21-35 Pivalic mixed anhydrides are often used to form amide bonds betweenamino acids. Unlike with a symmetrical anhydride, this reaction is highly regioselective, with the nucleophile adding only to the amino-acid carbonyl. Provide the complete mechanism for the reaction below and explain the regioselectivity.

A nucleophilic substitution reaction occurs when an electron-rich nucleophile contacts a positively charged electrophile in order to replace a leaving group.

The reaction between pivaloyl/amino acid mixed anhydride and the amino acid is proposed (potential nucleophile). During the bulky tri methyl acetyl group at the pivaloyl acetyl function, the latter prefers to contribute exclusively to the amino acid carbonyl function to produce the amide bond. The mechanical representation of this act of region elective control is as follows:

The amino acid carboxyl has a nucleophile, which is oxygen. Thus

Step 1:

Carbonyl carbon tetrahedral intermediate is attacked by a nucleophile.

Step 2:

Pivalic acid, a potentially food-leaving group, is eliminated and the product is formed.

Mechanism: The reaction is catalyzed by acyl substitution by a nucleophile at the acyl carbon of the amino acid terminal of the supplied mixed a hydride. This is to avoid steric crowding caused by the substrate's pivaloyl end.

The nucleophile amino acid assaults the amino carbonyl function via the nitrogen of the amino group ${\mathrm{NH}}_2$, causing the tetrahedral intermediate to be formed. The non-rate limiting lon of pivalic acid, a good leaving group (as indicated below), and the restoration of the trifunal carbon ${\mathrm{sp}}^2$ in the product follow.

The electron-releasing mesomeric action of ${\mathrm{CH}}_3$and carbon stabilizes the resonance of the weak base.

In consequence, the weaker the base (pivaloyl), the better it is as a leaving group and the reaction proceeds more quickly.