The importance of molecular structure in the reactivity of organic compounds is illustrated by the reactions that produce aldehydes and ketones.
Due to the presence of the polarized carbonyl (C=O) bond, aldehydes and ketones are useful for nucleophilic addition reactions at the C=O bond and for reactions at adjacent positions; Aldehydes are also useful for their ability to be easily oxidized.
Nucleophilic additions at the C=O bond
Due to the electron-poor nature of the carbon in the C=O bond present in aldehydes and ketones, nucleophiles (molecules/ions with free electrons to donate) react at this carbon. The reactions include hemiacetal, acetal, imine, enamine, hydride reagents, and cyanohydrin reactions.
Hemiacetals are characterized by a hydroxyl group (alcohol, -OH) using its electron-rich oxygen to attack the carbon on an aldehyde or ketone. The electron flow from the hydroxyl oxygen to the aldehyde/ketone carbon causes a buildup of electrons at the aldehyde/ketone oxygen, turning the double bond between carbon and oxygen into a single bond. The hydrogen from the hydroxyl then rearranges to move from the hydroxyl oxygen to the aldehyde/ketone oxygen, forming a hemiacetal (-O-C-OH).
Acetals undergo the same mechanism. The difference is that hemiacetals form under 1 equivalent of hydroxyl groups (alcohol groups) and acetals form under 2 equivalents of hydroxyl groups. Under this circumstance, rather than forming a -OH substituent as seen in a hemiacetal, the aldehyde/ketone oxygen forms a single O-X bond with whatever is at the end of the hydroxyl group, resulting in an acetal (-O-C-O-).
Imines and Enamines are formed by the same nucleophilic addition reaction seen in acetals and hemiacetals. Imines are formed by the addition of primary amines (-NH2), forming (-N=C) and enamines are formed by the addition of secondary amines (-NH), forming (-N-C=C). In these cases, the oxygen on the aldehyde/ketone reacts with additional water and leaves.
Hydride reagents such as LiAl4 and NaBH4 participate in nucleophilic addition with aldehydes/ketones, reducing the oxygen in the C=O bond to a hydroxyl (OH) and attaching a proton to the functional group, resulting in going from (H2-C=O) to (H3-C-OH).
The last example of reversible addition is that of hydrogen cyanide (HC≡N), which adds to aldehydes and many ketones to give products called cyanohydrins. A cyano group (-C≡N) undergoes nucleophilic addition and reduces the carbonyl in the aldehyde/ketone to a hydroxyl group. The cyano group attaches to the aldehyde/ketone carbon.
Oxidation of Aldehydes
Due to the free hydrogen seen in aldehydes, aldehydes can be oxidized to transform the carbonyl group (C=O) to a carboxylic acid group (-COOH).
Reactions at Adjacent Positions: Enolate Chemistry
As with alkenes, hydration (addition of water) to alkynes requires a strong acid, usually sulfuric acid, and is facilitated by mercuric sulfate. However, unlike the additions to double bonds which give alcohol products, addition of water to alkynes gives ketone products ( except for acetylene which yields acetaldehyde ). The explanation for this deviation lies in enol-keto tautomerization, illustrated by the following equation. The initial product from the addition of water to an alkyne is an enol (a compound having a hydroxyl substituent attached to a double-bond), and this immediately rearranges to the more stable keto tautomer.
Tautomers are defined as rapidly interconverted constitutional isomers, usually distinguished by a different bonding location for a labile hydrogen atom (colored red here) and a differently located double bond. The equilibrium between tautomers is not only rapid under normal conditions, but it often strongly favors one of the isomers ( acetone, for example, is 99.999% keto tautomer ). Even in such one-sided equilibria, evidence for the presence of the minor tautomer comes from the chemical behavior of the compound. Tautomeric equilibria are catalyzed by traces of acids or bases that are generally present in most chemical samples. The three examples shown below illustrate these reactions for different substitutions of the triple-bond. The tautomerization step is indicated by a red arrow. For terminal alkynes the addition of water follows the Markovnikov rule, as in the second example below, and the final product ia a methyl ketone ( except for acetylene, shown in the first example ). For internal alkynes ( the triple-bond is within a longer chain ) the addition of water is not regioselective. If the triple-bond is not symmetrically located ( i.e. if R & R’ in the third equation are not the same ) two isomeric ketones will be formed.
With the addition of water, alkynes can be hydrated to form enols that spontaneously tautomerize to ketones. Reaction is catalyzed by mercury ions. Follows Markovnikov’s Rule: Terminal alkynes give methyl ketones.
- The first step is an acid/base reaction where the π electrons of the triple bond acts as a Lewis base and attacks the proton therefore protinating the carbon with the most hydrogen substituents.
- The second step is the attack of the nucleophilic water molecule on the electrophilic carbocation, which creates an oxonium ion.
- Next you deprotonate by a base, generating an alcohol called an enol, which then tautomerizes into a ketone.
- Tautomerism is a simultaneous proton and double bond shift, which goes from the enol form to the keto isomer form
A useful carbon-carbon bond-forming reaction known as the Aldol Reaction is yet another example of electrophilic substitution at the alpha carbon in enolate anions. The fundamental transformation in this reaction is a dimerization of an aldehyde (or ketone) to a beta-hydroxy aldehyde (or ketone) by alpha C–H addition of one reactant molecule to the carbonyl group of a second reactant molecule. Due to the carbanion like nature of enolates they can add to carbonyls in a similar manner as Grignard reagents. For this reaction to occur at least one of the reactants must have α hydrogens.
The aldol reaction has a three-step mechanism:
- Step 1: Enolate formation
- Step 2: Nucleophilic attack by the enolate
- Step 3: Protonation
The products of aldol reactions often undergo a subsequent elimination of water, made up of an alpha-hydrogen and the beta-hydroxyl group. The product of this
-elimination reaction is an α,β-unsaturated aldehyde or ketone. Base-catalyzed elimination occurs with heating. The additional stability provided by the conjugated carbonyl system of the product makes some aldol reactions thermodynamically and mixtures of stereoisomers (E & Z) are obtained from some reactions. Reactions in which a larger molecule is formed from smaller components, with the elimination of a very small by-product such as water, are termed Condensations. Hence, the following examples are properly referred to as aldol condensations. Overall the general reaction involves a dehydration of an aldol product to form an alkene:
The aldol condensation has a two-step mechanism:
- Step 1: Form enolate
- Step 2: Form enone
Molecules which contain two carbonyl functionalities have the possibility of forming a ring through an intramolecular aldol reaction. In most cases two sets of α hydrogens need to be considered. As with most ring forming reaction five and six membered rings are preferred.
As with other aldol reaction the addition of heat causes an aldol condensation to occur.
The previous examples of aldol reactions and condensations used a common reactant as both the enolic donor and the electrophilic acceptor. The product in such cases is always a dimer of the reactant carbonyl compound. Aldol condensations between different carbonyl reactants are called crossed or mixed reactions, and under certain conditions such crossed aldol condensations can be effective.
The success of these mixed aldol reactions is due to two factors. First, aldehydes are more reactive acceptor electrophiles than ketones, and formaldehyde is more reactive than other aldehydes. Second, aldehydes lacking alpha-hydrogens can only function as acceptor reactants, and this reduces the number of possible products by half. Mixed aldols in which both reactants can serve as donors and acceptors generally give complex mixtures of both dimeric (homo) aldols and crossed aldols. Because of this most mixed aldol reactions are usually not performed unless one reactant has no alpha hydrogens.
The following abbreviated formulas illustrate the possible products in such a case, red letters representing the acceptor component and blue the donor. If all the reactions occurred at the same rate, equal quantities of the four products would be obtained. Separation and purification of the components of such a mixture would be difficult.
AACH2CHO + BCH2CHO + NaOH → A–A + B–B + A–B + B–A
The aldol condensation of ketones with aryl aldehydes to form α,β-unsaturated derivatives is called the Claisen-Schmidt reaction.
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Key Points
• Ketones and Aldehydes are reacted at the carbon in their carbonyl group in nucleophilic additions.
• Aldehydes can be oxidized to carboxylic acids; ketones cannot.
• Due to the electron-poor nature of the carbon in the C=O bond present in aldehydes and ketones, nucleophiles (molecules/ions with free electrons to donate) react at this carbon.
• Hemiacetals are characterized by a hydroxyl group (alcohol, -OH) using its electron-rich oxygen to attack the carbon on an aldehyde or ketone.
• Acetals undergo the same mechanism as hemiacetals. The difference is that hemiacetals form under 1 equivalent of hydroxyl groups (alcohol groups) and acetals form under 2 equivalents of hydroxyl groups.
• Imines and Enamines are formed by the same nucleophilic addition reaction seen in acetals and hemiacetals.
• Hydride reagents such as LiAl4 and NaBH4 participate in nucleophilic addition with aldehydes/ketones, reducing the oxygen in the C=O bond to a hydroxyl (OH) and attaching a proton to the functional group, resulting in going from (H2-C=O) to (H3-C-OH).
• The last example of reversible addition is that of hydrogen cyanide (HC≡N), which adds to aldehydes and many ketones to give products called cyanohydrins.
• Due to the free hydrogen seen in aldehydes, aldehydes can be oxidized to transform the carbonyl group (C=O) to a carboxylic acid group (-COOH).
• Due to enol-keto tautomerization, addition of water to alkynes gives ketone products.
• A useful carbon-carbon bond-forming reaction known as the Aldol Reaction is yet another example of electrophilic substitution at the alpha carbon in enolate anions.
• Reactions in which a larger molecule is formed from smaller components, with the elimination of a very small by-product such as water, are termed Condensations.
• The aldol condensation of ketones with aryl aldehydes to form α,β-unsaturated derivatives is called the Claisen-Schmidt reaction.
Key Terms
Aldehyde: An organic compound containing the group —CHO, formed by the oxidation of alcohols.
Ketone: An organic compound containing a carbonyl group =C=O bonded to two hydrocarbon groups, made by oxidizing secondary alcohols.
Primary amines: Primary amines (1º) arise when one of three hydrogen atoms in ammonia is replaced by an alkyl or aromatic group.
Secondary amines: Secondary amines (2º) have two organic substituents (alkyl, aryl or both) bound to the nitrogen together with one hydrogen.
Carboxylic acid: An organic acid containing a carboxyl group; -COOH.
Reduction: A chemical reaction that involves the gaining of electrons by one of the atoms involved in the reaction between two chemicals.
Oxidation: Any chemical reaction that involves the moving of electrons. Specifically, it means the substance that gives away electrons is oxidized.
Grignard reagents: A Grignard reagent or Grignard compound is a chemical compound with the generic formula R−Mg−X, where X is a halogen and R is an organic group, normally an alkyl or aryl.
Crossed or mixed reactions: Aldol condensations between different carbonyl reactants.
Claisen-Schmidt reaction: The reaction between an aldehyde or ketone having an α-hydrogen with an aromatic carbonyl compound lacking an α-hydrogen.
