Mechanism nitrile hydrolysis

The mechanism of nitrile hydrolysis will be described in Section 20.19. 

Base catalyzed nitrile hydrolysis involves nucleophilic addition of hydroxide ion to the polar C N bond to give an imine anion in a process similar to nucleophilic addition to a polar C=0 bond to give an alkoxide anion. Protonation then gives a hydroxy imine, which tautomerizes (Section 8.4) to an amide in a step similar to the tautomerization of an enol to a ketone. The mechanism is shown in Figure 20.4. 

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. 

An interesting method for the hydrolysis of nitriles to amides involves two redox processes with H2O2 and a peroxycarboximidic acid (236) intermediate stage, as shown in equation 84. The mechanism of hydrolysis was established for acetonitrile and benzonitrile... 

The right side of Figure 7.13 shows the details of the different variants of the Pinner reaction described above. The addition of methanol to the C=N triple bond follows the mechanism of the nitrile hydrolysis under acidic conditions (cf. Figure 7.8). 

The mechanism of acid-catalyzed nitrile hydrolysis is shown in Problem 20.45. 

Table 3.3 Electrochemical ligand parameters of the five species which may be involved in nitrile hydrolysis (substrates, products, intermediates). Whereas nitriles are not tightly bound, hydroxide binds to either metal center more strongly than both carboxamide and the corresponding base, acylamidate. Here, however, relative Brpnsted acidities of water and carboxamides must be taken into account. Water can only be transferred to a nitiile before being deprotonated at Zn(II) but not at Co(II) which means that this is not the actual mechanism of biochemical nitiile hydrolysis. Negative values of -log are given in brackets because they correspond to unstable complexes which hardly persist in water...

Carboxylic acitls can be prepared from nitriles by reaction with hot aqueous acic or base by a mechanism that we ll see in Section 20.9. Since nitriles themselves are usually made by Srsj2 reaction of a primary or secondary alkyl halide with CN , the two-step sequence of cyanide displacement followed by nitrile hydrolysis is a good way to make a carboxylic acid from an alkyl halide (RBr RC=N RCO2H). 

The mechanism of nitrile hydrolysis in both acid and base consists of three parts [1] nucleophilic addition of H2O or OH to form the imidic acid tautomer [2] tautomerization to form the amide, and [3] hydrolysis of the amide to form RCOOH or RCOO. The mechanism is shown for the basic hydrolysis of RCN to RCOO (Mechanism 22.11). 

The first four steps of the mechanism for hydrolysis of nitriles in basic solution are given in Mechanism 19.8. These steps convert the nitrile to an amide, which then proceeds to the hydrolysis products according to the mechanism of amide hydrolysis in Mechanism 19.7 (page 846). 

The acid-catalyzed mechanism for nitrile hydrolysis also goes through the amide as an intermediate. Problem 19.25 encourages you to propose a mechanism for that process. 

By hydrolysis of cyanohydrins and other nitriles. We saw, in Section 16.9, that aldehydes and ketones can be converted to cyanohydrins and that these can be hydrolyzed to ct-hydroxy acids. In the hydrolysis the —CN group is converted to a — CO2H group. The mechanism of nitrile hydrolysis is discussed in Section 17.8H ... 

On the other hand, nitrilases operate by a completely different mechanism (Scheme 2.101). They possess neither coordinated metal atoms, nor cofactors, but act through an essential nucleophilic sulfhydryl residue of a cysteine [641, 642], which is encoded in the nitrilase-sequence motif Glu-Lys-Cys [643]. The mechanism of nitrilases is similar to general base-catalyzed nitrile hydrolysis Nucleophihc attack by the sulfhydryl residue on the nitrile carbon atom forms an enzyme-bound thioimidate intermediate, which is hydrated to give a tetrahedral intermediate. After the elimination of ammonia, an acyl-enzyme intermediate is formed, which (like in serine hydrolases) is hydrolyzed to yield a carboxyhc acid [644]. 

The mechanism of nitrile hydrolysis involves acid or base promoted addition of water across the triple bond. This gives an intermediate imidate that tautomerizes to an amide. The amide is then hydrolyzed to the carboxylic acid. The addition of water to the nitrile resembles the hydration of an alkyne (eq. 3.52). The oxygen of water behaves as a nucleophile and bonds to the electrophilic carbon of the nitrile. Amide hydrolysis will be discussed in Section 10.20. 

This process is called hydrolysis, and the mechanism for nitrile hydrolysis will be discussed later in this chapter. This reaction provides us with a two-step process for converting an alkyl halide to a carboxylic add. 

Af). Tracer studies using indicate that the mechanism of hydrolysis by col involves direct nucleophilic attack at the nitrile group by COs with subsequent elimination of CO2. 

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