Basic Hydrolysis of an Amide

The dianion loses a molecule of ammonia (or an amine) this step is synchronized with a proton transfer from water due to the basicity of NHj.  

Hydrolysis of amides by enzymes is central to the digestion of proteins. The mechanism for protein hydrolysis by the enzyme chymotrypsin is presented in Section 24.11. 

What products would you obtain from acidic and basic hydrolysis of each of the following amides  

Amides react with P4O10 (a compound that is often called phosphorus pentoxide and written P2O5) or with boiling acetic anhydride to form nitriles  

This is a useful synthetic method for preparing nitriles that are not available by nucleophilic substitution reactions between alkyl halides and cyanide ion. 

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The same mechanism is involved in the basic hydrolysis of an amide and also results in the formation of a water soluble carboxylate ion. The leaving group from an amide is initially charged (i.e. R,N ). However, this is a strong base and reacts with water to form a free amine and a hydroxide ion. 

Problem-Solving Strategy Proposing Reaction Mechanisms 1007 Mechanism 21-8 Transesterification 1008 21-7 Hydrolysis of Carboxylic Acid Derivatives 1009 Mechanism 21-9 Saponification of an Ester 1010 Mechanism 21-10 Basic Hydrolysis of an Amide 1012 Mechanism 21-11 Acidic Hydrolysis of an Amide 1012 Mechanism 21-12 Base-Catalyzed Hydrolysis of a Nitrile 1014 21-8 Reduction of Acid Derivatives 1014... 

Esterification Using Diazomethane 966 Conversion of an Acid Chloride to an Anhydride 1001 Conversion of an Acid Chloride to an Ester 1001 Conversion of an Acid Chloride to an Amide 1002 Conversion of an Acid Anhydride to an Ester 1002 Conversion of an Acid Anhydride to an Amide 1003 Conversion of an Ester to an Amide (Ammonolysis of an Ester) 1003 Transesterification 1008 Saponification of an Ester 1010 Basic Hydrolysis of an Amide 1012 Acidic Hydrolysis of an Amide 1012... 

In basic hydrolysis, a hydroxide ion attacks the nitrile carbon atom, and subsequent protonation leads to the amide tautomer. Further attack by the hydroxide ion leads to hydrolysis in a manner analogous to that for the basic hydrolysis of an amide (Section 17.8F). (Under the appropriate conditions, amides can be isolated when nitriles are hydrolyzed.)... 

Acid-Catalyzed Esterification 790 Base-Promoted Hydrolysis of an Ester 793 DCC-Promoted Amide Synthesis 798 Acidic Hydrolysis of an Amide 799 Basic Hydrolysis of an Amide 799 Acidic Hydrolysis of a Nitrile 801 Basic Hydrolysis of a Nitrile 801... 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

Both esters and amides undergo hydrolysis reactions. In a hydrolysis reaction, the ester or amide bond is cleaved, or split in two, to form two products. As mentioned earlier, the hydrolysis of an ester produces a carboxylic acid and an alcohol. The hydrolysis of an amide produces a carboxylic acid and an amine. There are two methods of hydrolysis acidic hydrolysis and basic hydrolysis. Both methods are shown in Figure 2.9. Hydrolysis usually requires heat. In acidic hydrolysis, the ester or amide reacts with water in the presence of an acid, such as H2SO4. In basic hydrolysis, the ester or amide reacts with the OH ion, from NaOH or water, in the presence of a base. Soap is made by the basic hydrolysis of ester bonds in vegetable oils or animal fats. 

A) The acid hydrolysis of an amide produces a carboxylic acid and an amine. (B) The basic hydrolysis of an ester produces the salt of a carboxylic acid and an alcohol. 

Under acidic conditions the equilibrium for the hydrolysis of an amide is driven toward the products by the protonation of the ammonia or amine that is formed. Under basic conditions the equilibrium is driven toward the products by the formation of the carboxylate anion, which is at the bottom of the reactivity scale. The pH of the final solution may need to be adjusted, depending on which product is to be isolated. If the carboxylic acid is desired, the final solution must be acidic, whereas isolation of the amine requires that the solution be basic. Several examples are shown in the following equations. Also, note that the last step of the Gabriel amine synthesis, the hydrolysis of the phthalimide (see Section 10.6 and Figure 10.5 on page 365), is an amide... 

Possible mechanism of the hydrolysis of an amide under basic conditions. 

Therefore, it is important to use an excess of water so as to shift the equilibria to the products. In contrast to esters, the hydrolysis of an amide in acid does result in the formation of an ion (Following fig.). The leaving group here is an amine and since amines are basic, they will react with the acid to form a water soluble aminum ion. This is an irreversible step that pulls the equilibrium through to the products. 

The hydrolysis of an amide results in a carboxyl group and an ammonium chloride ion for every amide group in the molecule. Either 1 mole of NaOH (basic conditions) or 1 mole of HCl (acidic conditions) is consumed for every amide group in the molecule. 

Hydrolysis of an Amide (Section 18.4D) Either add or base is required in an amount equivalent to that of the amide. In add, the mechanism is similar to that for esters, except the departing amine is basic and reacts with a proton to give an ammonium ion product. This last step consumes a proton, explaining why the process is not catalytic in acid. 

Hydrolysis of an amide breaks the carbon-nitrogen bond and produces a carboxylic acid and either ammonia or an amine. The reaction resembles esters hydrolysis, but there are important differences. Ester hydrolysis occurs relatively easily, but amides resist hydrolysis. Under acid conditions, 6 M HCl and refluxing for 24 hours are required. Under basic conditions, a 40% solution of sodium hydroxide is used. Under these conditions, the salt of a carboxylate anion is produced. As in saponification of esters, an acid-base reaction to form the carboxylate anion pulls the reaction to completion. 

The mechanism for acid-catalyzed hydrolysis of amides involves attack by water on the protonated amide. An inqjortant feature of the chemistry of amides is that the most basic site in an amide is the carbonyl oxygen. Very little of the N-protonated form is present. The major factor that contributes to the stability of the O-protonated form is the... 

Active Figure 20.4 MECHANISM Mechanism of the basic hydrolysis of a nitrile to yield an amide, which is subsequently... 

The basic hydrolysis of imidate salt 118 takes a different course from that of imidate salt 112, yielding first only the amide rotamer 120B which is then slowly isomerized to the equilibrium mixture (ratio 3 1) of 120A and 120B. Treatment of the ester ammonium salt 119 under the same basic conditions gave directly the aminoalcohol 123. This result shows that the amino-ester 122 is not an intermediate in the basic hydrolysis of imidate 118. The formation of the amide rotamer 120B is therefore the result of the direct fragmentation of a tetrahedral intermediate whidh is formed from 118. 

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