The
Claisen condensationA 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,...
(not to be confused with the
Claisen rearrangementThe Claisen rearrangement is a powerful carbon-carbon bond-forming chemical reaction discovered by Rainer Ludwig Claisen. The heating of an allyl vinyl ether will initiate a [3,3]-sigmatropic rearrangement to give a γ,δ-unsaturated carbonyl....
) is a
carbon-carbon bondA carbon-carbon bond is a covalent bond between two carbon atoms. The most common form is the single bond – a bond composed of two electrons, one from each of the two atoms. The carbon-carbon single bond is a sigma bond and is said to be formed between one hybridized orbital from each of the...
forming
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 and redox reactions. In organic synthesis, organic reactions are used...
that occurs between 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...
s or one ester and another
carbonylIn organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom : C=O.The term carbonyl can also refer to carbon monoxide as a ligand in an inorganic or organometallic complex In organic chemistry, a carbonyl group is a functional group...
compound in the presence of a strong base, resulting in a β-keto ester or a β-di
ketoneIn organic chemistry, a ketone is a type of compound that features a carbonyl group bonded to two other carbon atoms, i.e., R3CCO-CR3 where R can be a variety of atoms and groups of atoms...
. It is named after
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...
, who first published his work on the reaction in 1881
.
At least one of the reagents must be enolizable (have an
α-protonThe alpha carbon in organic chemistry refers to the first carbon that attaches to a functional group . By extension, the second carbon is the beta carbon, and so on. This nomenclature can also be applied to the hydrogen atoms attached to the carbons...
and be able to undergo
deprotonationDeprotonation is a chemistry term that refers to the removal of a proton from a molecule, forming the conjugate base. The relative ability for a molecule to give up a proton is measured by a pKa value. A low pKa value indicates that the compound is acidic and will easily...
to form the
enolate anionEnols are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Enols and carbonyl compounds are in fact isomers; this is called keto-enol tautomerism:...
).
The
Claisen condensationA 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,...
(not to be confused with the
Claisen rearrangementThe Claisen rearrangement is a powerful carbon-carbon bond-forming chemical reaction discovered by Rainer Ludwig Claisen. The heating of an allyl vinyl ether will initiate a [3,3]-sigmatropic rearrangement to give a γ,δ-unsaturated carbonyl....
) is a
carbon-carbon bondA carbon-carbon bond is a covalent bond between two carbon atoms. The most common form is the single bond – a bond composed of two electrons, one from each of the two atoms. The carbon-carbon single bond is a sigma bond and is said to be formed between one hybridized orbital from each of the...
forming
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 and redox reactions. In organic synthesis, organic reactions are used...
that occurs between 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...
s or one ester and another
carbonylIn organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom : C=O.The term carbonyl can also refer to carbon monoxide as a ligand in an inorganic or organometallic complex In organic chemistry, a carbonyl group is a functional group...
compound in the presence of a strong base, resulting in a β-keto ester or a β-di
ketoneIn organic chemistry, a ketone is a type of compound that features a carbonyl group bonded to two other carbon atoms, i.e., R3CCO-CR3 where R can be a variety of atoms and groups of atoms...
. It is named after
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...
, who first published his work on the reaction in 1881
.
Requirements
At least one of the reagents must be enolizable (have an
α-protonThe alpha carbon in organic chemistry refers to the first carbon that attaches to a functional group . By extension, the second carbon is the beta carbon, and so on. This nomenclature can also be applied to the hydrogen atoms attached to the carbons...
and be able to undergo
deprotonationDeprotonation is a chemistry term that refers to the removal of a proton from a molecule, forming the conjugate base. The relative ability for a molecule to give up a proton is measured by a pKa value. A low pKa value indicates that the compound is acidic and will easily...
to form the
enolate anionEnols are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Enols and carbonyl compounds are in fact isomers; this is called keto-enol tautomerism:...
). There are a number of different combinations of enolizable and nonenolizable carbonyl compounds that form a few different types of Claisen condensations.
The base used must not interfere with the reaction by undergoing
nucleophilicIn chemistry, a nucleophile is a reagent that forms a chemical bond to its reaction partner by donating both bonding electrons. Because nucleophiles donate electrons, they are by definition Lewis bases . All molecules or ions with a free pair of electrons can act as nucleophiles...
substitutionIn organic and inorganic chemistry, nucleophilic substitution is a fundamental class of substitution reaction in which an "electron rich" nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom attached to a group or atom called the leaving group; the...
or
additionIn organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....
with a carbonyl carbon. For this reason, the conjugate sodium
alkoxideAn 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...
base of the alcohol formed (e.g.
sodium ethoxideSodium ethoxide is an alkoxide salt with the chemical formula C2H5ONa.-Preparation:It is commercially available as a dry yellow solid, or as a solution in ethanol...
if
ethanolEthanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug, best known as the type of alcohol found in alcoholic beverages and in modern thermometers. Ethanol is one of the oldest recreational drugs...
is formed) is often used, since the alkoxide is regenerated. In mixed Claisen condensations, a non-nucleophilic base such as
lithium diisopropylamideLithium diisopropylamide is the chemical compound with the formula [
2CH]
2NLi. Generally abbreviated LDA, it is a strong base used in organic chemistry for the deprotonation of weakly acidic compounds. The reagent has been widely accepted because it is soluble in non-polar...
, or LDA, may be used, since only one compound is enolizable. LDA cannot be used in the classic Claisen or Dieckmann condensations, since virtually all ester will be converted to ester enolate and condensation will not occur.
The alkoxy portion of the ester must be a good
leaving groupIn chemistry, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl-, Br-, and I-, and sulfonate esters,...
.
MethylIn chemistry, a methyl group is a hydrophobic alkyl functional group named after methane . It has the formula -3 and is often abbreviated -Me...
and
ethylIn chemistry, an ethyl group is an alkyl functional group derived from ethane . It has the formula -C
2H
5 and is very often abbreviated -Et....
esters, which yield the methoxy and ethoxy leaving groups, respectively, are usually used.
Types
The classic Claisen condensation, where only one enolizable ester is used.
The mixed (or "crossed") Claisen condensation, where an enolizable ester or ketone and a nonenolizable ester are used.
The
Dieckmann condensationThe 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....
, where a molecule with two ester groups reacts
intramolecularIntramolecular in chemistry describes a process or characteristic limited within the structure of a single molecule; a property or phenomenon limited to the extent of a single molecule.- Examples :...
ly, forming a
cyclicIn organic chemistry, a cyclic compound is a compound in which a series of carbon atoms are connected to form a loop or ring. Benzene is a well known example...
β-keto ester. In this case, the ring formed must not be
strainedRing strain is an organic chemistry term that describes the destabilization of a cyclic molecule—such as a cycloalkane—due to the non-favorable high energy spatial orientations of its atoms...
, usually a 5- or 6-membered chain or ring.
Mechanism
In the first step of the mechanism, an α-proton is removed by a strong base, resulting in the formation an enolate anion, which is made relatively stable by the
delocalizationIn chemistry delocalized electrons are electrons in a molecule that are not associated with a single atom or to a covalent bond. Delocalized electrons are contained within an orbital that extends over several adjacent atoms. Classically, delocalized electrons can be found in conjugated systems of...
of
electronAn electron is a subatomic particle that carries a negative electric charge. It has no known substructure and is believed to be a point particle. An electron has a mass that is approximately 1836 times less than that of the proton. The intrinsic angular momentum of the electron is a half integer...
s. Next, the carbonyl carbon of the (other) ester is nucleophilically attacked by the enolate anion. The alkoxy group is then eliminated (resulting in (re)generation of the alkoxide), and the alkoxide removes the newly-formed doubly α-proton to form a new, highly resonance-stabilized enolate anion. Aqueous
acidAn acid is traditionally considered any chemical compound that, when dissolved in water, gives a solution with a hydrogen ion activity greater than in pure water, i.e. a pH less than 7.0...
(e.g.
sulfuric acidSulfuric acid, , is a strong mineral acid. It is soluble in water at all concentrations. Sulfuric acid has many applications, and is one of the top products of the chemical industry. World production in 2001 was 165 million tonnes, with an approximate value of US$8 billion...
or
phosphoric acidPhosphoric acid, also known as orthophosphoric acid or phosphoric acid, is a mineral acid having the chemical formula H3PO4. Orthophosphoric acid molecules can combine with themselves to form a variety of compounds which are also referred to as phosphoric acids, but in a more...
) is added in the final step to
neutralizeIn chemistry, neutralization, or neutralisation is a chemical reaction whereby an acid and a base react to form water and a salt....
the enolate and any base still present. The newly-formed β-keto ester or β-diketone is then isolated. Note that the reaction requires a
stoichiometricStoichiometry is the calculation of quantitative relationships of the reactants and products in a balanced chemical reaction...
amount of base as the removal of the doubly α-proton thermodynamically drives the otherwise
endergonicEndergonic means absorbing energy in the form of work. Its etymology stems from the suffix -ergonic, as derived from the Greek root ergon, meaning work, combined with the prefix end-, as derived from the Greek root en, meaning put into. Endergonic reactions are not spontaneous...
reaction.
Stobbe condensation
The
Stobbe condensation is a modification specific for the diethyl
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...
of
succinic acidSuccinic acid is a dicarboxylic acid. Succinate plays a biochemical role in the citric acid cycle...
requiring less strong bases . An example is its reaction with
benzophenoneBenzophenone is the organic compound with the formula 2CO, generally abbreviated Ph2CO. Benzophenone is a widely used building block in organic chemistry, being the parent diarylketone.-Uses:...
:
A
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...
which explains the formation of both an ester group and a
carboxylic acidCarboxylic acids are organic acids characterized by the presence of a carboxyl group, which has the formula -COH, usually written -COOH or -CO2H. Carboxylic acids are Brønsted-Lowry acids — they are proton donors. Salts and anions of carboxylic acids are called...
group is centered around a
lactoneIn chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
intermediate (
5):
External links