REACTIONS OF ALDEHYDES AND KETONES

Reactions of Aldehydes and Ketones

Aldehydes and ketones undergo a variety of reactions that lead to many different products. The most common reactions are nucleophilic addition reactions, which lead to the formation of alcohols, alkenes, diols, cyanohydrins (RCH(OH)C&tbond;N), and imines R ₂C&dbond;NR), to mention a few representative examples.

Reactions of carbonyl groups

The main reactions of the carbonyl group are nucleophilic additions to the carbon‐oxygen double bond. As shown below, this addition consists of adding a nucleophile and a hydrogen across the carbon‐oxygen double bond.

Due to differences in electronegativities, the carbonyl group is polarized. The carbon atom has a partial positive charge, and the oxygen atom has a partially negative charge.

Aldehydes are usually more reactive toward nucleophilic substitutions than ketones because of both steric and electronic effects. In aldehydes, the relatively small hydrogen atom is attached to one side of the carbonyl group, while a larger R group is affixed to the other side. In ketones, however, R groups are attached to both sides of the carbonyl group. Thus, steric hindrance is less in aldehydes than in ketones.

Electronically, aldehydes have only one R group to supply electrons toward the partially positive carbonyl carbon, while ketones have two electron‐supplying groups attached to the carbonyl carbon. The greater amount of electrons being supplied to the carbonyl carbon, the less the partial positive charge on this atom and the weaker it will become as a nucleus.

Addition of water

The addition of water to an aldehyde results in the formation of a hydrate.

The formation of a hydrate proceeds via a nucleophilic addition mechanism.

1. Water, acting as a nucleophile, is attracted to the partially positive carbon of the carbonyl group, generating an oxonium ion.

2. The oxonium ion liberates a hydrogen ion that is picked up by the oxygen anion in an acid‐base reaction.

Small amounts of acids and bases catalyze this reaction. This occurs because the addition of acid causes a protonation of the oxygen of the carbonyl group, leading to the formation of a full positive charge on the carbonyl carbon, making the carbon a good nucleus. Adding hydroxyl ions changes the nucleophile from water (a weak nucleophile) to a hydroxide ion (a strong nucleophile). Ketones usually do not form stable hydrates.

Addition of alcohol

Reactions of aldehydes with alcohols produce either hemiacetals (a functional group consisting of one —OH group and one —OR group bonded to the same carbon) or acetals (a functional group consisting of two —OR groups bonded to the same carbon), depending upon conditions. Mixing the two reactants together produces the hemiacetal. Mixing the two reactants with hydrochloric acid produces an acetal. For example, the reaction of methanol with ethanal produces the following results:

A nucleophilic substitution of an OH group for the double bond of the carbonyl group forms the hemiacetal through the following mechanism:

1. An unshared electron pair on the alcohol's oxygen atom attacks the carbonyl group.

2. The loss of a hydrogen ion to the oxygen anion stabilizes the oxonium ion formed in Step 1.

The addition of acid to the hemiacetal creates an acetal through the following mechanism:

1. The proton produced by the dissociation of hydrochloric acid protonates the alcohol molecule in an acid‐base reaction.

2. An unshared electron pair from the hydroxyl oxygen of the hemiacetal removes a proton from the protonated alcohol.

3. The oxonium ion is lost from the hemiacetal as a molecule of water.

4. A second molecule of alcohol attacks the carbonyl carbon that is forming the protonated acetal.

5. The oxonium ion loses a proton to an alcohol molecule, liberating the acetal.

Stability of acetals

Acetal formation reactions are reversible under acidic conditions but not under alkaline conditions. This characteristic makes an acetal an ideal protecting group for aldehyde molecules that must undergo further reactions. A protecting group is a group that is introduced into a molecule to prevent the reaction of a sensitive group while a reaction is carried out at some other site in the molecule. The protecting group must have the ability to easily react back to the original group from which it was formed. An example is the protection of an aldehyde group in a molecule so that an ester group can be reduced to an alcohol.

In the previous reaction, the aldehyde group is converted into an acetal group, thus preventing reaction at this site when further reactions are run on the rest of the molecule.

Notice in the previous reaction that the ketone carbonyl group has been reduced to an alcohol by reaction with LiAlH ₄. The protected aldehyde group has not been reduced. Hydrolysis of the reduction product recreates the original aldehyde group in the final product.

Addition of hydrogen cyanide

The addition of hydrogen cyanide to a carbonyl group of an aldehyde or most ketones produces a cyanohydrin. Sterically hindered ketones, however, don't undergo this reaction.

The mechanism for the addition of hydrogen cyanide is a straightforward nucleophilic addition across the carbonyl carbony oxygen bond.

Addition of ylides (the Wittig reaction)

The reaction of aldehydes or ketones with phosphorus ylides produces alkenes of unambiguous double‐bond locations. Phosphorous ylides are prepared by reacting a phosphine with an alkyl halide, followed by treatment with a base. Ylides have positive and negative charges on adjacent atoms.

The following illustration shows the preparation of 2‐methylbutene by a Wittig reaction.

Addition of organometallic reagents

Grignard reagents, organolithium compounds, and sodium alkynides react with formaldehyde to produce primary alcohols, all other aldehydes to produce secondary alcohols, and ketones to produce tertiary alcohols.

Addition of ammonia derivatives

Aldehydes and ketones react with primary amines to form a class of compounds called imines.

The mechanism for imine formation proceeds through the following steps:

1. An unshared pair of electrons on the nitrogen of the amine is attracted to the partial‐positive carbon of the carbonyl group.

2. A proton is transferred from the nitrogen to the oxygen anion.

3. The hydroxy group is protonated to yield an oxonium ion, which easily liberates a water molecule.

4. An unshared pair of electrons on the nitrogen migrate toward the positive oxygen, causing the loss of a water molecule.

5. A proton from the positively charged nitrogen is transferred to water, leading to the imine's formation.

Imines of aldehydes are relatively stable while those of ketones are unstable. Derivatives of imines that form stable compounds with aldehydes and ketones include phenylhydrazine, 2,4‐dinitrophenylhydrazine, hydroxylamine, and semicarbazide.

Oximes, 2,4‐dinitrophenylhydrazones, and semicarbazones are often used in qualitative organic chemistry as derivatives for aldehydes and ketones.

Oxidations of aldehydes and ketones

Aldehydes can be oxidized to carboxylic acid with both mild and strong oxidizing agents. However, ketones can be oxidized to various types of compounds only by using extremely strong oxidizing agents. Typical oxidizing agents for aldehydes include either potassium permanganate (KMnO ₄) or potassium dichromate (K ₂Cr ₂O ₇) in acid solution and Tollens reagent. Peroxy acids, such as peroxybenzoic acid:

Baeyer‐Villiger oxidation is a ketone oxidation, and it requires the extremely strong oxidizing agent peroxybenzoic acid. For example, peroxybenzoic acid oxidizes phenyl methyl ketone to phenyl acetate (an ester).

Aldol reactions

In addition to nucleophilic additions, aldehydes and ketones show an unusual acidity of hydrogen atoms attached to carbons alpha (adjacent) to the carbonyl group. These hydrogens are referred to as α hydrogens, and the carbon to which they are bonded is an α carbon. In ethanal, there is one α carbon and three α hydrogens, while in acetone there are two α carbons and six α hydrogens.

Although weakly acidic (K _a 10 ⁻¹⁹ to 10 ⁻²⁰), α hydrogens can react with strong bases to form anions. The unusual acidity of α hydrogens can be explained by both the electron withdrawing ability of the carbony group and resonance in the anion that forms. The electron withdrawing ability of a carbonyl group is caused by the group's dipole nature, which results from the differences in electronegativity between carbon and oxygen.

The anion formed by the loss of an α hydrogen can be resonance stabilized because of the mobility of the π electrons that are on the adjacent carbonyl group.

The resonance, which stabilizes the anion, creates two resonance structures — an enol and a keto form. In most cases, the keto form is more stable.

Halogenation of ketones

In the presence of a base, ketones with α hydrogens react to form α haloketones.

Likewise, when methyl ketones react with iodine in the presence of a base, complete halogenation occurs.

The generation of sodium hypoiodate in solution from the reaction of iodine with sodium hydroxide leads to the formation of iodoform and sodium benzoate, as shown here.

Because iodoform is a pale yellow solid, this reaction is often run as a test for methyl ketones and is called the iodoform test.

Aldol condensation

Aldehydes that have α hydrogens react with themselves when mixed with a dilute aqueous acid or base. The resulting compounds, β‐hydroxy aldehydes, are referred to as aldol compounds because they possess both an aldehyde and alcohol functional group.

The aldol condensation proceeds via a carbanion intermediate. The mechanism of base‐catalyzed aldol condensation follows these steps:

1. The base removes an α hydrogen.

2. The carbanion undergoes nucleophilic addition with the carbonyl group of a second molecule of ethanal, which leads to formation of the condensation product.

3. A reaction with water protonates the alkoxide ion.

If the aldol is heated in basic solution, the molecule can be dehydrated to form an α β‐unsaturated aldehyde.

Cross-aldol condensation

An aldol condensation between two different aldehydes produces a cross‐aldol condensation. If both aldehydes possess α hydrogens, a series of products will form. To be useful, a cross‐aldol must be run between an aldehyde possessing an α hydrogen and a second aldehyde that does not have α hydrogens.

Ketonic aldol conDensation

Ketones are less reactive towards aldol condensations than alde‐hydes. With acid catalysts, however, small amounts of aldol product can be formed. But the Aldol product that forms will rapidly dehydrate to form a resonance‐stabilized product. This dehydration step drives the reaction to completion.

The acid‐catalyzed aldol condensation includes two key steps: the conversion of the ketone into its enolic form, and the attack on a protonated carbonyl group by the enol. The mechanism proceeds as follows:

1. The oxygen of the carbonyl group is protonated.

2. A water molecule acting as a base removes an acidic α hydrogen, which leads to an enol.

3. The enol attacks a protonated carbonyl group of a second ketone molecule.

Cyclizations via aldol condensation

Internal aldol condensations (condensations where both carbonyl groups are on the same chain) lead to ring formation.

The mechanism for cyclization via an aldol proceeds through an enolate attack on the aldehyde carbonyl.

1. The hydroxy ion removes a hydrogen ion α to the ketone carbonyl.

2. The enolate ion attacks the aldehyde carbonyl, closing the ring.

3. The alkoxide ion abstracts a proton from water in an acid‐base reaction.

4. The base removes a hydrogen ion to form a resonance‐stabilized molecule.

The benzoin condensation

Aromatic aldehydes form a condensation product when heated with a cyanide ion dissolved in an alcohol‐water solution. This condensation leads to the formation of α hydroxy ketones.

The cyanide ion is the only known catalyst for this condensation, because the cyanide ion has unique properties. For example, cyanide ions are relatively strong nucleophiles, as well as good leaving groups. Likewise, when a cyanide ion bonds to the carbonyl group of the aldehyde, the intermediate formed is stabilized by resonance between the molecule and the cyanide ion. The following mechanism illustrates these points.

The benzoin condensation reaction proceeds via a nucleophilic substitution followed by a rearrangement reaction.

1. The cyanide ion is attracted to the carbon atom of the carbonyl group.

2. The carbanion is resonance‐stabilized.

3. The carbanion attacks a second molecule of benzaldehyde.

4. The alkoxide ion removes a proton from the hydroxide group.

5. A pair of electrons on the alkoxide ion are attracted to the carbon bonded to the cyanide group, which then leaves to generate the product.