Carbonyl Condensation Reactions

Written by tutor John B.

Before reviewing carbonyl condensation reactions, let’s look at two structures that are important in understanding the behavior of the carbonyl group in condensation reactions. Alpha protons (protons attached to the carbons adjacent to carbonyls) are relatively acidic (pKa ≈ 20) due to resonance stabilization of the conjugate base. The hydrogen atom that detaches from the α-carbon has a good probability of reattaching to the partially negative oxygen instead of the carbon. Therefore, aldehydes and ketones exist in solution as a mixture of two isomers, the keto form, and the enol form (representing the unsaturated alcohol - ene = double bond, ol = alcohol). The two isomers, which differ only in the placement of a proton (and the double bond) are called tautomers. The equilibrium between the tautomers lies far to the keto side making the keto form more thermodynamically favored over the enol. The process of interconverting from the keto to the enol tautomer (shown below) is called enolization, or, less specifically, tautomerization. Enols are important intermediates in many reactions of aldehydes and ketones including carbonyl condensation reactions.

The process of enolization, interconverting from the keto tautomer to the enol tautomer

A carbonyl condensation reaction takes place between two carbonyl partners and involves both nucleophilic addition and α-substitution. One carbonyl is converted by base into a nucleophilic enolate ion, which then adds to the electrophilic carbonyl group of the second compound. As a result, the first molecule undergoes an α-substitution, while the second molecule undergoes a nucleophilic addition.

A carbonyl condenstation reaction, involving nucleophilic addition and alpha-substitution

The aldol condensation is a reaction that occurs between two aldehyde or ketone molecules. Aldol reactions are reversible – initially producing β-hydroxy aldehydes/ketones and then α,β-unsaturated products after dehydration. When an aldehyde reacts in an aldol condensation, it acts both as an electrophile (in its keto form) and a nucleophile (in its enol or enolate form). For example, when acetaldehyde is treated with a catalytic amount of base, an enolate ion is produced. The enolate ion is more nucleophilic than the enol because it is negatively charged. The nucleophilic enolate ion can react with the carbonyl group (an electrophile) of another acetaldehyde molecule. Both species are in the same flask which means that all of the acetaldehyde is not converted into enolate ion and the resulting product is 3-hydroxybutanal, which contains both alcohol and aldehyde functional groups. This type of compound is called an aldol, from aldehyde and alcohol.

An illustration of an aldol condensation reaction and its resulting compound

Two of the four general carbonyl-group reactions – carbonyl substitutions and α substitutions – take place under basic conditions and involve enolate-ion intermediates. Alpha-substitution reactions require a full equivalent of strong base and are normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at low temperature. On the other hand, carbonyl condensation reactions require only a catalytic amount of a relatively weak base rather than a full equivalent so that a small amount of enolate ion is generated in the presence of unreacted carbonyl compound. Once a condensation has occurred, the basic catalyst is regenerated.

The β-hydroxy aldehydes or ketones formed in aldol reactions can be easily dehydrated to yield α,β-unsaturated products, or conjugated enones – water condenses out of the reaction when the enone product forms.

A beta-hydroxy aldehyde (ketone) yielding a conjugated enone and water

Aldol condensations are most useful if we only use one type of aldehyde or ketone. Mixed aldol condensations between two different aldehydes or ketones generally give a mixture of all four possible products because we can’t easily control which will act as the nucleophile and which will act as the electrophile. However, a mixed reaction can be successful if one of the two molecules in an unusually good donor (very acidic α-hydrogens – ethyl acetoacetate, for example) or if it can act only as an electrophile (acceptor) due to the absence of α-hydrogens – benzaldehyde or formaldehyde, for example.

Intramolecular aldol condensations of 1,4- and 1,5-diketones also provide a way to make five- and six-membered rings. For example, base treatment of 2,5-hexanedione yields a cyclopentenone product. The mechanism of intramolecular aldol reactions is similar to that of intermolecular reactions. The only difference is that both the nucleophilic carbonyl anion donor and the electrophilic carbonyl acceptor are now in the same molecule.

Intramolecular aldol condensation yielding five and six-membered rings

The aldol reaction is very useful in synthesis. Whenever the target molecule contains either a β-hydroxy aldehyde/ketone or a conjugated enone functional group, it might come from an aldol reaction.

A diagram of aldol products and aldol reactants

The Claisen Condensation is a carbonyl condensation that occurs between two ester components and gives a β-keto ester product. The Claisen condensation is similar to the aldol condensation, but instead of an aldehyde acting as an electrophile and nucleophile, an ester acts as an electrophile and a nucleophile. In the simplest case, two moles of ethyl acetate react under basic conditions to produce a β-keto ester, specifically, ethyl 3-oxobutanoate, or acetoacetic ester. The reaction proceeds by addition of an enolate anion (created by the basic conditions deprotonating the α carbon) to the carbonyl group of another ester, followed by displacement of an ethoxide ion (good leaving group). Mixed Claisen condensations between two different esters are successful only when one of the two molecules has no acidic α hydrogens (for example, ethyl formate or ethyl benzoate) and, therefore, functions only as the electrophile (acceptor).

An example Claisen Condensation with 2 Ethyl acetate

Intramolecular Claisen condensations, called Dieckmann cyclization reactions, produce five- and six-membered cyclic β-keto esters starting from 1,6- and 1,7-diesters. One of the two ester groups is converted into an enolate ion, which then carries out a nucleophilic acyl substitution reaction on the second ester group at the other end of the molecule. A cyclic β-keto ester product results.

An example Dieckmann cyclization reactions producing a five-membered keto ester

When a carbon nucleophile adds to an α,β-unsaturated acceptor, a Michael reaction occurs through conjugate addition to the unsaturated acceptor. The best Michael reactions take place between relatively acidic donors (β-keto esters or β-diketones) and unhindered α,β-unsaturated acceptors. Enamines obtained from the reaction of a ketone with a secondary amine are also good Michael donors. Enamines are electronically similar to enolate ions and behave in the same way as enolate ions. In the Stork reaction, for example, an enamine adds to an α,β-unsaturated carbonyl acceptor in a three-step sequence to produce a ketone added to an α,β-unsaturated carbonyl compound with extension of the carbon chain.

An example Stork reaction with a conjugate addition product

Carbonyl condensation reactions are widely used in synthesis and are the most versatile methods for synthesizing complex molecules. The Robinson annulation reaction, which leads to formation of a substituted cyclohexanone, demonstrates the utility of a carbonyl condensation reaction. When a β-diketone or β-ketoester is treated with an α,β-unsaturated ketone, a Michael addition product results which undergoes intramolecular aldol cyclization. For example, 3-Buten-2-one reacts with ethyl acetoacetate to yield a Michael conjugate addition product (1,5-diketone). Treatment with sodium ethoxide converts the Michael product to a cyclohexenone through an intramolecular aldol condensation. In biological systems, a Robinson annulation reaction occurs during the synthesis of certain steroid hormones.

Aldol reactions occur in many biological pathways but are particularly common in carbohydrate metabolism where enzymes called aldolases catalyze the addition of a ketone enolate ion to an aldehyde. An example of an aldolase-catalyzed reaction occurs in glucose biosynthesis when dihydroxyacetone phosphate reacts with glyceraldehyde 3-phosphate to give fructose 1,6-bisphosphate.

Claisen condensations, like aldol reactions, also occur in a large number of biological pathways. The Claisen condensation is the mechanism by which intricate hydrocarbon molecules such as lipids, fats, and steroids are synthesized in biological systems. For example, Acetyl coenzyme A performs the function of ethyl acetate, and long chains of lipids are built up from units of two carbon atoms.

The great value of carbonyl condensations is that they are one of the few general methods for forming carbon-carbon bonds, thereby making it possible to build larger molecules from smaller molecules.

A carbonyl condensation reaction involves both nucleophilic addition and α-substitution.

A. True
B. False
The correct answer here would be A.

In an aldol condensation, any aldehyde or ketone will react and produce only two, predictable products.

A. True
B. False
The correct answer here would be B.

The Claisen condensation occurs between an aldehyde and an ester and requires a good leaving group.

A. True
B. False
The correct answer here would be B.

The Michael reaction is a conjugate addition reaction and requires relatively acidic donors and unhindered acceptors for the best results.

A. True
B. False
The correct answer here would be A.

Estrone, a polycyclic steroid hormone, can be synthesized using a Robinson annulation reaction.

A. True
B. False
The correct answer here would be A.

Which of the following will produce a five-membered ring via a Dieckmann cyclization?

A. 1,6-diketone
B. 1,7-diester
C. 1,7-diketone
D. a and c
E. b and d
The correct answer here would be A.

Which of the following is the ester analog of an aldol condensation?

A. Robinson annulation reaction
B. Michael reaction
C. Claisen condensation
D. Dieckmann cyclization
E. c and d
F. All are analogs of an aldol condensation
The correct answer here would be A.

In carbonyl condensation reactions,

A. the carbonyl acts as an electrophile
B. the carbonyl acts as a nucleophile
C. the carbonyl acts as both an electrophile and a nucleophile
The correct answer here would be C.

Alpha protons are relatively acidic due to resonance stabilization of the conjugate base.

A. True
B. False
The correct answer here would be A.

Aldol reactions are reversible.

A. True
B. False
The correct answer here would be A.
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