Amide , amines from nucleophilic acyl substitution

In the second major method of peptide synthesis the carboxyl group is activated by converting it to an active ester, usually a p-nitrophenyl ester. Recall from Section 20.12 that esters react with ammonia and amines to give amides. p-Nitrophenyl esters are much more reactive than methyl and ethyl esters in these reactions because p-nitrophenoxide is a better (less basic) leaving group than methoxide and ethoxide. Simply allowing the active ester and a C-protected amino acid to stand in a suitable solvent is sufficient to bring about peptide bond formation by nucleophilic acyl substitution. 

Ammonia and amines react with acid chlorides to give amides, also through the addition-elimination mechanism of nucleophilic acyl substitution. A carboxylic acid is efficiently converted to an amide by forming the acid chloride, which reacts with an amine to give the amide. A base such as pyridine or NaOH is often added to prevent HC1 from protonating the amine. 

Reactions of Amides Because amides are the most stable acid derivatives, they are not easily converted to other derivatives by nucleophilic acyl substitution. From a synthetic standpoint, their most important reaction is the reduction to amines, which is one of the best methods for synthesizing amines. Amides are hydrolyzed by strong acid or strong base. Just as nitriles can be hydrolyzed to amides, amides can be dehydrated to nitriles. 

The add chlorides prepared in this fashion are often not isolated and purified, but rather are used directly in a subsequent reaction. This is possible because both of the side products, HCl and SO2, are gases and readily lost or removed from the mixture. For example, if an amide is the desired product, then the crude acid chloride is simply allowed to react with an excess of an amine. An excess of the amine is used to neutralize the HCl that is generated during the preparation of the acid chloride (Eq. 20.7) and by the reaction of the acid chloride with the amine (Eq. 20.6). Like 18, acid chlorides are highly reactive, and they tend to undergo nucleophilic acyl substitution according to the general mechanism shown in Equation 20.2. 

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