Preview of Carbonyl Chemistry

Nucleophilic Addition Reactions of Aldehydes and Ketones (Chapter 19)

The most common reaction of aldehydes and ketones is the nucleophilic addition reaction, in which a nucleophile, :Nu^–, adds to the electrophilic carbon of the carbonyl group. Because the nucleophile uses an electron pair to form a new bond to carbon, two electrons from the carbon–oxygen double bond must move toward the electronegative oxygen atom to give an alkoxide anion. The carbonyl carbon rehybridizes from sp² to sp³ during the reaction, and the alkoxide ion product therefore has tetrahedral geometry.

Once formed, and depending on the nature of the nucleophile, the tetrahedral alkoxide intermediate can undergo one of two further reactions, as shown in Figure 18.9. Often, the tetrahedral alkoxide intermediate is simply protonated by water or acid to form an alcohol product. Alternatively, the tetrahedral intermediate can be protonated and expel the oxygen to form a new double bond between the carbonyl carbon and the nucleophile. We’ll study both processes in detail in Chapter 19.

Figure 18.9 The addition reaction of an aldehyde or a ketone with a nucleophile. Depending on the nucleophile, either an alcohol or a compound with a $\text{C}\text{═}\text{Nu}$ double bond is formed.

FORMATION OF AN ALCOHOL

The simplest reaction of a tetrahedral alkoxide intermediate is protonation to yield an alcohol. We’ve already seen two examples of this kind of process during reduction of aldehydes and ketones with hydride reagents such as NaBH₄ and LiAlH₄ (Section 17.4) and during Grignard reactions (Section 17.5). During a reduction, the nucleophile that adds to the carbonyl group is a hydride ion, H:^–, while during a Grignard reaction, the nucleophile is a carbanion, R₃C:^–.

FORMATION OF $\mathbf{\text{C=Nu}}$

The second mode of nucleophilic addition, which often occurs with amine nucleophiles, involves elimination of oxygen and formation of a $\text{C=N}\text{u}$ double bond. For example, aldehydes and ketones react with primary amines, RNH₂, to form imines, ${\text{R}}_2\text{C=NR}\prime$. These reactions use the same kind of tetrahedral intermediate as that formed during hydride reduction and Grignard reaction, but the initially formed alkoxide ion is not isolated. Instead, it is protonated and then loses water to form an imine, as shown in Figure 18.10.

Figure 18.10 MECHANISM

Formation of an imine, R₂C=NR′, by reaction of an amine with an aldehyde or a ketone.

Nucleophilic Acyl Substitution Reactions of Carboxylic Acid Derivatives (Chapter 21)

The second fundamental reaction of carbonyl compounds, nucleophilic acyl substitution, is related to the nucleophilic addition reaction just discussed but occurs only with carboxylic acid derivatives rather than with aldehydes and ketones. When the carbonyl group of a carboxylic acid derivative reacts with a nucleophile, addition occurs in the usual way, but the initially formed tetrahedral alkoxide intermediate is not isolated. Because carboxylic acid derivatives have a leaving group bonded to the carbonyl-group carbon, the tetrahedral intermediate can react further by expelling the leaving group and forming a new carbonyl compound:

The net effect of nucleophilic acyl substitution is the replacement of the leaving group by the entering nucleophile. We’ll see in Chapter 21, for instance, that acid chlorides are rapidly converted into esters by treatment with alkoxide ions (Figure 18.11).

Figure 18.11 MECHANISM

Nucleophilic acyl substitution of an acid chloride with an alkoxide ion yields an ester.

Alpha-Substitution Reactions (Chapter 22)

The third major reaction of carbonyl compounds, alpha substitution, occurs at the position next to the carbonyl group—the alpha (α) position. This reaction results in the substitution of an α hydrogen by an electrophile through the formation of an intermediate enol or enolate ion:

For reasons that we’ll explore in Chapter 22, the presence of a carbonyl group renders the hydrogens on the α carbon acidic. Carbonyl compounds therefore react with strong base to yield enolate ions.

Because they’re negatively charged, enolate ions act as nucleophiles and undergo many of the reactions we’ve already studied. For example, enolates react with primary alkyl halides in the S_N2 reaction. The nucleophilic enolate ion displaces halide ion, and a new C–C bond forms:

The S_N2 alkylation reaction between an enolate ion and an alkyl halide is a powerful method for making C–C bonds, thereby building up larger molecules from smaller precursors. We’ll study the alkylation of many kinds of carbonyl compounds in Chapter 22.

Carbonyl Condensation Reactions (Chapter 23)

The fourth and last fundamental reaction of carbonyl groups, carbonyl condensation, takes place when two carbonyl compounds react with each other. When acetaldehyde is treated with base, for instance, two molecules combine to yield the hydroxy aldehyde product known as aldol (aldehyde + alcohol):

Although carbonyl condensation appears to be different from the three processes already discussed, it’s actually quite similar. A carbonyl condensation reaction is simply a combination of a nucleophilic addition step and an α-substitution step. The initially formed enolate ion of one acetaldehyde molecule acts as a nucleophile and adds to the carbonyl group of another acetaldehyde molecule, as shown in Figure 18.12.

Figure 18.12 MECHANISM

A carbonyl condensation reaction between two molecules of acetaldehyde yields a hydroxy aldehyde product.