MCAT Organic Chemistry Review

Carboxylic Acids

8.2 Reactions of Carboxylic Acids

The properties of carboxylic acids make them highly reactive in a number of different categories. Several of the most important reactions are described here.

SYNTHESIS OF CARBOXYLIC ACIDS

As described in earlier chapters, carboxylic acids can be prepared via oxidation of aldehydes and certain alcohols. The oxidant is usually potassium permanganate (KMnO4), as shown in Figure 8.8, but several other oxidizing agents can also work. Remember that secondary and tertiary alcohols cannot be oxidized to carboxylic acids because they already have at least two bonds to other carbons.

Figure 8.8. Synthesis of a Carboxylic Acid via Oxidation of a Primary Alcohol

There are many other methods of generating carboxylic acids, including organometallic reagents (Grignard reagents) and hydrolysis of nitriles (–C≡N), but these are outside the scope of the MCAT.

NUCLEOPHILIC ACYL SUBSTITUTION

Many of the reactions in which carboxylic acids (and their derivatives) participate proceed via a single mechanism: nucleophilic acyl substitution. This mechanism is similar to nucleophilic addition to an aldehyde or ketone, which was discussed in Chapters 6 and 7 of MCAT Organic Chemistry Review. The key difference, however, focuses on the existence of a leaving group in carboxylic acids and their derivatives. In this case, after opening the carbonyl via nucleophilic attack and forming a tetrahedral intermediate, the carbonyl can reform, thereby kicking off the leaving group. This reaction is shown in Figure 8.9.

Figure 8.9. Nucleophilic Acyl Substitution Step 1: Nucleophilic addition; Step 2: Elimination of the leaving group and reformation of the carbonyl.

In these reactions, the nucleophilic molecule replaces the leaving group of an acyl derivative. Acyl derivatives encompass all molecules with a carboxylic acid-derived carbonyl, including carboxylic acids, amides, esters, anhydrides, and others. These reactions are favored by a good leaving group. Remember, weak bases, which are often the conjugate bases of strong acids, make good leaving groups. These reactions are also favored in either acidic or basic conditions, which can alter the reactivity of the electrophile and nucleophile.

Amides

Carboxylic acids can be converted into amides if the incoming nucleophile is ammonia (NH3) or an amine, as shown in Figure 8.10. This can be carried out in either an acidic or basic solution to drive the reaction forward.

Figure 8.10. Formation of an Amide by Nucleophilic Acyl Substitution

Amides are named by replacing the –oic acid suffix with –amide in the name of the parent carboxylic acid. Any alkyl groups on the nitrogen are placed atthe beginning of the name with the prefix N–. Amides exist in a resonance state where delocalization of electrons occurs between the oxygen and nitrogen atoms, as shown in Figure 8.11.

Figure 8.11. Resonance of Amides Resonance between the carbonyl and lone pair on the nitrogen stabilizes this bond and restricts its motion.

Amides that are cyclic are called lactams and are named by replacing –oic acid with –lactam. They may also be named by indicating the specific carbon that is bound during cyclization of the compound. Several examples are shown in Figure 8.12.

Figure 8.12. Examples of Lactams

Esters

Esters are a hybrid between a carboxylic acid and an ether (ROR′ ), which can be made by reacting carboxylic acids with alcohols under acidic conditions, as shown in Figure 8.13. Esterification is a condensation reaction, with water as a side product. In acidic solutions, the carbonyl oxygen can be protonated, which enhances the polarity of the bond, thereby placing additional positive charge on the carbonyl carbon and increasing its susceptibility to nucleophilic attack. This condensation reaction occurs most rapidly with primary alcohols.

Figure 8.13. Esterification: Reaction of a Carboxylic Acid with an Alcohol

KEY CONCEPT

Protonating the C=O makes the electrophilic carbon even more ripe for nucleophilic attack.

Esters are named in the same manner as salts of carboxylic acids. For example, the ester shown in the reaction in Figure 8.13 has the common name ethyl acetate, or the IUPAC name ethyl ethanoate.

Esters that are cyclic are called lactones and are named by replacing –oic acid with –lactone. Several examples are shown in Figure 8.14.

Figure 8.14. Examples of Lactones

Anhydrides

Anhydrides can be formed by the condensation of two carboxylic acids. They are named by replacing the acid at the end of the name of the parent carboxylic acid with anhydride, whether cyclic or linear. One example is the condensation of two molecules of ethanoic acid to form ethanoic anhydride, as shown in Figure 8.15. Just like the above reactions, anhydride formation occurs via nucleophilic acyl substitution.

Figure 8.15. Synthesis of an Anhydride via Carboxylic Acid Condensation

REDUCTION

Carboxylic acids can be reduced to primary alcohols by the use of lithium aluminum hydride (LiAlH4). Aldehyde intermediates may be formed in the course of this reaction, but they, too, will be reduced to the alcohol. The reaction occurs by nucleophilic addition of hydride to the carbonyl group. The reaction mechanism is shown in Figure 8.16.

Figure 8.16. Reduction of a Carboxylic Acid to a Primary Alcohol Reaction occurs by nucleophilic addition of hydride and proceeds through an aldehyde intermediate.

Lithium aluminum hydride is a strong reducing agent that can successfully reduce a carboxylic acid; a gentler reducing agent like sodium borohydride (NaBH4) is not strong enough to reduce carboxylic acids.

KEY CONCEPT

Carboxylic acids can be reduced by LiAlH4, but not the less reactive NaBH4.

DECARBOXYLATION

Decarboxylation describes the complete loss of the carboxyl group as carbon dioxide. This is a common way of getting rid of a carbon from the parent chain. 1,3-dicarboxylic acids and other β-keto acids may spontaneously decarboxylate when heated. Under these conditions, the carboxyl group is lost and replaced with hydrogen. Because both the electrophile and nucleophile are in the same molecule, the reaction proceeds through a six-membered ring in its transition state, as shown in Figure 8.17. The enol that is initially formed from the destruction of the ring tautomerizes to the more stable keto form.

Figure 8.17. Decarboxylation of Carboxylic Acids: Loss of CO2 The intramolecular reaction proceeds via a six-membered ring transition state, and the product tautomerizes from the enol to the more stable keto form.

BRIDGE

Decarboxylation is common in biochemical pathways in the body. Pyruvate dehydrogenase complex, described in Chapter 10 of MCAT Biochemistry Review, carries out the decarboxylation of pyruvate to help form acetyl-CoA, which can feed into the citric acid cycle.

SAPONIFICATION

When long-chain carboxylic acids react with sodium or potassium hydroxide, a salt is formed. This process, called saponification, occurs by mixing fatty acids with lye (sodium or potassium hydroxide), resulting in the formation of a salt that we know as soap. Soaps can solvate nonpolar organic compounds in aqueous solutions because they contain both a nonpolar tail and a polar carboxylate head, as shown in Figure 8.18.

Figure 8.18. Carboxylic Acid Salt (Soap)

When placed in aqueous solution, soap molecules arrange themselves into spherical structures called micelles, as shown in Figure 8.19. The polar heads face outward, where they can be solubilized by water, and the nonpolar hydrocarbon chains are oriented toward the inside of the sphere, protected from the solvent. Nonpolar molecules, such as grease, dissolve in the hydrocarbon interior of the spherical micelle; the micelle as a whole then dissolves in water due to the polarity of its exterior surface.

Figure 8.19. Soap Micelle The polar heads interact with the hydrophilic environment; the nonpolar tails are oriented toward the interior of the micelle.

BRIDGE

The formation of the phospholipid bilayer, micelles, and liposomes are all contingent on the bipolar nature of carboxylic acids with long hydrocarbon chains. These structures are discussed in Chapter 5 of MCAT Biochemistry Review.

MCAT Concept Check 8.2:

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

1.    For each of the derivatives below, list the nucleophile used to form the derivative in an acyl substitution reaction and the name of the cyclic form of that functional group.

Carboxylic Acid Derivative

Formed by Reaction with:

Name of Cyclic Form:

Amide

   

Ester

   

Anhydride

   

2.    Briefly describe the mechanism of nucleophilic acyl substitution reactions.

3.    Can carboxylic acids be reduced by sodium borohydride? Yes or No

4.    Under what conditions will a carboxylic acid spontaneously decarboxylate?