MCAT Organic Chemistry Review

Carboxylic Acid Derivatives

9.3 Nucleophilic Acyl Substitution Reactions

Although there are a seemingly infinite number of reactions in which carboxylic acid derivatives can participate, a much smaller group of reactions will appear on the MCAT. As we will observe, these reactions have much in common with those of carboxylic acids and other carbonyl-containing compounds. Many of the properties we have already discussed determine the ways in which these reactions proceed.

ANHYDRIDE CLEAVAGE

As with carboxylic acids, nucleophilic acyl substitution involves nucleophilic attack of the carbonyl carbon with displacement of a leaving group. All carboxylic acid derivatives can participate in nucleophilic substitution reactions, at different relative rates. Specifically, anhydrides are most reactive toward nucleophiles, followed by esters, and finally amides. One example of this is the formation of amides from the nucleophilic substitution reaction between ammonia and any carboxylic acid or derivative. The example shown in Figure 9.13 is not only a nucleophilic substitution reaction, but also a cleavage reaction because it splits an anhydride in two. In this reaction, ammonia acts as the nucleophile, one of the carbonyl carbons acts as the electrophile, and a carboxylic acid is the leaving group.

Figure 9.13. Nucleophilic Acyl Substitution: Anhydride to Amide and Carboxylic Acid

Alcohols can also act as nucleophiles toward anhydrides or carboxylic acids; this nucleophilic substitution reaction will result in the formation of esters and carboxylic acids, as shown in Figure 9.14.

Figure 9.14. Nucleophilic Acyl Substitution: Anhydride to Ester and Carboxylic Acid

Anhydrides can also be reverted to carboxylic acids by exposing them to water, as shown in Figure 9.15. For these reactions to be useful, the anhydride should be symmetric; otherwise, one forms a mixture of products.

Figure 9.15. Nucleophilic Acyl Substitution: Anhydride to Carboxylic Acids

TRANSESTERIFICATION

Alcohols can act as nucleophiles and displace the esterifying group on an ester. This process is called transesterification. In this reaction, one ester is simply transformed to another, as shown in Figure 9.16.

Figure 9.16. Nucleophilic Acyl Substitution: Transesterification Different alcohol chains are swapped into and out of the esterifying group position.

HYDROLYSIS OF AMIDES

Amides can be hydrolyzed under highly acidic conditions via nucleophilic substitution. The acidic conditions allow the carbonyl oxygen to become protonated, making the molecule more susceptible to nucleophilic attack by a water molecule. The product of this reaction is a carboxylic acid and ammonia. This should be no surprise because this is the reverse of the condensation reaction by which amides are formed. This reaction is shown in Figure 9.17.

Figure 9.17. Nucleophilic Acyl Substitution: Amide to Carboxylic Acid Strong acid or base is needed to catalyze the hydrolysis of amides, which are normally quite stable.

Hydrolysis can also occur if conditions are basic enough. The reaction is similar to an acid-catalyzed reaction, except that the carbonyl oxygen is not protonated and the nucleophile is a hydroxide ion. The product of this reaction would be the deprotonated carboxylate ion.

MCAT Concept Check 9.3:

Before you move on, assess your understanding of the material with these questions.

1.    In the formation of an amide from ammonia and an anhydride, what serves as the nucleophile? The electrophile?

·        Nucleophile:

·        Electrophile:

2.    Define transesterification.

3.    How do strongly acidic and strongly basic conditions catalyze the hydrolysis of an amide?

·        Strongly acidic conditions:

·        Strongly basic conditions: