followed by nucleophilic addition of water. Write all the steps involved in the acidic hydrolysis of a nitrile to yield a carboxylic acid, using curved arrows to represent electron flow in each step. 

Acid-Catalyzed Esterification 790 Base-Promoted Hydrolysis of an Ester 793 DCC-Promoted Amide Synthesis 798 Acidic Hydrolysis of an Amide 799 Basic Hydrolysis of an Amide 799 Acidic Hydrolysis of a Nitrile 801 Basic Hydrolysis of a Nitrile 801... 

Acid hydrolysis of a nitrile is carried out in cone. HCl, 75% H2SO4, or in its mixture with 85% phosphoric acid, at temperatures from 150 to 190 °C. In the case of volatile nitriles the reaction should be carried out in a sealed tube. 

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... 

In a departure from the prototype molecule, the benzylpiperi-done is first converted to the corresponding aminonitrile (a derivative closely akin to a cyanohydrin) by treatment with aniline hydrochloride and potassium cyanide (126). Acid hydrolysis of the nitrile affords the corresponding amide (127). Treatment with formamide followed by reduction affords the spiro oxazinone... 

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. 

Other examples of an attack on C from an alkoxy radical at C20 are recorded in the literature for instance, in the progesterone series the oxime (7) obtained from the photolysis of the corresponding nitrite was converted to the nitrile (8) J Oxidation and acid hydrolysis of the nitrile (8) gave 3,20-diketo-4-pregnen-18-oic acid (9) identical with a... 

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. 

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.

Acid hydrolysis of the nitrile in the API cimetidine leads to the corresponding amide which then undergoes further degradation through loss of the CONH2 moiety via a pathway that is analogous to a (3-keto acid decarboxylation (Fig. 30) (47). 

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