Aldol reaction

The aldol reaction is a means of forming carbon–carbon bonds in organic chemistry.Discovered independently by the Russian chemist Alexander Borodin in 1869 and by the French chemist Charles-Adolphe Wurtz in 1872, the reaction combines two carbonyl compounds (the original experiments used aldehydes) to form a new β-hydroxy carbonyl compound. These products are known as aldols, from the aldehyde + alcohol, a structural motif seen in many of the products. Aldol structural units are found in many important molecules, whether naturally occurring or synthetic.For example, the aldol reaction has been used in the large-scale production of the commodity chemical pentaerythritoland the synthesis of the heart disease drug Lipitor (atorvastatin, calcium salt). The aldol reaction is a means of forming carbon–carbon bonds in organic chemistry.Discovered independently by the Russian chemist Alexander Borodin in 1869 and by the French chemist Charles-Adolphe Wurtz in 1872, the reaction combines two carbonyl compounds (the original experiments used aldehydes) to form a new β-hydroxy carbonyl compound. These products are known as aldols, from the aldehyde + alcohol, a structural motif seen in many of the products. Aldol structural units are found in many important molecules, whether naturally occurring or synthetic.For example, the aldol reaction has been used in the large-scale production of the commodity chemical pentaerythritoland the synthesis of the heart disease drug Lipitor (atorvastatin, calcium salt). The aldol reaction unites two relatively simple molecules into a more complex one. Increased complexity arises because up to two new stereogenic centers (on the α- and β-carbon of the aldol adduct, marked with asterisks in the scheme below) are formed. Modern methodology is capable of not only allowing aldol reactions to proceed in high yield but also controlling both the relative and absolute configuration of these stereocenters. This ability to selectively synthesize a particular stereoisomer is significant because different stereoisomers can have very different chemical and biological properties. For example, stereogenic aldol units are especially common in polyketides, a class of molecules found in biological organisms. In nature, polyketides are synthesized by enzymes that effect iterative Claisen condensations. The 1,3-dicarbonyl products of these reactions can then be variously derivatized to produce a wide variety of interesting structures. Often, such derivitization involves the reduction of one of the carbonyl groups, producing the aldol subunit. Some of these structures have potent biological properties: the immunosuppressant FK506, the anti-tumor agent discodermolide, or the antifungal agent amphotericin B, for example. Although the synthesis of many such compounds was once considered nearly impossible, aldol methodology has allowed their efficient synthesis in many cases. A typical modern aldol addition reaction, shown above, might involve the nucleophilic addition of a ketone enolate to an aldehyde. Once formed, the aldol product can sometimes lose a molecule of water to form an α,β-unsaturated carbonyl compound. This is called aldol condensation. A variety of nucleophiles may be employed in the aldol reaction, including the enols, enolates, and enol ethers of ketones, aldehydes, and many other carbonyl compounds. The electrophilic partner is usually an aldehyde or ketone (many variations, such as the Mannich reaction, exist). When the nucleophile and electrophile are different, the reaction is called a crossed aldol reaction; on the converse, when the nucleophile and electrophile are the same, the reaction is called an aldol dimerization. The aldol reaction may proceed by two fundamentally different mechanisms. Carbonyl compounds, such as aldehydes and ketones, can be converted to enols or enol ethers. These species, being nucleophilic at the α-carbon, can attack especially reactive protonated carbonyls such as protonated aldehydes. This is the 'enol mechanism'. Carbonyl compounds, being carbon acids, can also be deprotonated to form enolates, which are much more nucleophilic than enols or enol ethers and can attack electrophiles directly. The usual electrophile is an aldehyde, since ketones are much less reactive. This is the 'enolate mechanism'. If the conditions are particularly harsh (e.g.: NaOMe/MeOH/reflux), condensation may occur, but this can usually be avoided with mild reagents and low temperatures (e.g., LDA (a strong base), THF, −78 °C). Although the aldol addition usually proceeds to near completion under irreversible conditions, the isolated aldol adducts are sensitive to base-induced retro-aldol cleavage to return starting materials. In contrast, retro-aldol condensations are rare, but possible. When an acid catalyst is used, the initial step in the reaction mechanism involves acid-catalyzed tautomerization of the carbonyl compound to the enol. The acid also serves to activate the carbonyl group of another molecule by protonation, rendering it highly electrophilic. The enol is nucleophilic at the α-carbon, allowing it to attack the protonated carbonyl compound, leading to the aldol after deprotonation. This usually dehydrates to give the unsaturated carbonyl compound. The scheme shows a typical acid-catalyzed self-condensation of an aldehyde. Acid-catalyzed aldol mechanism Acid-catalyzed dehydration