Basic hydrolysis of a nitrile

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. 

Carbonic anhydrase is an enzyme that interconverts water and carbon dioxide with carbonic acid. A carbonate dianion is shown in red within the structure of carbonic anhydrase above. 

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

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. 

An aq.-alc. soln. of the startg. cyanoketone warmed in pH 10 NaaCOg/NaHCOg buffer 7-hydroxy-a,a,y-trimethylbutyrolactam. Y 84%. - This reaction involves an unusually mild basic hydrolysis of a nitrile. F. e. s. R. V. Stevens and M. Kaplan, Chem. Commun. 1970, 822. 

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... 

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. 

Problem-Solving Strategy Proposing Reaction Mechanisms 1007 Mechanism 21-8 Transesterification 1008 21-7 Hydrolysis of Carboxylic Acid Derivatives 1009 Mechanism 21-9 Saponification of an Ester 1010 Mechanism 21-10 Basic Hydrolysis of an Amide 1012 Mechanism 21-11 Acidic Hydrolysis of an Amide 1012 Mechanism 21-12 Base-Catalyzed Hydrolysis of a Nitrile 1014 21-8 Reduction of Acid Derivatives 1014... 

Another way to convert an alkyl halide (or tosylate) to a carboxylic acid with an additional carbon atom is to displace the halide with sodium cyanide. The product is a nitrile with one additional carbon atom. Acidic or basic hydrolysis of the nitrile gives a carboxylic acid by a mechanism discussed in Chapter 21. This method is limited to halides and tosylates that are good SN2 electrophiles usually primary and unhindered. 

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. 

From 2-aminonicotinamides, the C—N chain in the 3-position of the pyridine originates from a carboxamide group which, in turn, may be obtained by hydrolysis of a nitrile function. Cyclization reactions usually require basic conditions and have been performed with a variety of reagents. 

Shiner, C. S. Fisher, A. M. Yacoby, F. Intermediacy of a-Chloro Amides in the Basic Hydrolysis of a-Chloro nitriles to Ketones Tetrahedron Lett. 1983, 24, 5687-5690. 

We have seen (earlier in this section) that primary alcohols and aldehydes can be oxidized to carboxylic acids. Carboxylic acids can also be prepared by the hydrolysis of nitriles. The hydrolysis of a nitrile can be carried out in either acidic or basic solution, as suggested below ... 

Although the biosynthetic cascade hypothesis predicts the co-occurrence of endiandric acids D (4) and A (1) in nature, the former compound was not isolated until after its total synthesis was completed in the laboratory (see Scheme 6). Our journey to endiandric acid D (4) commences with the desilylation of key intermediate 22 to give alcohol 31 in 95% yield. The endo side chain is then converted to a methyl ester by hydrolysis of the nitrile to the corresponding acid with basic hydrogen peroxide, followed by esterification with diazomethane to afford intermediate 32 in 92% overall yield. The exo side chain is then constructed by sequential bromination, cyanide displacement, ester hydrolysis (33), reduction, and olefination (4) in a straight-... 

The basic hydrolysis (reaction with water) of a nitrile (R-CN) followed by acidification yields a carboxylic acid. In general, an reaction (nucleophilic substitution) of an alkyl halide is used to generate the nitrile before hydrolysis. Figure 12-12 illustrates the formation of a carboxylic acid beginning with an alkyl halide. 

The conservation of charge is a fundamental law for all processes, such as the addition of nucleophiles to it systems or acid-base reactions. The first step of die basic hydrolysis of nitriles has die hydroxide ion adding to the it bond of die nitrile. For the purposes of mechanistic discussion, the hydroxide is shown widiout its counterion and die net charge on the reactant side of the equation is — 1. Consequently, the product of diis first step (and each subsequent step) must also have a net negative charge. 

Reactions of Nitriles Nitriles undergo acidic or basic hydrolysis to amides, which may be further hydrolyzed to carboxylic acids. Reduction of a nitrile by lithium aluminum hydride gives a primary amine, and the reaction with a Grignard reagent gives an imine that hydrolyzes to a ketone. 

A15.1.2.3 Nitriles. Nitriles are classihed as carboxylic acid derivatives because they are converted to carboxylic acids on hydrolysis. Like the hydrolysis of amides, nitrile hydrolysis is irreversible in the presence of acids or bases. Acid hydrolysis yields an ammonium ion and a carboxylic acid, e.g., cimeti-dine [15]. Nitriles are also susceptible to oxidation by peroxides under mildly basic conditions (e.g., pH 7.5 to 8). 

In a similar way, transition metal ions catalyze the basic hydrolysis of esters of a-amino acids [271]. The rate law [272, 273] is analogous to that observed in the hydration of phenanthroline-nitrile, viz. 

The transformation of alkyl halides with cyanides (equation 1) represents not only the classical route to nitriles, but, if modified properly, is still of very great practical importance even today. A whole series of review articles stress the scope and value of this reaction. Although the substituent R may be varied to a large extent, the primary as well as the benzylic halides generally give higher yields than secondary and tertiary ones, as, with the latter, the formation of alkenes gains in importance. This side reaction as well as the undesired formation of alcohols and ethers, which sometimes takes place in aqueous media or with alcohols as solvent, is of course due to the basicity of the cyanide ion. Under deleterious conditions one may even observe carboxylic acids, which result fi-om the hydrolysis of the nitriles. - Some of these undesired side reactions may be avoided by the use of CuCN instead of sodium or potassium cyanide. ... 

The basic hydrolysis of nitrile 50 with aqneons NaOH in ethanol was examined, which proceeded throngh intermediate amides 57, and reached 98% conversion to acid 3 within 4 hr with <1% of amides remaining. Both cis- and trani-amides were observed by liqnid chromatogra-phy/mass spectrometry (LC/MS) during reaction, and the strnctnre of trans-amide Sit was confirmed by LC/MS and independent synthesis (by treatment of trani-pyrrolidine acid with CDI and ammoninm hydroxide). It is reasonable to postnlate that the hydrolysis of both di-nitrile 50 and di-amide Sic to the corresponding di-acids was slow relative to epimerization, which provided a mechanism for complete conversion of di-nitrile 50 to trani-acid 3. 

The mechanism of the Strecker reaction has received considerable attention over its lifespan.4 The conversion of a carbonyl compound into an a-amino acid, by this method, requires a two-step process. The first step consists of the three-component condensation of cyanide and ammonia with the carbonyl compound 1 to produce an intermediate, a-aminonitrile 3. The second step involves the hydrolysis of the nitrile functional group to reveal the latent carboxylic acid 4. Whereas the second step is fairly straightforward and can be done under basic or acid conditions, the first step is more involved than one may expect. The widely accepted sequence for the first step is the nucleophilic addition of ammonia to the carbonyl carbon to produce the corresponding imine derivative 2. Once formed, this initial species is captured by the cyanide anion to generate the requisite a-aminonitrile 3. 

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