MCAT Organic Chemistry Review

Aldehydes and Ketones I: Electrophilicity and Oxidation—Reduction

6.2 Nucleophilic Addition Reactions

In each of the following reactions, the general reaction mechanism is the same: nucleophilic addition to a carbonyl. This is one of the most important reaction mechanisms on the MCAT, and many of the reactions of aldehydes, ketones, and more complex molecules share this general reaction mechanism. Rather than memorizing each reaction individually, focus on the overall pattern—then learn how a particular reaction exemplifies it.

MCAT EXPERTISE

Memorizing one reaction may help you to get one question right on the MCAT, but understanding trends and overarching concepts will allow you to answer many more questions correctly. You will see that the carbonyl carbon is a great target for nucleophilic attack in many of the reactions in this chapter.

As we have seen, the C=O bond is polarized, with a partial positive charge on the carbonyl carbon and a partial negative charge on the oxygen. This makes the carbonyl carbon an electrophile, ripe for nucleophilic attack.

When the nucleophile attacks, it forms a covalent bond to the carbon, breaking the π bond in the carbonyl. The electrons from the π bond are pushed onto the oxygen atom. Oxygen happily accepts extra electrons due to its electronegativity. Breaking the π bond forms a tetrahedral intermediate. Any time a carbonyl is opened, one should ask: Can I reform the carbonyl? If no good leaving group is present (as is the case with aldehydes and ketones), the carbonyl will not reform. Generally, O will accept a proton to form a hydroxyl group, resulting in an alcohol. However, if a good leaving group is present (as is the case with carboxylic acids and their derivatives), the carbonyl double bond can reform, pushing off the leaving group. Figure 6.5 shows the reaction mechanism of nucleophilic addition for an aldehyde.

Figure 6.5. Nucleophilic Addition Reaction Mechanism The nucleophile attacks the carbonyl carbon, opening the carbonyl. The carbonyl cannot reform because there is no good leaving group; thus, the O is protonated to generate an alcohol.

HYDRATION

In the presence of water, aldehydes and ketones react to form geminal diols (1,1-diols), as shown in Figure 6.6. In this case, the nucleophilic oxygen in water attacks the electrophilic carbonyl carbon. This hydration reaction normally proceeds slowly, but we can increase the rate by adding a small amount of catalytic acid or base.

Figure 6.6. Hydration Reaction The carbonyl is hydrated by water, then protonated, resulting in a geminal diol.

ACETALS AND HEMIACETALS

A similar reaction occurs when aldehydes and ketones are treated with alcohols. When one equivalent of alcohol (the nucleophile in this reaction) is added to an aldehyde or ketone, the product is a hemiacetal or hemiketal, respectively, as shown in Figure 6.7. Hemiacetals and hemiketals can be recognized by the retention of the hydroxyl group. This “halfway” step (hence the hemi– prefix) is the endpoint in basic conditions.

Figure 6.7. Hemiacetal Formation The oxygen in the alcohol functions as the nucleophile, attacking the carbonyl carbon, and generating a hemiacetal.

When two equivalents of alcohol are added, the reaction proceeds to completion, resulting in the formation of an acetal or ketal, as shown in Figure 6.8. This reaction proceeds by a nucleophilic substitution reaction (SN1) and is catalyzed by anhydrous acid. The hydroxyl group of a hemiacetal or hemiketal is protonated under acidic conditions and lost as a molecule of water. A carbocation is thus formed, and another equivalent of alcohol attacks this carbocation, resulting in the formation of an acetal or ketal. Acetals and ketals, which are comparatively inert, are frequently used as protecting groups for carbonyl functionalities. Molecules with protecting groups can easily be converted back to carbonyls with aqueous acid and heat.

Figure 6.8. Acetal and Ketal Formation Once a hemiacetal or hemiketal is formed, the hydroxyl group is protonated and released as a molecule of water; alcohol then attacks, forming an acetal or ketal.

IMINES AND ENAMINES

Nitrogen and nitrogen-based functional groups act as good nucleophiles due to the lone pair of electrons on nitrogen, and react readily with the electrophilic carbonyls of aldehydes and ketones. In the simplest case, ammonia adds to the carbon atom and water is lost, producing an imine, a compound with a nitrogen atom double-bonded to a carbon atom. This reaction is shown in Figure 6.9. Because a small molecule is lost during the formation of a bond between two molecules, this is an example of a condensation reaction. Because nitrogen replaces the carbonyl oxygen, this is also an example of a nucleophilic substitution. Some common ammonia derivatives that react with aldehydes and ketones are hydroxylamine (H2N–OH), hydrazine (H2N–NH2), and semicarbazide (H2N–NH–C(O)NH2); these form oximeshydrazones, and semicarbazones, respectively.

Figure 6.9. Imine Formation Ammonia is added to the carbonyl, resulting in the elimination of water, and generating an imine.

KEY CONCEPT

In the formation of hemiacetals and hemiketals, alcohol is the nucleophile, and the carbonyl carbon is the electrophile. In the formation of acetals and ketals, alcohol is the nucleophile, and the carbocation carbon (formerly the carbonyl carbon) is the electrophile.

Imines and related compounds can undergo tautomerization to form enamines, which contain both a double bond and a nitrogen-containing group. This is analogous to the ketoenol tautomerization of carbonyl compounds and will be explored in Chapter 7 of MCAT Organic Chemistry Review.

CYANOHYDRINS

Hydrogen cyanide (HCN) is a classic nucleophile on the MCAT. HCN has both triple bonds and an electronegative nitrogen atom, rendering it an extremely acidic compound (for an organic molecule, at least) with a pKa of 9.2. After the hydrogen dissociates, the nucleophilic cyanide anion can attack the carbonyl carbon atom, as shown in Figure 6.10. Reactions with aldehydes and ketones produce stable compounds called cyanohydrins once the oxygen has been reprotonated. The cyanohydrin gains its stability from the newly formed C–C bond.

Figure 6.10. Cyanohydrin Formation Cyanide functions as a nucleophile, attacking the carbonyl carbon and generating a cyanohydrin.

KEY CONCEPT

In a reaction with HCN, :CN: is the nucleophile; the carbonyl carbon is the electrophile.

MCAT Concept Check 6.2:

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

1.    When an aldehyde or ketone is reacted with one equivalent of an alcohol, what occurs? What would be different if it were reacted with two equivalents in acidic conditions?

·        Aldehyde or ketone + 1 equivalent of alcohol:

·        Aldehyde or ketone + 2 equivalents of alcohol:

2.    When nitrogen or nitrogen-containing derivatives react with aldehydes and ketones, what type of reaction happens, and what functional group is formed?

3.    When HCN reacts with an aldehyde or ketone, what functional group is produced? Is the product stable?