Hydrolysis nucleophilic acyl substitution 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... 

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 mechanism of amide hydrolysis in base has the usual two steps of the general mechanism for nucleophilic acyl substitution—addition of the nucleophUe followed by loss of a leaving group— plus an additional proton transfer. The initially formed carboxylic acid reacts further under basic conditions to form the resonance-stabilized carboxylate anion, and this drives the reaction to completion. Mechanism 22.10 is written for a 1° amide. 

Similar experiments have indicated the reversible formation of tetrahedral intermediates in hydrolysis of other esters, amides, anhydrides, and acid chlorides, and are the basis of the general mechanism we have shown for nucleophilic acyl substitution. 

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. 

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. 

Knowing how the protein chain is folded is a key element in understanding how an enzyme catalyzes a reaction. Biochemical processes are usually related to the core reaction types of organic chemistry and involve similar key intermediates. The reactions, however, are much faster and more selective. In proposing an enzyme-catalyzed mechanism for a reaction such as amide or ester hydrolysis, it is customary to assume it proceeds by way of a tetrahedral intermediate, then modify the usual nucleophilic acyl substitution mechanism by assigning various catalytic functions to selected amino acid side chains of the enzyme. 

N-Acetylazoles undergo hydrolysis more readily than regular amides. Suggest a reason for the enhanced reactivity of N-acetylazoles toward nucleophilic acyl substitution ... 

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. 

Among the various carboxylic acid derivatives, acyl chlorides are especially useful because they are readily converted to acid anhydrides, esters, and amides by nucleophilic acyl substitution (Table 19.1). Yields are high and the reaction rates are much greater than the corresponding rates of alkyl halides with the same nucleophiles. Benzoyl chloride, for example, is about 1,000 times more reactive than benzyl chloride toward hydrolysis at 25°C. 

This chapter will discuss methods for the preparation of esters, acid chlorides, anhydrides, and amides from carboxylic acids, based on acyl substitution reactions. Acyl substitution reactions of carboxylic acid derivatives will include hydrolysis, interconversion of one acid derivative into another, and reactions with strong nucleophiles such as organometallic reagents. In addition, the chemistry of dicarboxylic acid derivatives will be discussed, as well as cyclic esters, amides, and anhydrides. Sulfonic acid derivatives will be introduced as well as sulfate esters and phosphate esters. Finally, nitriles will be shown to be acid derivatives by virtue of their reactivity. 

There are tremendous variations in the rates of acyl substitution reactions with a common nucleophile such as water. The order of reactivity in a hydrolysis reaction is acyl chloride > acid anhydride > ester > amide (Table 21.3). 

The acylation is a straightforward nucleophilic substitution at the carbonyl group and the CFj>. group is chosen to make the anion at nitrogen more stable. Alkylation can occur only once wherea direct alkylation with Mel could occur several times. Hydrolysis of the amide is also easier with .. CF3CO group. 

Detailed mechanisms for the amidocarbonylation reaction have been proposed by both Pino [2] and Magnus [4], wherein the first step is the formation of a hemi-amidal, followed by the nucleophilic substitution of a hydroxyl group by cobalt tetracarbonyl hydride and carbonyl insertion to an (ct-amidoalkanoyl) cobalt intermediate. This intermediate then provides the desired 7V-acyl-a-amino acid by direct hydrolysis, or via an lactame intermediate, followed by hydrolysis. 

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