Amide hydrolysis, leaving groups

The mechanism for acid hydrolysis of an amide is similar to that given in Section 17.7A for the acid hydrolysis of an ester. Water acts as a nucleophile and attacks the protonated amide. The leaving group in the acidic hydrolysis of an amide is ammonia (or an amine). 

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. 

Basic hydrolysis occurs by nucleophilic addition of OH- to the amide carbonyl group, followed by elimination of amide ion (-NH2) and subsequent deprotonation of the initially formed carboxylic acid by amide ion. The steps are reversible, with the equilibrium shifted toward product by the final deprotonation of the carboxylic acid. Basic hydrolysis is substantially more difficult than the analogous acid-catalyzed reaction because amide ion is a very poor leaving group, making the elimination step difficult. 

For amide hydrolysis in base, the initial adduct would revert to starting materials (without remarkable stabilization, an amide ion is a hopeless leaving group, so that path b does not compete with path a), bnt a not very difflcnlt proton transfer gives an intermediate in which the amine is the better leaving gronp and path b can compete with path a. ... 

In HO -catalyzed hydrolysis (specific base catalyzed hydrolysis), the tetrahedral intermediate is formed by the addition of a nucleophilic HO ion (Fig. 3.1, Pathway b). This reaction is irreversible for both esters and amides, since the carboxylate ion formed is deprotonated in basic solution and, hence, is not receptive to attack by the nucleophilic alcohol, phenol, or amine. The reactivity of the carboxylic acid derivative toward a particular nucleophile depends on a) the relative electron-donating or -withdrawing power of the substituents on the carbonyl group, and b) the relative ability of the -OR or -NR R" moiety to act as a leaving group. Thus, electronegative substituents accelerate hydrolysis, and esters are more readily hydrolyzed than amides. 

The new crystal structure of the ribosome—RFl complex sheds more light into the interactions between the GGQ motif and the peptidyltransferase center. This complex represents the product state of peptide release since a deacylated tRNA is bound to the P site. Importantly, the main chain amide of the conserved glutamine hydrogen bonds to the 3 OH of A76 in the P site, which is the leaving group of the hydrolysis... 

In ester hydrolysis, rate-limiting formation of the tetrahedral intermediate usually apphes (Sec. 6.3.1) since the alkoxide group is easily expelled. In contrast, amide hydrolysis at neutral pH involves rate-limiting breakdown of the tetrtihedral intermediate, because RNH is a poor leaving group. The catalytic effect of metal ions on amide hydrolysis has been ascribed to accelerated breakdown of the tetrahedral intermediate. 

The sequence is completed by base hydrolysis of the amide and removal of the protecting group. This is much the same as an ester hydrolysis, and needs to include as last stage the ionisation of acetic acid since RNH is a poor leaving group, it is this ionisation that allows the reaction to proceed. 

Acid-catalysed hydrolysis. Under acidic conditions, the hydrolysis of an amide resembles the acid-catalysed hydrolysis of an ester, with protonation of the carbonyl group yielding an activated carbonyl group that undergoes nucleophilic attack by water. The intramolecular proton transfer produces a good leaving group as ammonia. Simultaneous deprotonation by water and loss of ammonia yields a carboxylic acid. 

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