Nucleophilic conjugate addition is a type of
organic reaction
Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, mechanistic organ ...
. Ordinary
nucleophilic addition
In organic chemistry, a nucleophilic addition (AN) reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic addit ...
s or 1,2-nucleophilic additions deal mostly with additions to
carbonyl
In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...
compounds. Simple
alkene
In organic chemistry, an alkene, or olefin, is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or at the terminal position. Terminal alkenes are also known as Alpha-olefin, α-olefins.
The Internationa ...
compounds do not show 1,2 reactivity due to lack of
polarity, unless the alkene is activated with special
substituent
In organic chemistry, a substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule.
The suffix ''-yl'' is used when naming organic compounds that contain a single bond r ...
s. With
α,β-unsaturated carbonyl compounds such as
cyclohexenone it can be deduced from
resonance structure
In chemistry, resonance, also called mesomerism, is a way of describing bonding in certain molecules or polyatomic ions by the combination of several contributing structures (or ''forms'', also variously known as ''resonance structures'' or '' ...
s that the β position is an
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 carr ...
site which can react with a
nucleophile
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
. The negative charge in these structures is stored as an
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 organyl substituent. Alkoxides are strong bases and, whe ...
anion. Such a nucleophilic addition is called a nucleophilic
conjugate addition or 1,4-nucleophilic addition. The most important active alkenes are the aforementioned conjugated carbonyls and
acrylonitrile
Acrylonitrile is an organic compound with the formula and the structure . It is a colorless, volatile liquid. It has a pungent odor of garlic or onions. Its molecular structure consists of a vinyl group () linked to a nitrile (). It is an im ...
s.
Reaction mechanism
Conjugate addition is the
vinylogous counterpart of direct nucleophilic addition. A
nucleophile
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
reacts with a
α,β-unsaturated carbonyl compound in the β position. The negative charge carried by the nucleophile is now delocalized in the alkoxide anion and the α carbon
carbanion
In organic chemistry, a carbanion is an anion with a lone pair attached to a tervalent carbon atom. This gives the carbon atom a negative charge.
Formally, a carbanion is the conjugate base of a carbon acid:
:
where B stands for the base (chemist ...
by
resonance
Resonance is a phenomenon that occurs when an object or system is subjected to an external force or vibration whose frequency matches a resonant frequency (or resonance frequency) of the system, defined as a frequency that generates a maximu ...
.
Protonation
In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), usually denoted by H+, to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brø ...
leads through
keto-enol tautomerism to the saturated carbonyl compound. In
vicinal difunctionalization the proton is replaced by another electrophile.
Reactions
* Conjugated carbonyls react with
secondary amine
In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...
s to form 3-aminocarbonyls (3-ketoamines). For example, the conjugate addition of
methylamine
Methylamine, also known as methanamine, is an organic compound with a formula of . This colorless gas is a derivative of ammonia, but with one hydrogen atom being replaced by a methyl group. It is the simplest primary amine.
Methylamine is sold ...
to cyclohexen-2-one gives the compound 3-(N-methylamino)-cyclohexanone.
* Conjugated carbonyls react with
hydrogen cyanide
Hydrogen cyanide (formerly known as prussic acid) is a chemical compound with the chemical formula, formula HCN and structural formula . It is a highly toxic and flammable liquid that boiling, boils slightly above room temperature, at . HCN is ...
to 1,4-keto-nitriles. See
hydrocyanation of unsaturated carbonyls. In the Nagata reaction the cyanide source is
diethylaluminum cyanide.
* The
Gilman reagent
A Gilman reagent is a diorganocopper compound with the formula Li uR2 where R is an alkyl or aryl. They are colorless solids.
Use in organic chemistry
These reagents are useful because, unlike related Grignard reagents and organolithium reage ...
is an effective nucleophile for 1,4-additions to conjugated carbonyls.
* The
Michael reaction involves conjugate additions of
enolate
In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl () compounds. Rarely isolated, they are widely used as reagents in the Organic synthesis, synthesis of organic compounds.
Bonding and structure
Enolate ...
s to conjugated carbonyls.
* The
Stork enamine reaction involves the conjugate addition of
enamine
An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates.
The word "enamine" is derived from the affix ''en''-, used as the suffix of alkene, and the r ...
s to conjugated carbonyls.
Scope
Conjugate addition is effective in the formation of new
carbon-carbon bonds with the help of
organometallic
Organometallic chemistry is the study of organometallic compounds, chemical compounds containing at least one chemical bond between a carbon atom of an organic molecule and a metal, including alkali, alkaline earth, and transition metals, and so ...
reagents such as the
organozinc iodide reaction with
methylvinylketone.

An example of an
asymmetric synthesis by conjugate addition is the synthesis of (R)-3-phenyl-cyclohexanone from cyclohexenone,
phenylboronic acid, a
rhodium
Rhodium is a chemical element; it has symbol Rh and atomic number 45. It is a very rare, silvery-white, hard, corrosion-resistant transition metal. It is a noble metal and a member of the platinum group. It has only one naturally occurring isot ...
acac catalyst and the
chiral ligand BINAP
BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) is an organophosphorus compound. This Optical isomerism, chiral diphosphines, diphosphine ligand is widely used in chiral synthesis, asymmetric synthesis. It consists of a pair of 2-diphe ...
.
In another example of asymmetric synthesis the α,β-unsaturated carbonyl compound first reacts with a
chiral
Chirality () is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek language, Greek (''kheir''), "hand", a familiar chiral object.
An object or a system is ''chiral'' if it is dist ...
imidazolidinone
Imidazolidinones are a class of 5-membered ring heterocycles structurally related to imidazolidine. Imidazolidinones feature a saturated C3N2 nucleus, except for the presence of a urea or amide functional group in the 2 or 4 positions.
2-Imid ...
catalyst
Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...
and
chiral auxiliary to an
iminium
In organic chemistry, an iminium cation is a polyatomic ion with the general structure . They are common in synthetic chemistry and biology.
Structure
Iminium cations adopt alkene-like geometries: the central C=N unit is nearly coplanar with a ...
compound in an
alkylimino-de-oxo-bisubstitution
In organic chemistry, alkylimino-de-oxo-bisubstitution is the organic reaction of carbonyl compounds with amines to imines. The reaction name is based on the IUPAC Nomenclature for Transformations. The reaction is acid catalyzed and the reactio ...
which then reacts
enantioselective
In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non- stereospecific creation of a new stereocenter or during a non-stereospecific transformation o ...
with the
furan
Furan is a Heterocyclic compound, heterocyclic organic compound, consisting of a five-membered aromatic Ring (chemistry), ring with four carbon Atom, atoms and one oxygen atom. Chemical compounds containing such rings are also referred to as f ...
nucleophile. The immediate reaction product is a
nucleophilic enamine
An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates.
The word "enamine" is derived from the affix ''en''-, used as the suffix of alkene, and the r ...
and the reaction
cascades with abstraction of chlorine from a chlorinated
quinone
The quinones are a class of organic compounds that are formally "derived from aromatic compounds benzene.html" ;"title="uch as benzene">uch as benzene or naphthalene] by conversion of an even number of –CH= groups into –C(=O)– groups with ...
. After removal of the amine catalyst the ketone is effectively functionalized with a nucleophile and an electrophile with
syn addition, syn:anti ratio of 8:1 and 97%
enantiomeric excess.

This principle is also applied in an enantioselective
multicomponent domino
Dominoes is a family of tile-based games played with gaming pieces. Each domino is a rectangular tile, usually with a line dividing its face into two square ''ends''. Each end is marked with a number of spots (also called '' pips'' or ''dots'' ...
conjugated addition of nucleophilic
thiol
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...
s such as benzylmercaptan and electrophilic
DEAD
Death is the end of life; the irreversible cessation of all biological functions that sustain a living organism. Death eventually and inevitably occurs in all organisms. The remains of a former organism normally begin to decompose sho ...
.
Toxicology
Suitably soluble Michael acceptors are toxic, because they alkylate DNA by conjugate addition. Such modification induces mutations, which are cytotoxic and carcinogenic. However,
glutathione
Glutathione (GSH, ) is an organic compound with the chemical formula . It is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources ...
is also able to react with them and for example
dimethyl fumarate reacts with it.
See also
*
Nucleophilic abstraction
References
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Supplementary information
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{{Alcohols
Addition reactions