View source for Chemistry:Nucleophilic conjugate addition

{{Short description|Organic reaction}}
[[Image:NucleophilicConjugateAddition.svg|right|frame|Nucleophilic conjugate addition]]'''Nucleophilic conjugate addition''' is a type of organic reaction. Ordinary nucleophilic additions or '''1,2-nucleophilic additions''' deal mostly with additions to carbonyl compounds. Simple alkene compounds do not show 1,2 reactivity due to lack of polarity, unless the alkene is activated with special substituents. With α,β-unsaturated carbonyl compounds such as cyclohexenone it can be deduced from resonance structures that the β position is an electrophilic site which can react with a nucleophile. The negative charge in these structures is stored as an alkoxide 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 [[Chemistry:Acrylonitrile|acrylonitrile]]s.

== Reaction mechanism==
Conjugate addition is the vinylogous counterpart of direct nucleophilic addition. A [[Chemistry:Nucleophile|nucleophile]] reacts with a [[Chemistry:Enone|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 [[Chemistry:Carbanion|carbanion]] by resonance. [[Chemistry:Protonation|Protonation]] leads through keto-enol tautomerism to the saturated carbonyl compound. In [[Chemistry:Vicinal difunctionalization|vicinal difunctionalization]] the proton is replaced by another electrophile.

== Reactions==
* Conjugated carbonyls react with secondary amines to form 3-aminocarbonyls (3-ketoamines). For example, the conjugate addition of [[Chemistry:Methylamine|methylamine]] to cyclohexen-2-one gives the compound 3-(N-methylamino)-cyclohexanone.
* Conjugated carbonyls react with [[Chemistry:Hydrogen cyanide|hydrogen cyanide]] to 1,4-keto-nitriles. See hydrocyanation of unsaturated carbonyls. In the '''Nagata reaction''' the cyanide source is diethylaluminum cyanide.
* The [[Chemistry:Gilman reagent|Gilman reagent]] is an effective nucleophile for 1,4-additions to conjugated carbonyls.
* The [[Chemistry:Michael reaction|Michael reaction]] involves conjugate additions of [[Chemistry:Enolate|enolate]]s to conjugated carbonyls.
* The Stork enamine reaction involves the conjugate addition of [[Chemistry:Enamine|enamine]]s to conjugated carbonyls.

== Scope==
Conjugate addition is effective in the formation of new carbon-carbon bonds with the help of organometallic reagents such as the organozinc iodide reaction with methylvinylketone.{{Ref|1}}

[[File:Conjugateadditionexample.png|center|(4R',5R')-5-(5-Ethyl-2,2-dimethyl-[1,3]-dioxolan-4-yl)-pentan-2-one]]

An example of an asymmetric synthesis by conjugate addition is the synthesis of (R)-3-phenyl-cyclohexanone from cyclohexenone, [[Chemistry:Phenylboronic acid|phenylboronic acid]], a [[Chemistry:Rhodium|rhodium]] acac catalyst and the chiral ligand BINAP.{{Ref|2}}

[[File:(R)-3-phenyl-cyclohexanone.svg|center|(R)-3-phenyl-cyclohexanone]]

In another example of asymmetric synthesis the α,β-unsaturated carbonyl compound first reacts with a [[Biology:Chirality|chiral]] [[Chemistry:Imidazolidinone|imidazolidinone]] [[Chemistry:Catalyst|catalyst]] and [[Chemistry:Chiral auxiliary|chiral auxiliary]] to an [[Chemistry:Iminium|iminium]] compound in an [[Chemistry:Alkylimino-de-oxo-bisubstitution|alkylimino-de-oxo-bisubstitution]] which then reacts enantioselective with the [[Chemistry:Furan|furan]] nucleophile. The immediate reaction product is a nucleophilic [[Chemistry:Enamine|enamine]] and the reaction [[Chemistry:Cascade reaction|cascades]] with abstraction of chlorine from a chlorinated [[Chemistry:Quinone|quinone]]. After removal of the amine catalyst the ketone is effectively functionalized with a nucleophile and an electrophile with syn:anti ratio of 8:1 and 97% [[Chemistry:Enantiomeric excess|enantiomeric excess]].{{Ref|3}}

[[File:EnantioselectiveOrganoCascadeCatalysis.svg|center|Enantioselective organocascade catalysis]]

This principle is also applied in an enantioselective [[Chemistry:Multi-component reaction|multicomponent]] domino conjugated addition of nucleophilic [[Chemistry:Thiol|thiol]]s such as benzylmercaptan and electrophilic [[Chemistry:Diethyl azodicarboxylate|DEAD]].{{Ref|4}}
[[File:ConjugatedAdditionofThiols.svg|center|Enantioselective conjugated addition of thiols to unsaturated aldehydes]]

== Toxicology ==
Suitably soluble Michael acceptors are toxic, because they alkylate DNA by conjugate addition. Such modification induces mutations, which are cytotoxic and carcinogenic. However, [[Chemistry:Glutathione|glutathione]] is also able to react with them and for example [[Chemistry:Dimethyl fumarate|dimethyl fumarate]] reacts with it. {{Citation needed|reason=Reliable source needed for the sentence|date=November 2016}}

== See also ==
* [[Chemistry:Nucleophilic abstraction|Nucleophilic abstraction]]

== References ==
# {{Note|1}} {{cite journal | title = Asymmetric Synthesis of exo-Isobrevicomin and exo-Brevicomin via Conjugated Addition of Primary Alkyl Iodides to α,β-Unsaturated Ketones |author1=Andréa L. de Sousa  |author2=Inês S. Resck  |name-list-style=amp | journal = J. Braz. Chem. Soc. | volume = 13 | issue = 2 | year = 2002 | doi = 10.1590/S0103-50532002000200015 | pages = 233| doi-access = free }}
# {{Note|2}}  {{OrgSynth | title = (R)-3-phenyl-cyclohexanone | author = Tamio Hayashi, Makoto Takahashi, Yoshiaki Takaya, and Masamichi Ogasawara | collvol = 10 | collvolpages = 609 | year = 2004 | prep = v79p0084}}
# {{Note|3}}  {{cite journal | title = Enantioselective Organo-Cascade Catalysis |author1=Yong Huang |author2=Abbas M. Walji |author3=Catharine H. Larsen |author4=David W. C. MacMillan | journal = J. Am. Chem. Soc. |date=Nov 2005 | volume = 127 | issue = 43 | pages = 15051–15053 | doi = 10.1021/ja055545d |issn = 0002-7863 |pmid=16248643 |url=https://authors.library.caltech.edu/77413/2/ja055545dsi20050921_124551.pdf }}
# {{Note|4}}  {{cite journal | title = Asymmetric Multicomponent Domino Reactions and Highly Enantioselective Conjugated Addition of Thiols to α,β-Unsaturated Aldehydes |author1=Mauro Marigo |author2=Tobias Schulte |author3=Johan Franzén |author4=Karl Anker Jorgensen  |name-list-style=amp | journal = J. Am. Chem. Soc. |date=Nov 2005 | volume = 127 | issue = 45 | pages = 15710–15711 | doi = 10.1021/ja055291w | pmid = 16277506 |issn = 0002-7863}}

{{Alcohols}}
[[Category:Addition reactions]]

{{Sourceattribution|Nucleophilic conjugate addition}}