Organic Chemistry: Concepts and Applications - Headley Allan D. 2020
Nucleophilic Substitution Reactions at Acyl Carbons
16.6 Substitution Reactions Involving Amides
There are two important features of amides that lead to the type of reactions observed for these molecules. They have similar features as those of esters: they have a polarized carbonyl double bond, and they have a potential leaving group. Amides, however, have an extremely poor leaving group in the form of the amide anion. Thus, the general reaction type that these molecules undergo is very similar to those that we have covered but will closely mimic the substitution reactions of esters. The general reaction that these types of molecules undergo is shown in Reaction (16-82).
(16-82)
The first step of the reaction mechanism is an addition reaction to the electrophilic carbon of the carbon—oxygen double bond to form a tetrahedral intermediate. The second step involves the elimination of the very basic and extremely poor leaving group, the amide anion. You will recall from Chapter 7 on acids and bases that the pKa of the conjugate acid of the amide anion is ammonia, which has a pKa of 35. This means that the amide anion is a very strong base and an extremely poor leaving group. As a result, these substitution reactions take place under acid catalysis in order to convert the very poor amide anion to protonated amide, which is a much better leaving group. These reactions also take place at elevated temperatures.
The first step of the mechanism for the reaction of amides with a nucleophile in an acidic medium is shown in Reaction (16-83).
(16-83)
In the second step as shown in Reaction (16-84), the nucleophile attacks the electrophilic carbon of the carbon—oxygen bond.
(16-84)
Since the medium is acidic, protonation of the amide group occurs as shown in Reaction (16-85).
(16-85)
In the last step of the mechanism, there is an acid—base reaction as given in Reaction (16-86).
(16-86)
16.6.1 Substitution Reactions of Amides with Water
It is obvious from the above mechanism that this reaction will not likely take place under basic conditions, but under acidic conditions where the amide anion can be protonated converting it to a better leaving group. Amides are hydrolyzed under acidic conditions to the corresponding carboxylic acid as given in the example in Reaction (16-87) for the hydrolysis of acetamide to produce acetic acid and an ammonium salt.
(16-87)
Note that these reactions typically occur at elevated temperatures. Another example is given below for the hydrolysis of benzamide in which the mechanism for the hydrolysis is shown below.
Since this newly formed intermediate is charged, the attack of the nucleophilic water can be accomplished.
The tetrahedral intermediate is then protonated on the nitrogen to form a new protonated intermediate, which loses ammonia.
By losing a proton, this intermediate will generate the carboxylic acid.
In the last step of the reaction, the ammonia is protonated since the medium is acidic.
Problem 16.23
Give the products that result from the acid hydrolysis of the following amides.
16.6.2 Substitution Reactions of Amides with Hard Metallic Hydrides
Amides can be reduced to form the corresponding amine. Owing to the polarity of the carbonyl bond of amides, hydride ions can be added to the carbonyl carbon from strong reducing agents such as LiAlH4, as shown in Reaction (16-88).
(16-88)
The mechanism for the above reaction involves an attack of the carbonyl carbon by the hydride ion from LiAlH4 as shown in Reaction (16-89).
(16-89)
You will recall that the NH2 is very basic and hence an extremely poor leaving group. Also, in this reaction using LAH, there is no proton present to convert the NH2 group into a good leaving group. As a result, the aluminum acts as a Lewis acid to assist with the departure of the oxygen as shown in Reaction (16-89). The iminium-type of intermediate is then attacked by another mole of hydride ions as shown in Reaction (16-90) to form the final amine product.
(16-90)
Problem 16.24
Give the appropriate starting amide, which upon reduction with LiAlH4 will give the amines shown below.
