Hydrolysis of a nitrile to an amide

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. 

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. 

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. 

Most reactions of substituents attached to carbon are trivial transformations, such as hydrolysis of a nitrile to an amide on a 3,4-dihydropyrrolo[l,2-c][l,3]thiazine <85EUP147317>, oxidation of a lactol (90) to a lactone by a Swem procedure <92SL847>, or equilibration via enolization as in pyrrolooxazinedione (190) (Equation (62)) <91NJC379>. Of more importance is the reductive debro-mination by tributyltin hydride of the bromomethyl derivatives formed by bromolactonization (see Section 8.11.6.4). 

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. 

Hydrolysis of a nitrile and an amide have both been converted for use in undergraduate laboratory classes (Scheme 6.13). The base-catalyzed hydrolysis of o-tol-unitrile can be performed using either a monomode (150 C for 10 min) or multimode unit (150 °C for 6 min) in sealed-vessel format. The shorter time required at the target temperature when using a multimode unit as opposed to the monomode systan is at first counterintuitive. However, the time taken to reach 150 C is significantly... 

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

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. 

The nitrile 70 gives a stabilised anion with NaH that reacts with the tosylate with inversion as expected. The rather unusual sulfonamide deprotection with HBr in phenol gave the amine 72 that was coupled to the rest of the molecule as an amide. Reduction of the amide to the amine and, finally, hydrolysis of the nitrile to the amide gave darifenacin 63. 

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. 

To decrease the number of operations, an obvious remedy is to redefine the route by using different starting materials that require fewer steps to produce the product. Another similar time-saving approach is to carry out more than one synthetic transformation in one step. For example, three double reactions were developed for the benzazepine 7 (Figure 2.9) hydrolysis of a nitrile and an oxazoline, reduction of an amide and an ester/lactone, and cyclization-demethylation [12], Such double reactions save considerable operating time and expenses on scale. 

Both acid- and base-induced hydrolysis of a nitrile gives the amide, but rather severe conditions are required for the reactions, and further hydrolysis of the intermediate amides gives the carboxylic acids (p. 902). In acid, the first step is protonation of the nitrile nitrogen to give a strong Lewis acid (A, Fig. 18.45), which is attacked by water. A series of proton shifts then gives an amide that is hydrolyzed to the carboxylic acid. 

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.

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). 

Base-Catalyzed Hydrolysis of a Nitrile 1014 Hydride Reduction of an Ester 1015 Reduction of an Amide to an Amine 1016 Reaction of an Ester with Two Moles of a Grignard Reagent 1018... 

Acid catalysed hydrolysis of the nitrile to give an amide then occurs this reaction proceeds by a sequence of addition-elimination steps. 

Hydrolysis of a Nitrile (Section 18.4E) Either acid or base is required in an amoimt equivalent to that of the nitrile. In acid, the mechanism involves an initial protonation of the nitrile N atom, followed by attack by water to give an imidic acid that tautomer-izes to give an amide, and the rest proceeds the same as for amide hydrolysis in acid. 

Treatment of a nitrile with an equivalent amount of 100% formic acid in a bomb permits hydrolysis to the pure amide in almost quantitative yield59. 

Fischer Esterification—Acid-Catalyzed Conversion of Carboxylic Acids to Esters 848 Conversion of Carboxylic Acids to Amides with DCC 850 Acid-Catalyzed Hydrolysis of an Ester to a Carboxyhc Acid 851 Base-Promoted Hydrolysis of an Ester to a Carboxyhc Acid 852 Amide Hydrolysis in Base 856 Hydrolysis of a Nitrile in Base 864 Reduction of a Nitrile with LiAlH4 865 Reduction of a Nitrile with DIBAL-H 866... 

Stereospecific nitrilases were used for the conversion of a-arninonitiiles to optically active L-amino acids (Fig. 4). In an early investigation, L-alanine was formed by an l-specific nitrilase from alginate-immobilized cells of Acinetobacter sp. APN [25]. A decrease of the enantioselectivity with the time was supposed to be caused by a racemase forming d- from L-alanine. The stereoinversion of racemic a-aminopropionitrile led to a conversion yield above 50%. Similar L-a-amino acid preparations showed no stereoinversion and additionally accumulated the D-amide due to the presence of a nitrile hydratase/ amidase system [26,27]. Additionally, a number of L-a-amino acids were synthesized by a 45-kDa monomeric nitrilase from R. rhodochrous PA-34 [28]. Remarkable in this case was the preferential hydrolysis of a-aminopropionitrile to D-alanine in contrast to the l-alanine formation by the Acinetobacter nitrilase (Fig. 4). 

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