Aldol Condensation

In organic synthesis, aldol condensations are a very important class of reactions. Charles - Adolph Wurtz and Alexander Porfyrevich Borodin discovered the reaction independently in 1872. The name aldol was chosen because there is often an aldehyde and an alcohol group in the product of an aldol condensation.

Generally speaking, an aldol condensation is a nucleophile attack on a carbonyl to make a ketone or aldehyde of β-hydroxy. The nucleophile is generally an enolate of an aldehyde or ketone attacking another aldehyde or ketone molecule. An acidic or basic solution can catalyze the condensation of aldol.

By bases such as hydroxide ions and alcoxide ions, an aldehyde is partially converted to its enolate anion.

RCH₂CHO + HO- RCH=CHO- + H₂O

Aldehyde Water Enolate Water

The enolate is subjected to nucleophilic addition to the carbonyl group in a solution that contains both an aldehyde and its enolate ion. This addition is similar to the addition of reactions to aldehydes and ketones from other nucleophilic reagents.

     O

     ||

RCH₂CH

      O- O-O OH O

     / | || H₂O | ||

RCH₂CH RCH₂CH—RCHCH RCH₂CH—RCHCH

Product of Aldol Addition

The alkoxide formed in the nucleophilic addition step then abstracts a proton from the solvent (usually water or ethanol) to yield the product of aldol addition. This product is known as an aldol because it comprises a function of aldehyde and a group of hydroxyl(ald+ ol = aldol)

An important feature of aldol addition is that carbon–carbon bond formation occurs between the α-carbon atom of one aldehyde and the carbonyl group of another. This was because the generation of carbanion (enolate) can involve only proton abstraction from the α-carbon atom.

Figure 1: The reactive sites in aldol addition are the carbonyl group of one aldehyde molecule and the α-carbon atom of another.

One of these protons is removed by base to form an enolate

     O O OH O

     || || base || ||

  RCH₂CH + RCH₂CH RCH₂CH--RCHCH 

Carbonyl group to which this is the carbon–carbon that is formed in formed in the reaction

Aldol Addition Occurs Readily with Aldehydes:

     O

     || NaOH, H₂O

2 CH₃CH CH₃CHCH₂CHO 4 - 5°C |

                                     OH

Acetaldehyde 3-Hydroxybutanal (50%) (Acetaldol)

             O O

          || KOH, H₂O ||

2CH₃CH₂CH₂CH CH₃CH₂CH₂CHCHCH

               6 - 8°C | |

                                              OH CH₂CH₃

Butanal 2-Ethyl-3-hydroxyhexanal (75%)

The α-hydroxy aldehyde products of aldol addition undergo dehydration on heating,to yield α, β-unsaturated aldehydes:

     OH O O

      | || Heat ||

  RCH₂CHCHCH RCH₂CH=CCH + H₂O

           | 6 - 8°C | 

          R R

β -Hydroxy aldehyde α, β-unsaturated aldehydes Water

The combination of the newly formed dual bond with the carbonyl group stabilizes α, β - unsaturated aldehyde, provides the driving force for dehydration and controls the selectivity of its region. Dehydration can be done by acid or base heating the aldol. Normally, if α, β -unsaturated aldehyde is the desired product, all that is done is to carry out the base-catalyzed aldol addition reaction at elevated temperature. Under these conditions, once the aldol addition product is formed, it rapidly loses water to form α, β-unsaturated aldehyde.

                   O O

                  || NaOH, H₂O ||

  2CH₃CH₂CH₂CH CH₃CH₂CH₂CH=CCH |

                                             CH₂CH₃

Butanal 2-Ethyl-2-hexenal (86%) 

                              (Major Product)

Reactions in which two molecules of an aldehyde combine to form α, β– unsaturated aldehyde and a molecule of water are called aldol condensations.

To be dehydrated to alkenes, alcohols require acid catalysis. It may, therefore, seem strange that products to add aldol may be dehydrated in the base. This is another example of how increased proton acidity at α - carbon atom affects carbonyl compound reactions. Elimination may occur in a concerted E2 fashion or may be progressive and proceed through an enolate ion.

1. Dehydration of Aldol Products

Aldol reaction products are often subjected to subsequent water removal, consisting of a α-hydrogen group and beta - hydroxyl group. The product of this beta - elimination reaction, as shown in the following diagram, is α, β-unsaturated aldehyde or ketone. For this elimination, acid - catalyzed conditions are more commonly used (e.g. # 1, 2 & 5), but base - catalyzed elimination also occurs, particularly in heating (e.g. # 3, 4 & 5). The additional stability provided by the product's conjugated carbonyl system makes some thermodynamically favorable ketone aldol reactions (# 4 & 5) and stereoisomer (E & Z) mixtures are obtained from reaction #4. Reaction #5 is an interesting example of a reaction of intramolecular aldol; these reactions create a new ring. 

Condensations are called reactions in which a larger molecule is formed from smaller components, eliminating a very small by-product such as water. The following examples are therefore properly referred to as condensations of aldols. In the presence of acid and base catalysts, the dehydration step of an aldol condensation is also reversible. Therefore, when heating with aqueous solutions of strong acids or bases, many α, β-unsaturated carbonyl compounds fragment into smaller aldehydes or ketones, a process known as the retro-aldehyde reaction.

The Acid - 

catalyzed water removal is not exceptional, as this has been noted as a common alcohol reaction. Nevertheless, it is found that the conditions required for beta-elimination are less than those used for simple alcohols. The most surprising aspect of beta-elimination, however, is that it can be base-catalyzed. 

As the equations show these eliminations could proceed from either the beta-hydroxy aldol product's keto or enol tautomers. Although the keto tautomer route is not unreasonable (remember the increased acidity in carbonyl compounds of the α-hydrogens), the enol tautomer provides a more favourable pathway for both acid and base-catalyzed elimination of beta oxygen.

2. Mixed Aldol Condensations

As both the enolic donor and the electrophilic acceptor, the previous examples of aldol reactions and condensations used a common reactant. The product is always a dimer of the carbonyl reactant compound in such cases. Crossed or mixed reactions are called aldol condensations between different carbonyl reactants, and under certain conditions, such crossed aldol condensations may be effective. Some examples are shown below, and in most cases, under the conditions used, beta - elimination of water occurs. The exception, reaction # 3, is carried out under mild conditions with excess reactive aldehyde formaldehyde serving as an electrophilic acceptor. The first reaction shows that ketones with two sets of α-hydrogens can react at both sites if they are supplied with sufficient acceptor co-reactant. The interesting difference in regioselectivity in the second reaction (the reactants in the central shaded region) shows some subtle differences between the reactions of acid and base-catalyzed aldol. The base-catalyzed reaction is performed by an enolate anion donor species and the kinetically favoured removal of the proton is from the less replaced α-carbon. The acid-catalyzed aldol goes through the tautomer of the enol, and the more stable of the two tautomers of the enol is the double bond with the more replaced.Finally, there are two reactive α-carbons in reaction #4 and there may be a reversible aldol reaction in both. Only one of the two aldol products can undergo water beta-elimination, so the eventual isolated product is derived from this sequence of reaction. The Claisen-Schmidt reaction is called the aldol condensation of ketones with aryl aldehydes into α,β-unsaturated derivatives.

Two factors are responsible for the success of these mixed aldol reactions. First, aldehydes are more reactive electrophiles than ketones, and more reactive than other aldehydes is formaldehyde. Second, aldehydes that lack α-hydrogens can only function as acceptor reactants, thereby reducing by half the number of possible products.Mixed aldols in which both reactants can serve as donors and acceptors generally provide complex mixtures of dimeric (homo) aldols as well as crossed aldols. In such a case, the following abbreviated formulas illustrate the possible products, red letters representing the component of the acceptor and the donor blue.If all reactions occurred at the same rate, the same quantity would be obtained for the four products. It would be difficult to separate and purify the components of such a mixture.

Application of Aldol Condensation

The reaction enables carbon - carbon bonds to be formed. The reaction leads to the establishment of a C - C bond in Gluconeogenesis and Photosynthesis. This is regarded as an important reaction in metabolism biochemistry, where glycolysis is the fifth step. However, it works in the opposite way in glycolysis and serves to end the carbon - carbon bond. The reaction is commonly used to produce solvents such as alcohol isophorone and diacetone. It works as an intermediate for perfume production. It is also used in pharmaceutical manufacturing, unsaturated ketones and chalcones known as aromatic ketones. Usually, it is used to create plasticizers as well.