page_title: Aldol reaction
section_title: Intramolecular reaction
hierarchical_section_title: Aldol reaction / Intramolecular reaction
context_page_description: 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 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 pentaerythritol
  and the synthesis of the heart disease drug Lipitor.
  The aldol reaction unites two relatively simple molecules into a more complex one. Increased complexity arises because up to two new stereogenic centers 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.
context_section_description: Intramolecular aldol reaction is the condensation reaction of two aldehyde groups or ketone groups in the same molecule. Five- or six-membered α, β-unsaturated ketone or aldehydes are formed as products. This reaction is an important approach to the formation of carbon-carbon bonds in organic molecules containing ring systems. As an example, under strong basic conditions (e.g. sodium hydroxide), hexane-2,5-dione (compound A in Figure 1) can cyclize via intramolecular aldol reaction to form the 3-methylcyclopent-2-en-1-one (compound B).
  The mechanism of the intramolecular aldol reaction involves formation of a key enolate intermediate followed by an intramolecular nucleophilic addition process. First, hydroxide abstracts the α-hydrogen on a terminal carbon to form the enolate. Next, a nucleophilic attack of the enolate on the other keto group forms a new carbon-carbon bond (red) between carbons 2 and 6. At last, usually under heating conditions, the elimination of water molecule yields the cyclized α,β-unsaturated ketone.
  Intramolecular aldol reactions have been widely used in total syntheses of various natural products, especially alkaloids and steroids. An example is the application of an intramolecular aldol reaction in the ring closure step for total synthesis of (+)-Wortmannin by Shigehisa, et al. (Figure 2).
caption: Fig. 1: Mechanism of an exemplary intramolecular aldol reaction in basic conditions.