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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, photochemical ...
. Ordinary
nucleophilic addition In organic chemistry, a nucleophilic addition 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 additions d ...
s or 1,2-nucleophilic additions deal mostly with additions to
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 containi ...
compounds. Simple
alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic ...
compounds do not show 1,2 reactivity due to lack of polarity, unless the alkene is activated with special
substituent A substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule. (In organic chemistry and biochemistry, the terms ''substituent'' and ''functional group'', as well as '' side ...
s. With α,β-unsaturated carbonyl compounds such as
cyclohexenone Cyclohexenone is an organic compound which is a versatile intermediate used in the synthesis of a variety of chemical products such as pharmaceuticals and fragrances. It is colorless liquid, but commercial samples are often yellow. Industrially, ...
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 ar ...
. 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 organic 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 although commercial samples can be yellow due to impurities. It has a pungent odor of garlic or onions. In terms of its molecula ...
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 ar ...
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 in which carbon is trivalent (forms three bonds) and bears a formal negative charge (in at least one significant resonance form). Formally, a carbanion is the conjugate base of a carbon acid: :R3 ...
by
resonance Resonance describes the phenomenon of increased amplitude that occurs when the frequency of an applied periodic force (or a Fourier component of it) is equal or close to a natural frequency of the system on which it acts. When an oscil ...
.
Protonation In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), (H+) to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brønsted–Lowry acid ...
leads through
keto-enol tautomerism 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 (). Th ...
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 compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...
s to form 3-aminocarbonyls (3-ketoamines). For example, the conjugate addition of
methylamine Methylamine 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 as a solution in methanol, ...
to cyclohexen-2-one gives the compound 3-(N-methylamino)-cyclohexanone. * Conjugated carbonyls react with
hydrogen cyanide Hydrogen cyanide, sometimes called prussic acid, is a chemical compound with the formula HCN and structure . It is a colorless, extremely poisonous, and flammable liquid that boils slightly above room temperature, at . HCN is produced on a ...
to 1,4-keto-nitriles. See
hydrocyanation of unsaturated carbonyls In organic chemistry, hydrocyanation is a process for conversion of alkenes to nitriles. The reaction involves the addition of hydrogen cyanide and requires a catalyst. This conversion is conducted on an industrial scale for the production of pr ...
. In the Nagata reaction the cyanide source is
diethylaluminum cyanide Diethylaluminum cyanide ("Nagata's reagent") is the organoaluminum compound with formula ((C2H5)2AlCN)n. This colorless compound is usually handled as a solution in toluene. It is a reagent for the hydrocyanation of α,β-unsaturated ketones. ...
. * The
Gilman reagent A Gilman reagent is a lithium and copper ( diorganocopper) reagent compound, R2CuLi, where R is an alkyl or aryl. These reagents are useful because, unlike related Grignard reagents and organolithium reagents, they react with organic halides to ...
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 synthesis of organic compounds. Bonding and structure Enolate anions are electr ...
s to conjugated carbonyls. * The
Stork enamine reaction The Stork enamine alkylation involves the addition of an enamine to a Michael acceptor (e.g, an α,β -unsaturated carbonyl compound) or another electrophilic alkylation reagent to give an alkylated iminium product, which is hydrolyzed by dilute ...
involves the conjugate addition of enamines 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 s ...
reagents such as the
organozinc Organozinc compounds in organic chemistry contain carbon (C) to zinc (Zn) chemical bonds. Organozinc chemistry is the science of organozinc compounds describing their physical properties, synthesis and reactions.The Chemistry of Organozinc Compou ...
iodide reaction with methylvinylketone. An example of an
asymmetric synthesis Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecu ...
by conjugate addition is the synthesis of (R)-3-phenyl-cyclohexanone from cyclohexenone,
phenylboronic acid Phenylboronic acid or benzeneboronic acid, abbreviated as PhB(OH)2 where Ph is the phenyl group C6H5-, is a boronic acid containing a phenyl substituent and two hydroxyl groups attached to boron. Phenylboronic acid is a white powder and is commonl ...
, a
rhodium Rhodium is a chemical element with the 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 i ...
acac catalyst and the
chiral ligand Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecu ...
BINAP. 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 (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from i ...
imidazolidinone
catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
and
chiral auxiliary In stereochemistry, a chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxiliary can bias the ...
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 al ...
compound in an alkylimino-de-oxo-bisubstitution which then reacts
enantioselective In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical an ...
with the
furan Furan is a heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen atom. Chemical compounds containing such rings are also referred to as furans. Furan is a colorless, flammable, highl ...
nucleophile. The immediate reaction product is a
nucleophilic 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 ...
enamine 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 uch as benzene or naphthalene">benzene.html" ;"title="uch as benzene">uch as benzene or naphthalene] by conversion of an even number of –CH= group ...
. 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, commonly known as dominoes. 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 c ...
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 gro ...
s such as benzylmercaptan and electrophilic
DEAD Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...
.


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 antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pe ...
is also able to react with them and for example
dimethyl fumarate Dimethyl fumarate (DMF) is the methyl ester of fumaric acid and is named after the earth smoke plant (''Fumaria officinalis''). Dimethyl fumarate combined with three other fumaric acid esters (FAEs) is solely licensed in Germany as an oral ther ...
reacts with it.


See also

* Nucleophilic abstraction


References

# # # # {{Alcohols Addition reactions