Nucleophilic acyl substitution reaction amides

Amides are the least reactive caiboxyhc acid deiivative and the only nucleophilic acyl substitution reaction they undeigo is hydrolysis Amides are fanly stable m water but the amide bond is cleaved on heating m the presence of strong acids 01 bases Nomi nally this cleavage produces an amine and a caiboxyhc acid... 

Amides, like esters, are abundant in all living organisms—proteins, nucleic acids, and many pharmaceuticals have amide functional groups. The reason for this abundance of amides, of course, is that they are stable to the conditions found in living organisms. Amides are the least reactive of the common acid derivatives and undergo relatively few nucleophilic acyl substitution reactions. 

Electrostatic potential maps of a typical amide (acetamide) and an acyl azide (acetyl azide) are shown. Which of the two do you think is more reactive in nucleophilic acyl substitution reactions Explain. 

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Sections 21.4 and 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. 

Amino groups are often protected as their tert-butoxycarbonvl amide, or Boc, derivatives. The Boc protecting group is introduced by reaction of the amino acid with di-fert-butyl dicarbonate in a nucleophilic acyl substitution reaction and is removed by brief treatment with a strong organic acid such as trifluoro-acetic acid, CF3C02H. 

Preparation of amides Ammonia, 1° and 2° amines react with carboxylic acids to produce, respectively, 1°, 2° and 3° amides, through a nucleophilic acyl substitution reaction. The reaction of ammonia and a carhoxylic acid initially forms a carhoxylate anion and an ammonium cation. Normally the... 

According to the electrostatic potential maps, the carbonyl carbon of acetyl azide is more electron-poor and therefore more reactive in nucleophilic acyl substitution reactions. Resonance donation of nitrogen lone-pair electrons to the carbonyl group is greater in an amide than in an acyl azide. 

Penicillin and related P-lactams kill bacteria by a nucleophilic acyl substitution reaction. All penicillins have an unreactive amide side chain and a very reactive amide that is part of a p-lactam. The P-lactam is more reactive than other amides because it is part of a strained, four-membered ring that is readily opened with nucleophiles. 

Carboxylic acid derivatives such as esters and amides undergo nucleophilic acyl substitution reactions with the ketone dianion derived fiom benzophenone, providing modest yields of the corresponding carbonyl products (equations 102 and 103). Benzhydrol is a significant by-product in these reactions. 

Amides are the least reactive of the carboxylic acid derivatives they can be prepared from any of the other acid derivatives. Hydrolysis, either acid- or base-catalyzed, to form acids is the only nucleophilic acyl substitution reaction. 

PEPTIDE BOND FORMATION Polypeptides are linear polymers composed of amino acids linked together by peptide bonds. Peptide bonds (Figure 5.11) are amide linkages formed when the unshared electron pair of the a-ami no nitrogen atom of one amino acid attacks the a-carboxyl carbon of another in a nucleophilic acyl substitution reaction. A generalized acyl substitution reaction is shown ... 

Carboxylic acids can undergo nucleophilic acyl substitution reactions only when they are in their acidic forms. The basic form of a carboxylic acid does not undergo nucleophilic acyl substitution reactions because the negatively charged carboxylate ion is resistant to nucleophilic attack (Section 17.12). Tbus, carboxylate ions are even less reactive toward nucleophilic acyl substitution reactions than are amides. 

A carboxyhc acid derivative will undergo a nucleophilic acyl substitution reaction provided that the newly added group in the tetrahedral intermediate is not a much weaker base than the group that was attached to the acyl group in the reactant. The weaker the base attached to the acyl group, the easier it is for both steps of the nucleophilic acyl substitution reaction to take place. The relative reactivities toward nucleo-phihc acyl substitution acyl halides > acid anhydrides > carboxylic acids and esters > amides > carboxylate ions. 

In the hydrolysis reaction of an amide in the presence of acids or bases, the products formed are carboxylic acid and amine. This is a nucleophilic acyl substitution reaction. 

In the preparation of amides, acid chlorides or anhydrides may be used to react with the selected amine. It is known that acid chlorides are more reactive than the corresponding anhydrides in this type of nucleophilic acyl substitution reaction. Offer a reasonable explanation for this observation. 

The mechanism of hydrolysis is directly analogous to the hydrolysis of amides, as seen in Section 21.12. The hydrolysis step is slow, and many alternative approaches have been developed. One such alternative employs hydrazine to release the amine and involves two successive nucleophilic acyl substitution reactions. 

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