Mechanism amide hydrolysis

Mechanistically amide hydrolysis is similar to the hydrolysis of other carboxylic acid derivatives The mechanism of the hydrolysis m acid is presented m Figure 20 7 It proceeds m two stages a tetrahedral intermediate is formed m the first stage and disso ciates m the second... 

Hydrolysis of esters and amides by enzymes that form acyl enzyme intermediates is similar in mechanism but different in rate-limiting steps. Whereas formation of the acyl enzyme intermediate is a rate-limiting step for amide hydrolysis, it is the deacylation step that determines the rate of ester hydrolysis. This difference allows elimination of the undesirable amidase activity that is responsible for secondary hydrolysis without affecting the rate of synthesis. Addition of an appropriate cosolvent such as acetonitrile, DMF, or dioxane can selectively eliminate undesirable amidase activity (128). 

FIGURE 20.7 The mechanism of amide hydrolysis in acid solution. Steps 1 through 3 show the formation of the tetrahedral intermediate. Dissociation of the tetrahedral intermediate is shown in steps 4 through 6. 

On the basis of the general mechanism for amide hydrolysis in acidic solution shown in Figure 20.7, write an analogous sequence of steps for the... 

FIGURE 20.8 The mechanism of amide hydrolysis in basic solution. 

Conversion of Amides into Carboxylic Acids Hydrolysis Amides undergo hydrolysis to yield carboxylic acids plus ammonia or an amine on heating in either aqueous acid or aqueous base. The conditions required for amide hydrolysis are more severe than those required for the hydrolysis of add chlorides or esters but the mechanisms are similar. Acidic hydrolysis reaction occurs by nucleophilic addition of water to the protonated amide, followed by transfer of a proton from oxygen to nitrogen to make the nitrogen a better leaving group and subsequent elimination. The steps are reversible, with the equilibrium shifted toward product by protonation of NH3 in the final step. 

Amide hydrolysis is common in biological chemistry. Just as the hydrolysis of esters is the initial step in the digestion of dietary fats, the hydrolysis of amides is the initial step in the digestion of dietary proteins. The reaction is catalyzed by protease enzymes and occurs by a mechanism almost identical to that we just saw for fat hydrolysis. That is, an initial nucleophilic acyl substitution of an alcohol group in the enzyme on an amide linkage in the protein gives an acyl enzyme intermediate that then undergoes hydrolysis. 

The same framework of eight possible mechanisms that was discussed for ester hydrolysis can also be applied to amide hydrolysis. Both the acid- and base-catalyzed hydrolyses are essentially irreversible, since salts are formed in both cases. For basic catalysis the mechanism is Bac2-... 

There is much evidence for this mechanism, similar to that discussed for ester hydrolysis. A MO study on the mechanism of amide hydrolysis is available. In certain cases, kinetic studies have shown that the reaction is second order in OH , indicating that 107 can lose a proton to give 108. Depending on the nature... 

For acid catalysis, matters are less clear. The reaction is generally second order, and it is known that amides are primarily protonated on the oxygen (Chapter 8, Ref. 24). Because of these facts it has been generally agreed that most acid-catalyzed amide hydrolysis takes place by the Aac2 mechanism. 

A1 mechanism 31 A-Se2 mechanism 34 A2 mechanism 36 Other mechanisms 38 Amide hydrolysis 51... 

Many hydrolysis reactions, e.g. of esters and some amides, switch from an A2 mechanism to an A1 mechanism as the acidity is increased, and we will see several of these under the A2 reaction and amide hydrolysis headings. 

The need for a good understanding of the mechanism of the reaction is well illustrated by the case of amide hydrolysis. Many early enterprises sought to employ transition state analogues (TSAs) that were based on a stable anionic... 

Before discussmg the mechanism of cleavage of carboxylic acid esters and amides by hydrolases, some chemical principles are worth recalling. The chemical hydrolysis of carboxylic acid derivatives can be catalyzed by acid or base, and, in both cases, the mechanisms involve addition-elimination via a tetrahedral intermediate. A general scheme of ester and amide hydrolysis is presented in Fig. 3. / the chemical mechanisms of ester hydrolysis will be... 

Model primary amides (8.168, R = Me or Ph, X = H, Cl, or N02) were used to investigate the mechanism of hydrolysis of their AA (acyloxy )melh-yl] derivatives [217], These compounds were hydrolyzed very rapidly, with tm values at pH 7.4 and 37° of ca. 1 min. This is much faster than predicted from structure-reactivity relationships, and led to the suggestion of an elimination-addition mechanism involving a reactive N-acy I inline intermediate (acyl-N=CH2). In contrast, N- [(acyloxy)methy 1] derivatives of imides... 

A new, more general, way to combine ab initio quantum mechanical calculations with classical mechanical free-energy perturbation approach (QM/FE approach) to calculate the energetics of enzyme-catalysed reactions and the same reaction in solution has been reported." The calculated free energies were in fairly good agreement with the experimental data for the activation energies of the first test case, amide hydrolysis in trypsin and in aqueous solution. 

There are three fundamental questions concerning the mechanism of action of carboxypeptidase (1) How do metal ions affect ester and amide hydrolysis (2) Under what conditions will a neighbouring carboxyl group participate in ester and amide hydrolysis emd what is the mechanism of such participation (3) How will a metal ion affect... 

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... 

T.H. Fife, Kinetic and Mechanistic Effects of Ease of C-N-hond Breaking in Amide Hydrolysis, The Mechanisms of Hydrolysis of N-Acylimidazoles and N-Acyl-benzimidazoles, Acc. Chem. Res. 26, 325 (1993). 

This chapter deals with the kinetics and mechanisms of the hydrolysis of carboxylic acid derivatives of general formula RCOX. These include carboxylic acid halides, amides, and anhydrides with small sections on carboxylic acid cyanides etc. Many recent developments in this field have been made with acid derivatives in which R is not an aliphatic or aromatic group, for example, carbamic acid derivatives, and these are reported where relevant, as are reactions such as ethanolysis, aminolysis, etc. where they throw light on the mechanisms of hydrolysis. 

The failure of the acidity function approach is shown in the work of Leisten212, who studied the rates of hydrolysis of the thirteen amides listed in Table 27 in 5.9, 7.2 and 8.5 M perchloric acid. If the mechanism of hydrolysis is of the A-2 type213, where a rapid reversible initial protonation of the amide is followed by the attack of water on to the conjugate acid, then the Ziicker-Hammett hypothesis214 would predict that the rates of hydrolysis in solutions of different acidity should be proportional to the acid concentration. Therefore, kx (the rate coefficient for the attack of water onto the conjugate acid) should be proportional to [H30+ ] lh0. In Table 27 the values of the first-order coefficients for hydrolysis at 5.86 and 7.19 M HC104 are given and compared with the calculated value. 

---