Nucleophilic Addition Reactions II


We have seen that alcohols undergo acid catalysed nucleophilic addition to aldehydes and ketones to produce hemiacetals, acetals, hemiketals, and ketals as summarized in Figure 1.

Figure 1

Nucleophilic Addition of Alcohols to Aldehydes and Ketones

Amines undergo similar acid catalysed nucleophilic addition reactions. The following discussion is limited to the reactions of primary amines with aldehydes and ketones. Primary amines are amines in which the nitrogen atom is bonded to 1 carbon atom. Figure 2 presents several examples of primary amines.

Figure 2

Three Primary Amines

More important than the number of carbons attached to the nitrogen is the number of hydrogens. The reason for this becomes apparent when we consider, step-by-step, what happenes upon addition of a primary amine to an aldehyde or ketone. As a simple example, consider the reaction of methylamine with acetaldehyde. This reaction could be performed by dissolving acetaldehyde and methylamine in aqueous acid. Under those reaction conditions, the equilibria shown in Equations 1 and 2 would be established.

The trick here is to adjust the pH of the solution so that some of the aldehyde will be protonated while some of the amine is unprotonated. Protonating the aldehyde makes the carbonyl carbon more electrophilic, thus increasing its reactivity toward the nucleophilic nitrogen of an unprotonated methylamine. Figure 3 outlines the complete reaction.

Figure 3

Nucleophilic Addition of Methylamine to Acetaldehyde

The ammonium ion 1 enclosed in the box in Step 2 of the process is analogous to the oxonium ion produced in the reaction of acetaldehyde with methanol. The resonance contributor 2 highlighted in Step 4 parallels that generated during the formation of acetaldehyde dimethylacetal. While these two structures are very similar, the products they yield are very different, as Figure 4 indicates.

Figure 4

Alternative Fates for Similar Structures

The difference stems from the fact that in intermediate 2 the nitrogen atom has an exchangeable H attached to it while the oxygen atom in intermediate 3 does not. Formation of the carbon-nitrogen double bond by deprotonation of the nitrogen atom is simply the most likely fate of intermediate 2. Since intermediate 3 does not have a comparable pathway available to it, an alternative reaction occurs: the electron deficient carbon gains a pair of electrons by forming a bond with another methanol molecule.


Equation 1 outlines the reaction of a cyclic ketone with a type of amine called a hydrazine. (In this equation TBS represents an OH protecting group while Ar stands for an aromatic ring.) Although hydrazines are technically not primary amines, they possess the more essential feature required for the formation of imines: two hydrogen atoms attached to the terminal nitrogen atom. (What happens to those two hydrogens and the oxygen atom of the carbonyl group?)

Reaction 1 constituted an early step in the first synthesis of taxol. The product of reaction 1 is a special type of imine called a hydrazone.

Before the development of modern spectroscopic techniques, hydrazones and related compounds such as oximes and semicarbazides played important roles in the characterization of the structures of aldehydes and ketones. Equations 2-4 illustrate the formation of one compound of each type.

Imines are formed as intermediates in the Strecker synthesis of amino acids. This reaction sequence begins with the reaction of an aldehyde with ammonia to produce an imine. The imine then reacts with cyanide ion to form an a-aminonitrile. Hydrolysis of the nitrile group yields the amino acid. The overall sequence is outlined in Figure 5 for the amino acid phenylalanine.

Figure 5

The Strecker Synthesis of Phenylalanine

As a final example, Figure 6 depicts the formation of an imine from the reaction of pyridoxal-5'-phosphate with the amino group of the aspartic acid.

Figure 6

An Imine Intermediate in a Biochemical Decarboxylation

Pyridoxal-5'-phosphate is the coenzyme form of vitamin B6. It is involved in a variety of important biochemical transformations. In the present case, the imine intermediate undergoes loss of carbon dioxide, followed by a series of proton transfers, to produce another amino acid, alanine. Note that the reaction sequence is catalytic in that pyridoxal-5'-phosphate is regenerated.