The Claisen
condensation
Condensation is the change of the state of matter from the gas phase into the liquid phase, and is the reverse of vaporization. The word most often refers to the water cycle. It can also be defined as the change in the state of water vapor ...
is a
carbon–carbon bond
A 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 formed bet ...
forming
reaction
Reaction may refer to a process or to a response to an action, event, or exposure:
Physics and chemistry
* Chemical reaction
*Nuclear reaction
*Reaction (physics), as defined by Newton's third law
* Chain reaction (disambiguation).
Biology and ...
that occurs between two
ester
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glyceride ...
s or one ester and another
carbonyl
In 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. A compound containin ...
compound in the presence of a
strong base
In chemistry, there are three definitions in common use of the word base, known as Arrhenius bases, Brønsted bases, and Lewis bases. All definitions agree that bases are substances that react with acids, as originally proposed by G.-F. R ...
, resulting in a β-keto ester or a β-
diketone
In organic chemistry, a dicarbonyl is a molecule containing two carbonyl () groups. Although this term could refer to any organic compound containing two carbonyl groups, it is used more specifically to describe molecules in which both carbonyls ...
. It is named after
Rainer Ludwig Claisen, who first published his work on the reaction in 1887.
Requirements
At least one of the
reagents
In chemistry, a reagent ( ) or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms ''reactant'' and ''reagent'' are often used interchangeably, but reactant specifies a ...
must be
enol
In organic chemistry, alkenols (shortened to enols) are a type of reactive structure or intermediate in organic chemistry that is represented as an alkene ( olefin) with a hydroxyl group attached to one end of the alkene double bond (). The ...
izable (have an
α-proton and be able to undergo
deprotonation
Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju.edu ...
to form the
enolate anion). There are a number of different combinations of enolizable and nonenolizable carbonyl compounds that form a few different
types
Type may refer to:
Science and technology Computing
* Typing, producing text via a keyboard, typewriter, etc.
* Data type, collection of values used for computations.
* File type
* TYPE (DOS command), a command to display contents of a file.
* ...
of Claisen.
The base used must not interfere with the reaction by undergoing
nucleophilic substitution
In chemistry, a nucleophilic substitution is a class of chemical reactions in which an electron-rich chemical species (known as a nucleophile) replaces a functional group within another electron-deficient molecule (known as the electrophile). ...
or
addition
Addition (usually signified by the plus symbol ) is one of the four basic operations of arithmetic, the other three being subtraction, multiplication and division. The addition of two whole numbers results in the total amount or '' sum'' of ...
with a carbonyl carbon. For this reason, the conjugate sodium
alkoxide
In chemistry, an alkoxide is the conjugate base of an alcohol and therefore consists of an organic group bonded to a negatively charged oxygen atom. They are written as , where R is the organic substituent. Alkoxides are strong bases and, wh ...
base of the alcohol formed (e.g.
sodium ethoxide
Sodium ethoxide, also referred to as sodium ethylate, is the ionic, organic compound with the formula , or NaOEt (Et = ethane). It is a white solid, although impure samples appear yellow or brown. It dissolves in polar solvents such as ethanol ...
if
ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...
is formed) is often used, since the alkoxide is regenerated. In mixed Claisen condensations, a
non-nucleophilic base such as
lithium diisopropylamide
Lithium diisopropylamide (commonly abbreviated LDA) is a chemical compound with the molecular formula . It is used as a strong base and has been widely utilized due to its good solubility in non-polar organic solvents and non-nucleophilic nature ...
, or LDA, may be used, since only one compound is enolizable. LDA is not commonly used in the classic Claisen or
Dieckmann condensations due to enolization of the
electrophilic
In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carrie ...
ester.
The alkoxy portion of the ester must be a relatively good
leaving group In chemistry, a leaving group is defined by the IUPAC as an atom or group of atoms that detaches from the main or residual part of a substrate during a reaction or elementary step of a reaction. However, in common usage, the term is often limited ...
.
Methyl
In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in ...
and
ethyl esters, which yields
methoxide
In organic chemistry, methoxides are organic salts with a anion. They are the simplest alkoxides. Sodium methoxide and potassium methoxide have widespread use, though other metal-cation variants such as lithium methoxide, rubidium methoxid ...
and ethoxide, respectively, are commonly used.
Types
* The classic Claisen condensation, a self-condensation between two molecules of a compound containing an enolizable ester.
:
* The mixed (or "crossed") Claisen condensation, where one enolizable ester or ketone and one nonenolizable ester are used.
:
* The
Dieckmann condensation, where a molecule with two ester groups reacts
intramolecularly, forming a
cyclic β-keto ester. In this case, the ring formed must not be
strained, 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 of an enolate anion, which is made relatively stable by the
delocalization
In chemistry, delocalized electrons are electrons in a molecule, ion or solid metal that are not associated with a single atom or a covalent bond.IUPAC Gold Boo''delocalization''/ref>
The term delocalization is general and can have slightly dif ...
of electrons. 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
An aqueous solution is a solution in which the solvent is water. It is mostly shown in chemical equations by appending (aq) to the relevant chemical formula. For example, a solution of table salt, or sodium chloride (NaCl), in water would be r ...
acid
In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a s ...
(e.g.
sulfuric acid
Sulfuric acid ( American spelling and the preferred IUPAC name) or sulphuric acid ( Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen and hydrogen, with the molecular fo ...
or
phosphoric acid
Phosphoric acid (orthophosphoric acid, monophosphoric acid or phosphoric(V) acid) is a colorless, odorless phosphorus-containing solid, and inorganic compound with the chemical formula . It is commonly encountered as an 85% aqueous solution, ...
) is added in the final step to
neutralize 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
stoichiometric
Stoichiometry refers to the relationship between the quantities of reactants and products before, during, and following chemical reactions.
Stoichiometry is founded on the law of conservation of mass where the total mass of the reactants equa ...
amount of base as the removal of the doubly α-proton thermodynamically drives the otherwise
endergonic
In chemical thermodynamics, an endergonic reaction (; also called a heat absorbing nonspontaneous reaction or an unfavorable reaction) is a chemical reaction in which the standard change in free energy is positive, and an additional driving fo ...
reaction. That is, Claisen condensation does not work with
substrates having only one
α-hydrogen
In the nomenclature of organic chemistry, a locant is a term to indicate the position of a functional group or substituent within a molecule.
Numeric locants
The International Union of Pure and Applied Chemistry (IUPAC) recommends the use of n ...
because of the driving force effect of deprotonation of the β-keto ester in the last step.
Stobbe condensation
The Stobbe condensation is a modification specific for the diethyl
ester
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glyceride ...
of
succinic acid
Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. The name derives from Latin ''succinum'', meaning amber. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological r ...
requiring less strong bases. An example is its reaction with
benzophenone
Benzophenone is the organic compound with the formula (C6H5)2CO, generally abbreviated Ph2CO. It is a white solid that is soluble in organic solvents. Benzophenone is a widely used building block in organic chemistry, being the parent diarylket ...
:
:
A
reaction mechanism
In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.
A chemical mechanism is a theoretical conjecture that tries to describe in detail what takes place at each stage of ...
that explains the formation of both an ester group and a
carboxylic acid
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyli ...
group is centered on a
lactone
Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring.
Lactones are formed by intramolecular esterification of the c ...
intermediate (5):
:
The Stobbe condensation was used in the first step of Reinhard Sarges' synthesis of
tametraline
Tametraline (CP-24,441) is the parent of a series of chemical compounds investigated at Pfizer that eventually led to the development of sertraline (CP-51,974-1).
Sertraline has been called "3,4-dichloro-tametraline". This is correct but it is a ...
and it can also be used in the synthesis of
dimefadane.
See also
*
Aldol condensation
An aldol condensation is a condensation reaction in organic chemistry in which two carbonyl moieties (of aldehydes or ketones) react to form a β-hydroxyaldehyde or β-hydroxyketone (an aldol reaction), and this is then followed by dehydration to ...
*
Fatty acid synthesis
In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is conve ...
*
Polyketide synthase
Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynt ...
*
Dieckmann condensation
References
External links
*
{{DEFAULTSORT:Claisen Condensation
Condensation reactions
Carbon-carbon bond forming reactions
Name reactions