The aldol reaction is an important carbon-carbon bond formation reaction in organic chemistry. In its usual form, it involves the nucleophilic addition of a ketone enolate to an aldehyde to form a β-hydroxy ketone, or "aldol" (aldehyde + alcohol), a structural unit found in many naturally occurring molecules and pharmaceuticals. Sometimes, the aldol addition product loses a molecule of water during the reaction to form an α,β-unsaturated ketone. This is called an aldol condensation. The aldol reaction was discovered independently by Charles-Adolphe Wurtz and by Alexander Porfyrevich Borodin in 1872. Borodin observed the aldol dimerization of 3-hydroxybutanal from acetaldehyde under acidic conditions. The aldol reaction is used widely in the large scale production of commodity chemicals such as pentaerythritol and in the pharmaceutical industry for the synthesis of optically pure drugs. For example, Pfizer's initial route to the heart disease drug Lipitor (INN: atorvastatin), approved in 1996, employed two aldol reactions, allowing access to multigram-scale quantities of the drug.
The aldol structural motif is especially common in polyketides, a class of natural products from which many pharmaceuticals are derived, including the potent immunosuppressant FK506, the tetracycline antibiotics, and the antifungal agent amphotericin B. Extensive research on the aldol reaction has produced highly efficient methods which enable the otherwise challenging synthesis of many polyketides in the laboratory. This is important because many polyketides, along with other biologically active molecules, occur naturally only quantities impractically small for further investigation. The synthesis of many such compounds, once considered nearly impossible, can now be performed routinely on the laboratory scale, and is approaching economic viability on a larger scale in some cases, such as the highly active anti-tumor agent discodermolide. In biochemistry, the aldol reaction is one of the key steps of glycolysis, where it is catalyzed by enzymes called aldolases.
The aldol reaction is particularly valuable in organic synthesis because it produces products with two new stereogenic centers (on the α- and β-carbon of the aldol adduct, marked with asterisks in the scheme above). Modern methods, described below, now allow the relative and absolute configuration of these centers to be controlled. This is of particular importance when synthesizing pharamaceuticals, since molecules with the same structural connectivity but different stereochemistry often have vastly different chemical and biological properties.
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, although many variations, such as the Mannich reaction, exist. When the nucleophile and electrophile are different (the usual case), the reaction is called a crossed aldol reaction (as opposed to dimers formed in an aldol dimerization).