Aldol and Claisen condensations

The key idea

A hydrogen on the carbon next to a C=O group (the \alpha-carbon) is weakly acidic. A base such as hydroxide can remove it, giving a negatively charged enolate ion. The enolate's \alpha-carbon is nucleophilic, so it can attack the \delta+ carbon of another carbonyl group, forming a new C–C bond.

Aldol addition

With dilute NaOH, two molecules of ethanal combine:

The product, 3-hydroxybutanal, contains both an aldehyde and an alcohol, hence 'aldol'. Mechanism: OH^- removes an \alpha-H; the enolate attacks the carbonyl carbon of a second ethanal; the alkoxide formed takes a proton from water, regenerating OH^-, so hydroxide is a catalyst.

Condensation

On heating, the aldol loses water to give an \alpha,\beta-unsaturated carbonyl, here but-2-enal. The new C=C is conjugated with the C=O, which makes this elimination favourable. A reaction in which two molecules join with loss of a small molecule such as water is called a condensation.

Crossed aldols

Mixing two different carbonyl compounds that can both form enolates gives up to four products. A clean reaction needs one partner with no \alpha-hydrogens. Benzaldehyde and propanone with NaOH give (E)-4-phenylbut-3-en-2-one, and with excess benzaldehyde, dibenzylideneacetone, a yellow solid used as a ligand for palladium. This is the Claisen–Schmidt reaction.

Claisen condensation

Esters react similarly with sodium ethoxide. Two molecules of ethyl ethanoate give ethyl 3-oxobutanoate (ethyl acetoacetate) and ethanol. The difference from the aldol is that the alkoxide group is a leaving group, so the second step is substitution rather than addition.

Why it matters

These reactions lengthen carbon chains and build rings. They also link carbonyl chemistry to biology, because enzymes called aldolases and thiolases catalyse the same steps in metabolism.

Aldol: equilibria and conditions

Aldol addition is reversible. For aldehydes the equilibrium favours the adduct; for ketones it often lies towards starting materials (propanone gives only a little 4-hydroxy-4-methylpentan-2-one at equilibrium, so the product is removed or the reaction driven by dehydration). Dehydration proceeds by E1cB: the \alpha-proton of the aldol is acidic, and the enolate expels hydroxide; acid conditions instead go via the enol. Conjugation in the enone drives the overall condensation.

Controlling crossed aldols

Four strategies:

1. Use a non-enolisable electrophile (aromatic aldehydes, methanal, glyoxylates), added to the enolisable partner so its enolate always meets an excess of electrophile. 2. Exploit reactivity differences: aldehydes are better electrophiles than ketones, so a ketone enolate attacking an aldehyde dominates. 3. Pre-form one enolate completely with LDA at −78 °C, then add the electrophile (directed aldol). 4. Use an enol equivalent: silyl enol ethers with a Lewis acid (Mukaiyama), or enamines.

Intramolecular aldol

1,4- and 1,5-diketones cyclise to five- and six-membered enones. Hexane-2,5-dione gives 3-methylcyclopent-2-en-1-one; the alternative three-membered ring is too strained, and the reversibility of the steps lets the system find the most stable ring. The Robinson annulation ends with this step.

Claisen condensation

Ester enolate adds to a second ester; the tetrahedral intermediate expels alkoxide, giving a \beta-ketoester. Key points:

• The base must match the ester's alkoxide (NaOEt with ethyl esters) to avoid transesterification scrambling.
• The product \beta-ketoester (pK_a about 11) is deprotonated by ethoxide; this irreversible-in-practice step pulls an otherwise unfavourable equilibrium, so a full equivalent of base is needed and the ester must have two \alpha-hydrogens. Acidic work-up releases the neutral product.
• Dieckmann cyclisation of diethyl hexanedioate gives ethyl 2-oxocyclopentanecarboxylate.
• Crossed Claisen uses non-enolisable acylating partners: ethyl methanoate, diethyl carbonate, diethyl ethanedioate, ethyl benzoate.
• Ketone enolates acylated by esters give 1,3-diketones.

The \beta-ketoester products can be alkylated at the doubly activated carbon, then hydrolysed and decarboxylated on heating via a cyclic six-membered transition state, giving ketones (acetoacetic ester synthesis).

Worked example

Design a route to 2-methyl-1-phenylpent-1-en-3-one. Disconnect the C=C (aldol logic): benzaldehyde plus pentan-3-one. Pentan-3-one is symmetrical, so either \alpha-carbon gives the same enolate; NaOH in ethanol with heating gives the condensation product directly.

Biological counterparts

Class I aldolases form an enamine from a lysine residue; class II use Zn^{2+} to stabilise the enolate. Thiolases and citrate synthase perform Claisen chemistry with thioesters, whose \alpha-protons are more acidic and whose thiolate is a better leaving group than alkoxide.