An
aldol condensation is an
organic reactionOrganic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical reactions and redox reactions. In organic synthesis,...
in which an
enolEnols are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Alkenes with a hydroxyl group on both sides of the double bond are called enediols. Deprotonated anions of enols are called enolates...
or an enolate ion reacts with a
carbonylIn organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by a
dehydrationIn chemistry and the biological sciences, a dehydration reaction is usually defined as a chemical reaction that involves the loss of water from the reacting molecule. Dehydration reactions are a subset of elimination reactions...
to give a conjugated
enoneAn enone is an unsaturated chemical compound or functional group consisting of a conjugated system of an alkene and a ketone. The simplest enone is methyl vinyl ketone or CH2=CHCOCH3....
.
Aldol condensations are important in
organic synthesisOrganic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...
, providing a good way to form carbon–carbon bonds. The
Robinson annulationThe Robinson annulation is an organic reaction used to create a six-member ring α,β-unsaturated cyclic ketone, using a ketone and methyl vinyl ketone...
reaction sequence features an aldol condensation; the
Wieland-Miescher ketoneThe Wieland–Miescher ketone is a racemic bicyclic diketone and is a versatile synthon which has so far been employed in the total synthesis of more than 50 natural products, predominantly sesquiterpenoids, diterpenes and steroids possessing possible biological properties including anticancer,...
product is an important starting material for many organic syntheses. Aldol condensations are also commonly discussed in university level
organic chemistryOrganic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
classes as a good bond-forming reaction that demonstrates important
reaction mechanismIn chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.Although only the net chemical change is directly observable for most chemical reactions, experiments can often be designed that suggest the possible sequence of steps in...
s. In its usual form, it involves the
nucleophilicA nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
addition of a
ketoneIn organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
enolate to an
aldehydeAn aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
to form a β-hydroxy ketone, or "
aldol" (
aldehyde + alcoh
ol), a structural unit found in many naturally occurring molecules and pharmaceuticals.
The name
aldol condensation is also commonly used, especially in
biochemistryBiochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
, to refer to the
aldol reactionThe aldol reaction is a powerful means of forming carbon–carbon bonds in organic chemistry.Discovered independently by Charles-Adolphe Wurtz and Alexander Porfyrevich Borodin in 1872, the reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound...
itself, as catalyzed by
aldolaseAldolase A is an enzyme that catalyses a reverse aldol reaction: The substrate, fructose 1,6-bisphosphate is broken down into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate . This reaction is a part of glycolysis. Three aldolase isozymes , encoded by three different genes, are...
s. However, the aldol reaction is not formally a
condensation reactionA condensation reaction is a chemical reaction in which two molecules or moieties combine to form one single molecule, together with the loss of a small molecule. When this small molecule is water, it is known as a dehydration reaction; other possible small molecules lost are hydrogen chloride,...
because it does not involve the loss of a small molecule.
The reactions between a ketone and an aldehyde (crossed aldol condensation) or between two aldehydes also go by the name
Claisen-Schmidt condensation. These reactions are named after two of its pioneering investigators
Rainer Ludwig ClaisenRainer Ludwig Claisen was a famous German chemist best known for his work with condensations of carbonyls and sigmatropic rearrangements. He was born in Cologne as the son of a jurist and studied chemistry at the university of Bonn , where he became a member of K.St.V. Arminia...
and J. G. Schmidt, who independently published on this topic in 1880 and 1881. An example is the synthesis of
dibenzylideneacetoneDibenzylideneacetone or dibenzalacetone, often abbreviated dba, is an organic compound with the formula C17H14O. It is a bright-yellow solid insoluble in water, but soluble in ethanol. Dibenzylideneacetone is used as a sunscreen component and as a ligand in organometallic chemistry, for instance in...
.
Mechanism
The first part of this reaction is an
aldol reactionThe aldol reaction is a powerful means of forming carbon–carbon bonds in organic chemistry.Discovered independently by Charles-Adolphe Wurtz and Alexander Porfyrevich Borodin in 1872, the reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound...
, the second part a dehydration—an
elimination reactionAn elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism...
. Dehydration may be accompanied by
decarboxylationDecarboxylation is a chemical reaction that releases carbon dioxide . Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carbonation, the addition of CO2 to...
when an activated carboxyl group is present. The aldol addition product can be dehydrated via two mechanisms; a strong
baseFor the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...
like
potassium t-butoxidePotassium tert-butoxide is the chemical compound with the formula 3COK. This colourless solid is a strong base useful in organic synthesis. It exists as a tetrameric cubane-like cluster...
,
potassium hydroxidePotassium hydroxide is an inorganic compound with the formula KOH, commonly called caustic potash.Along with sodium hydroxide , this colorless solid is a prototypical strong base. It has many industrial and niche applications. Most applications exploit its reactivity toward acids and its corrosive...
or
sodium hydrideSodium hydride is the chemical compound with the empirical formula NaH. It is primarily used as a strong base in organic synthesis. NaH is representative of the saline hydrides, meaning it is a salt-like hydride, composed of Na+ and H− ions, in contrast to the more molecular hydrides such as...
in an enolate mechanism, or in an acid-catalyzed
enolEnols are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Alkenes with a hydroxyl group on both sides of the double bond are called enediols. Deprotonated anions of enols are called enolates...
mechanism.
- :
Condensation types
It is important to distinguish the aldol condensation from other
addition reactionAn addition reaction, in organic chemistry, is in its simplest terms an organic reaction where two or more molecules combine to form a larger one....
s to carbonyl compounds.
- When the base is an amine and the active hydrogen compound is sufficiently activated the reaction is called a Knoevenagel condensation
The Knoevenagel condensation reaction is an organic reaction named after Emil Knoevenagel. It is a modification of the Aldol condensation.A Knoevenagel condensation is a nucleophilic addition of an active hydrogen compound to a carbonyl group followed by a dehydration reaction in which a molecule...
.
- In a Perkin reaction
The Perkin reaction is an organic reaction developed by William Henry Perkin that can be used to make cinnamic acids i.e. α-β-unsaturated aromatic acid by the aldol condensation of aromatic aldehydes and acid anhydrides in the presence of an alkali salt of the acid.Several reviews have been written....
the aldehyde is aromatic and the enolate generated from an anhydride.
- A Claisen condensation
The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone...
involves two esterEsters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
compounds.
- A Dieckmann condensation
The Dieckmann condensation is the intramolecular chemical reaction of diesters with base to give β-ketoesters. It is named after the German chemist Walter Dieckmann . The equivalent intermolecular reaction is the Claisen condensation....
involves two ester groups in the same molecule and yields a cyclic molecule
- A Henry reaction involves an aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
and an aliphatic nitro compoundNitro compounds are organic compounds that contain one or more nitro functional groups . They are often highly explosive, especially when the compound contains more than one nitro group and is impure. The nitro group is one of the most common explosophores used globally...
.
- A Robinson annulation
The Robinson annulation is an organic reaction used to create a six-member ring α,β-unsaturated cyclic ketone, using a ketone and methyl vinyl ketone...
involves a α,β-unsaturatedIn chemistry, saturation has six different meanings, all based on reaching a maximum capacity...
ketoneIn organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
and a carbonylIn organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
group, which first engage in a Michael reactionThe Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an alpha, beta unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C-C bonds...
prior to the aldol condensation.
- In the Guerbet reaction
The Guerbet reaction, named after Marcel Guerbet , is an organic reaction converting a primary aliphatic alcohol into its β-alkylated dimer alcohol with loss of one equivalent of water. This reaction requires a catalyst and elevated temperatures....
, an aldehyde, formed in situIn situ is a Latin phrase which translated literally as 'In position'. It is used in many different contexts.-Aerospace:In the aerospace industry, equipment on board aircraft must be tested in situ, or in place, to confirm everything functions properly as a system. Individually, each piece may...
from an alcohol, self-condenses to the dimerized alcohol.
- In the Japp-Maitland condensation
The Japp-Maitland condensation is an organic reaction and a type of Aldol reaction and a tandem reaction. In a reaction between the ketone 2-pentanone and the aldehyde benzaldehyde catalyzed by base the bis Aldol adduct is formed first...
water is removed not by an elimination reaction but by a nucleophilic displacement
Aldox process
In industry the
Aldox process developed by
Royal Dutch ShellRoyal Dutch Shell plc , commonly known as Shell, is a global oil and gas company headquartered in The Hague, Netherlands and with its registered office in London, United Kingdom. It is the fifth-largest company in the world according to a composite measure by Forbes magazine and one of the six...
and
ExxonExxon is a chain of gas stations as well as a brand of motor fuel and related products by ExxonMobil. From 1972 to 1999, Exxon was the corporate name of the company previously known as Standard Oil Company of New Jersey or Jersey Standard....
, converts
propylenePropene, also known as propylene or methylethylene, is an unsaturated organic compound having the chemical formula C3H6. It has one double bond, and is the second simplest member of the alkene class of hydrocarbons, and it is also second in natural abundance.-Properties:At room temperature and...
and
syngasSyngas is the name given to a gas mixture that contains varying amounts of carbon monoxide and hydrogen. Examples of production methods include steam reforming of natural gas or liquid hydrocarbons to produce hydrogen, the gasification of coal, biomass, and in some types of waste-to-energy...
directly to
2-Ethylhexanol2-Ethylhexanol is a fatty alcohol, an organic compound is a branched, eight-carbon chiral alcohol. It is a colorless liquid that is nearly insoluble in water but soluble in most organic solvents...
via
hydroformylationHydroformylation, also known as oxo synthesis or oxo process, is an important industrial process for the production of aldehydes from alkenes. This chemical reaction entails the addition of a formyl group and a hydrogen atom to a carbon-carbon double bond...
to butyraldehyde, aldol condensation to 2-ethylhexenal and finally
hydrogenationHydrogenation, to treat with hydrogen, also a form of chemical reduction, is a chemical reaction between molecular hydrogen and another compound or element, usually in the presence of a catalyst. The process is commonly employed to reduce or saturate organic compounds. Hydrogenation typically...
.
In one study
crotonaldehydeCrotonaldehyde is a chemical compound with the formula CH3CH=CHCHO. The compound is usually sold as a mixture of the E- and Z-isomers, which differ with respect to the relative position of the methyl and formyl groups. The E-isomer is more common...
is directly converted to 2-ethylhexanal in a
palladiumPalladium is a chemical element with the chemical symbol Pd and an atomic number of 46. It is a rare and lustrous silvery-white metal discovered in 1803 by William Hyde Wollaston. He named it after the asteroid Pallas, which was itself named after the epithet of the Greek goddess Athena, acquired...
/ Amberlyst /
supercritical carbon dioxideSupercritical carbon dioxide is a fluid state of carbon dioxide where it is held at or above its critical temperature and critical pressure.Carbon dioxide usually behaves as a gas in air at STP or as a solid called dry ice when frozen...
system :
Scope
Ethyl 2-methylacetoacetate and campholenic aldehyde react in an Aldol condensation. The synthetic procedure is typical for this type of reactions. In the process, in addition to water, an equivalent of ethanol and carbon dioxide are lost in
decarboxylationDecarboxylation is a chemical reaction that releases carbon dioxide . Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carbonation, the addition of CO2 to...
.
Ethyl glyoxylate
2 and diethyl 2-methylglutaconate
1 react to
isoprenetricarboxylic acid 3 (
isopreneIsoprene , or 2-methyl-1,3-butadiene, is a common organic compound with the formula CH2=CCH=CH2. Under standard conditions it is a colorless liquid...
skeleton) with
sodium ethoxideAn alkoxide is the conjugate base of an alcohol and therefore consists of an organic group bonded to a negatively charged oxygen atom. They can be written as RO−, where R is the organic substituent. Alkoxides are strong bases and, when R is not bulky, good nucleophiles and good ligands...
. This reaction product is very unstable with initial loss of
carbon dioxideCarbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
and followed by many secondary reactions. This is believed to be due to steric strain resulting from the methyl group and the
carboxylicCarboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
group in the
cis-dienoidIn organic chemistry a diene or diolefin is a hydrocarbon that contains two carbon double bonds.Conjugated dienes are functional groups, with a general formula of CnH2n-2. Dienes and alkynes are functional isomers...
structure.
Occasionally an aldol condensation is buried in a multistep reaction or in
catalytic cycleA catalytic cycle in chemistry is a term for a multistep reaction mechanism that involves a catalyst . The catalytic cycle is the main method for describing the role of catalysts in biochemistry, organometallic chemistry, materials science, etc. Often such cycles show the conversion of a...
such as the one sketched below:
In this reaction an
alkynal 1 is converted into a
cycloalkeneA cycloalkene or cycloolefin is a type of alkene hydrocarbon which contains a closed ring of carbon atoms, but has no aromatic character. Some cycloalkenes, such as cyclobutene and cyclopentene, can be used as monomers to produce polymer chains. Unless the rings are very large, cycloalkenes are...
7 with a
rutheniumRuthenium is a chemical element with symbol Ru and atomic number 44. It is a rare transition metal belonging to the platinum group of the periodic table. Like the other metals of the platinum group, ruthenium is inert to most chemicals. The Russian scientist Karl Ernst Claus discovered the element...
catalyst and the actual condensation takes place with intermediate
3 through
5. Support for the
reaction mechanismIn chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.Although only the net chemical change is directly observable for most chemical reactions, experiments can often be designed that suggest the possible sequence of steps in...
is based on isotope labeling.
The reaction between
menthoneMenthone is a naturally occurring organic compound with a molecular formula C10H18O. l-Menthone , shown at right, is the most abundant in nature of the four possible stereoisomers. Menthone is a monoterpene and a ketone...
and
anisaldehydeAnisaldehyde, or anisic aldehyde, is an organic compound that consists of a benzene ring substituted with an aldehyde and a methoxy group. It is a clear colorless liquid with a strong aroma. It comes in 3 varieties, ortho, meta, and para in which the two functional groups are alpha, beta, and...
is complicated due to steric shielding of the ketone group. The solution is use of a strong base such as
potassium hydroxidePotassium hydroxide is an inorganic compound with the formula KOH, commonly called caustic potash.Along with sodium hydroxide , this colorless solid is a prototypical strong base. It has many industrial and niche applications. Most applications exploit its reactivity toward acids and its corrosive...
and a very polar solvent such as
DMSODimethyl sulfoxide is an organosulfur compound with the formula 2SO. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water...
in the reaction below :
Due to epimerization through a common enolate ion (intermediate
A) the reaction product has (R,R) cis configuration and not (R,S) trans as in the starting material. Because it is only the cis isomer that precipitates from solution this product is formed exclusively.