Editing Enamine

{{Short description|Class of chemical compounds}}
[[File:Enamine-2D-skeletal.svg|thumb|150px|The general structure of an enamine]]
An '''enamine''' is an [[unsaturated compound]] derived by the condensation of an [[aldehyde]] or [[ketone]] with a secondary [[amine]].<ref>{{cite book | author = Clayden, Jonathan | title = Organic chemistry | publisher = Oxford University Press | location = Oxford, Oxfordshire | year = 2001 | isbn = 978-0-19-850346-0 | url = https://archive.org/details/organicchemistry00clay_0 | url-access = registration }}</ref><ref>{{March6th}}</ref> Enamines are versatile intermediates.<ref>Enamines: Synthesis: Structure, and Reactions, Second Edition, Gilbert Cook (Editor).  1988, Marcel Dekker, NY.  {{ISBN|0-8247-7764-6}}</ref><ref>{{OrgSynth|author=R. B. Woodward, I. J. Pachter, and M. L. Scheinbaum |year=1974|title=2,2- (Trimethylenedithio)cyclohexanone|volume=54|pages=39|collvol=5|collvolpages=1014|prep=CV6P1014}}</ref>

The word "enamine" is derived from the affix ''en''-, used as the suffix of [[alkene]], and the root ''amine''. This can be compared with [[enol]], which is a functional group containing both alkene (''en''-) and [[Alcohol (chemistry)|alcohol]] (-''ol''). Enamines are considered to be nitrogen analogs of enols.<ref>[http://pharmaxchange.info/press/2011/04/imines-and-enamines-nitrogen-analogs-of-enols-and-enolates/ Imines and Enamines | PharmaXChange.info]</ref>

If one or both of the nitrogen substituents is a hydrogen atom it is the [[tautomer]]ic form of an [[imine]]. This usually will rearrange to the imine; however there are several exceptions (such as [[aniline]]). The enamine-imine tautomerism may be considered analogous to the [[keto-enol tautomerism]]. In both cases, a hydrogen atom switches its location between the heteroatom (oxygen or nitrogen) and the second carbon atom.

Enamines are both good nucleophiles and good bases.  Their behavior as carbon-based nucleophiles is explained with reference to the following resonance structures.
:[[File:EnamineResonanceStructures.svg|thumb|center|Resonance structures for an enamine]]

==Formation==
:[[File:Enamine.png|thumb|center|320px|Condensation to give an enamine.<ref>{{OrgSynth|author=R. D. Burpitt and J. G. Thweatt |year=1968|title=Cyclodecanone|volume=48|pages=56|collvol=5|collvolpages=277|prep=CV5P0277}}</ref>]]
Enamines can be easily produced from commercially available starting reagents. Commonly enamines are produced by an acid-catalyzed nucleophilic reaction of ketone<ref>{{Cite journal |last1=Stork |first1=Gilbert. |last2=Brizzolara |first2=A. |last3=Landesman |first3=H. |last4=Szmuszkovicz |first4=J. |last5=Terrell |first5=R. |date=1963 |title=The Enamine Alkylation and Acylation of Carbonyl Compounds |url=https://pubs.acs.org/doi/abs/10.1021/ja00885a021 |journal=Journal of the American Chemical Society |language=en |volume=85 |issue=2 |pages=207–222 |doi=10.1021/ja00885a021 |bibcode=1963JAChS..85..207S |issn=0002-7863}}</ref> or aldehyde<ref>{{Cite journal |last1=Mannich |first1=C. |last2=Davidsen |first2=H. |date=1936 |title=Über einfache Enamine mit tertiär gebundenem Stickstoff |trans-title=On simple enamines with triple-bonded nitrogen |url=https://onlinelibrary.wiley.com/doi/10.1002/cber.19360690921 |journal=Berichte der Deutschen Chemischen Gesellschaft (A and B Series) |language=de |volume=69 |issue=9 |pages=2106–2112 |doi=10.1002/cber.19360690921 |issn=0365-9488|url-access=subscription }}</ref> species containing an [[α-hydrogen]] with secondary amines.  Acid catalysis is not always required, if the pK<sub>aH</sub> of the reacting amine is sufficiently high (for example, [[pyrrolidine]], which has a pK<sub>aH</sub> of 11.26). If the pK<sub>aH</sub> of the reacting [[amine]] is low, however, then acid catalysis is required through both the addition and the dehydration steps<ref>{{cite journal|last1=Capon|first1=Brian|last2=Wu|first2=Zhen Ping|title=Comparison of the tautomerization and hydrolysis of some secondary and tertiary enamines|journal=The Journal of Organic Chemistry|date=April 1990|volume=55|issue=8|pages=2317–2324|doi=10.1021/jo00295a017}}</ref> (common [[Desiccant|dehydrating agents]] include [[MgSO4|MgSO<sub>4</sub>]] and [[Na2SO4|Na<sub>2</sub>SO<sub>4</sub>]]).<ref name="scripps_Lockner_Nov_07">{{cite web|last1=Lockner|first1=James|title=Stoichiometric Enamine Chemistry|url=http://www.scripps.edu/baran/images/grpmtgpdf/Lockner_Nov_07.pdf|publisher=Baran Group, The Scripps Research Institute|access-date=26 November 2014}}</ref> Primary amines are usually not used for enamine synthesis due to the preferential formation of the more thermodynamically stable imine species.<ref name="chemwiki_Enamine_Reactions">{{cite web|last1=Farmer|first1=Steven|title=Enamine Reactions|publisher=UC Davis Chem Wiki|url=http://chemwiki.ucdavis.edu/Organic_Chemistry/Reactivity_of_Alpha_Hydrogens/Enamine_Reactions|date=2013-10-16}}</ref> Methyl ketone self-condensation is a side-reaction which can be avoided through the addition of [[Titanium tetrachloride|TiCl<sub>4</sub>]]<ref>{{cite journal|last1=Carlson|first1=R|last2=Nilsson|first2=A|title=Improved Titanium Tetrachloride Procedure for Enamine Synthesis|journal=Acta Chemica Scandinavica|date=1984|volume=38B|pages=49–53|doi=10.3891/acta.chem.scand.38b-0049 |doi-access=free}}</ref> into the reaction mixture (to act as a water [[Scavenger (chemistry)|scavenger]]).<ref name="scripps_Lockner_Nov_07"/><ref>{{cite journal|last1=White|first1=William Andrew|last2=Weingarten|first2=Harold|title=A versatile new enamine synthesis|journal=The Journal of Organic Chemistry|date=January 1967|volume=32|issue=1|pages=213–214|doi=10.1021/jo01277a052}}</ref> An example of an aldehyde reacting with a secondary amine to form an enamine via a [[carbinolamine]] intermediate is shown below:
:{{chem2|R2NH  +  R'CH2CHO  <->  R2NC(OH)(H)CH2R'}} (carbonolamine formation)
:{{chem2|R2NC(OH)(H)CH2R' <->  R2NCH\dCHR' + H2O}} (enamine formation)

==Structure==
[[File:EnamineXRD.svg|thumb|110 px|Selected bond distances ([[picometer]]s) in an enamine.  Atoms in red are nearly coplanar.<ref>{{cite journal |doi=10.1002/hlca.19780610839 |title=Structural Studies of Crystalline Enamines |date=1978 |last1=Brown |first1=Kevin L. |last2=Damm |first2=Lorenz |last3=Dunitz |first3=Jack D. |last4=Eschenmoser |first4=Albert |last5=Hobi |first5=Reinhard |last6=Kratky |first6=Christoph |journal=Helvetica Chimica Acta |volume=61 |issue=8 |pages=3108–3135 }}</ref>]]
As shown by [[X-ray crystallography]], the {{chem2|C3NC2}} portion of enamines is close to planar.  This arrangement reflects the sp<sup>2</sup> [[hybridization]] of the {{chem2|C\dCN}} core.

==Reactions==
===Alkylation===
Even though enamines are more nucleophilic than their enol counterparts, they can still react selectively, rendering them useful for alkylation reactions. The enamine nucleophile can attack [[haloalkanes]] to form the alkylated [[iminium]] salt intermediate which then hydrolyzes to regenerate a ketone (a starting material in enamine synthesis). This reaction was pioneered by [[Gilbert Stork]], and is sometimes referred to by the name of its inventor (the [[Stork enamine alkylation]]). Analogously, this reaction can be used as an effective means of [[acylation]]. A variety of alkylating and acylating agents including benzylic, allylic halides can be used in this reaction.<ref>{{cite book|last1=Wade|first1=L.G.|title=Organic Chemistry|url=https://archive.org/details/organicchemistry00wade_1|url-access=registration|date=1999|publisher=Prentice Hall|location=Saddle River, NJ|pages=[https://archive.org/details/organicchemistry00wade_1/page/1019 1019]|isbn=9780139227417}}</ref>
:{{chem2|R2N\sCH\dCHR' +  R"X -> [R2N+\dCH\sCHR'R"]X-}}  (alkylation of enamine)
:{{chem2|[R2N+\dCH\sCHR'R"]+X-  + H2O ->  R2NH  + R'R"CHCHO}}  (hydrolysis of the resulting iminium salt, giving a 2-alkylated aldehyde)

===Acylation===

In a reaction much similar to the enamine alkylation, enamines can be acylated to form a final [[dicarbonyl]] product. The enamine starting material undergoes a nucleophilic addition to [[acyl halides]] forming the iminium salt intermediate which can hydrolyze in the presence of acid.<ref name="chemwiki_Enamine_Reactions"/>
:{{chem2|R2N\sCH\dCHR' +  R"COCl -> [R2N+\dCH\sCHR'C(O)R"]Cl-}}  (acylation of enamine)
:{{chem2|[R2N+\dCH\sCHR'C(O)R"]+Cl  + H2O ->  R2NH  + O\dC(H)CH(R')CR"\dO}}  (hydrolysis of the resulting acyl iminium salt, giving a C-acylated aldehyde)

===Metalloenamines===

Strong bases such as [[Lithium amide#Other lithium amides|LiNR<sub>2</sub>]] can be used to deprotonate imines and form metalloenamines.  Metalloenamines can prove synthetically useful due to their nucleophilicity (they are more nucleophilic than enolates). Thus they are better able to react with weaker electrophiles (for example, they can be used to open [[Epoxide|epoxides]].<ref>{{cite web|last1=Evans|first1=D.|title=Enolates and Metalloenamines II|url=http://isites.harvard.edu/fs/docs/icb.topic93502.files/Lectures_and_Handouts/25-Enolates-2.pdf|access-date=10 December 2014}}{{Dead link|date=August 2019 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>)  Most prominently, these reactions have allowed for [[Asymmetric synthesis|asymmetric]] alkylations of ketones through transformation to chiral intermediate metalloenamines.<ref>{{cite journal|last1=Meyers|first1=A. I.|last2=Williams|first2=Donald R.|title=Asymmetric alkylation of acyclic ketones via chiral metallo enamines. Effect of kinetic vs. thermodynamic metalations.|journal=The Journal of Organic Chemistry|date=August 1978|volume=43|issue=16|pages=3245–3247|doi=10.1021/jo00410a034}}</ref>

===Halogenation===
[[Chlorination reaction|Chlorination]] of enamines followed by hydrolysis gives α-halo derivatives:
:{{chem2|R2NCH\dCHR' +  Cl2 -> [R2N+\dCH\sCHR'CCl]Cl-}}  (chlorination of enamine)
:{{chem2|[R2N+\dCH\sCHR'Cl]Cl-  + H2O ->  R2NH  + R'CH(Cl)CHO}}  (hydrolysis of chloroiminium, giving a chloroaldehyde)
In addition to chlorination, bromination and even iodination have been demonstrated.<ref>{{cite journal|last1=Seufert|first1=Walter|last2=Eiffenberger|first2=Franz|title=Zur Halogenierung von Enaminen — Darstellung von β-Halogen-iminium-halogeniden|journal=Chemische Berichte|date=1979|volume=112|issue=5|pages=1670–1676|doi=10.1002/cber.19791120517}}</ref> 

===Oxidative coupling===
Enamines can be efficiently [[Cross-coupling reaction|cross-coupled]] with enol silanes through treatment with [[ceric ammonium nitrate]].<ref>{{cite journal|last1=Jang|first1=HY|last2=Hong|first2=JB|last3=MacMillan|first3=DWC|title=Enantioselective organocatalytic singly occupied molecular orbital activation: the enantioselective alpha-enolation of aldehydes.|journal=J. Am. Chem. Soc.|date=2007|volume=129|issue=22|pages=7004–7005|doi=10.1021/ja0719428|pmid=17497866|url=https://authors.library.caltech.edu/76937/2/ja0719428si20070430_050938.pdf}}<!--|access-date=30 November 2014--></ref> Oxidative dimerization of aldehydes in the presence of amines proceeds through the formation of an enamine followed by a final [[pyrrole]] formation.<ref>{{cite journal|last1=Li|first1=Q|last2=Fan|first2=A|last3=Lu|first3=Z|last4=Cui|first4=Y|last5=Lin|first5=W|last6=Jia|first6=Y|title=One-pot AgOAc-mediated synthesis of polysubstituted pyrroles from primary amines and aldehydes: application to the total synthesis of purpurone|journal=Organic Letters|date=2010|volume=12|issue=18|pages=4066–4069|doi=10.1021/ol101644g|pmid=20734981}}</ref> This method for symmetric pyrrole synthesis was developed in 2010 by the Jia group, as a valuable new pathway for the synthesis of pyrrole-containing natural products.<ref>{{cite journal|last1=Guo|first1=Fenghai|last2=Clift|first2=Michael D.|last3=Thomson|first3=Regan J.|title=Oxidative Coupling of Enolates, Enol Silanes, and Enamines: Methods and Natural Product Synthesis|journal=European Journal of Organic Chemistry|date=September 2012|volume=2012|issue=26|pages=4881–4896|doi=10.1002/ejoc.201200665|pmid=23471479|pmc=3586739}}</ref>

===Annulation===

Enamines chemistry has been implemented for the purposes of producing a one-pot enantioselective version of the [[Robinson annulation]]. The Robinson annulation, published by Robert Robinson in 1935, is a base-catalyzed reaction that combines a ketone and a [[methyl vinyl ketone]] (commonly abbreviated to MVK) to form a [[cyclohexenone]] fused ring system. This reaction may be catalyzed by [[proline]] to proceed through chiral enamine intermediates which allow for good stereoselectivity.<ref>{{cite journal|last1=List|first1=Benjamin|title=Proline-catalyzed asymmetric reactions|journal=Tetrahedron|date=2002|volume=58|issue=28|pages=5573–5590|doi=10.1016/s0040-4020(02)00516-1}}<!--|access-date=29 November 2014--></ref> This is important, in particular in the field of natural product synthesis, for example, for the synthesis of the [[Wieland–Miescher ketone|Wieland-Miescher ketone]] – a vital building block for more complex biologically active molecules.<ref>{{cite journal|last1=Bui|first1=Tommy|last2=Barbas|title=A proline-catalyzed asymmetric Robinson Annulation|journal=Tetrahedron Letters|date=2000|volume=41|issue=36|pages=6951–6954|doi=10.1016/s0040-4039(00)01180-1}}<!--|access-date=29 November 2014--></ref><ref>{{cite web|last1=Wiener|first1=Jake|title=Enantioselective Organic Catalysis:Non-MacMillan Approaches|url=https://www.princeton.edu/chemistry/macmillan/group-meetings/jjmw-orgcats.pdf|access-date=29 November 2014|archive-url=https://web.archive.org/web/20171026175935/http://www.princeton.edu/chemistry/macmillan/group-meetings/jjmw-orgcats.pdf|archive-date=26 October 2017|url-status=dead}}</ref>

==Reactivity==
Enamines act as nucleophiles that require less acid/base activation for reactivity than their enolate counterparts. They can offer a greater selectivity with fewer side reactions. Ketone enamines are more reactive than their aldehyde counterparts.<ref>{{cite book|last1=Zvi Rappoport|first1=Zvi|title=Enamines|series=PATAI'S Chemistry of Functional Groups|date=May 1994|isbn= 9780470024768 |doi=10.1002/0470024763}}</ref> Cyclic ketone enamines follow a reactivity trend where the five membered ring is the most reactive due to its maximally planar conformation at the nitrogen, following the trend  5>8>6>7 (the seven membered ring being the least reactive). This trend has been attributed to the amount of p-character on the nitrogen lone pair orbital - the higher p character corresponding to a greater nucleophilicity because the p-orbital would allow for donation into the alkene π- orbital. Analogously, if the N lone pair participates in stereoelectronic interactions on the amine moiety, the lone pair will pop out of the plane (will [[Pyramidalization|pyramidalize]]) and compromise donation into the adjacent π C-C bond.<ref>{{cite journal|last1=Mayr|first1=H.|title=Structure-Nucleophilicity Relationships for Enamines|journal=Chem. Eur. J.|date=2003|volume=9|issue=10|pages=2209–18|doi=10.1002/chem.200204666|pmid=12772295}}</ref>

[[File:Modulating Enamine Nucleophilicity via Stereoelectronicand Inductive Effects.png|center|500px|Modulating enamine nucleophilicity via stereoelectronicand inductive Effects]]

There are many ways to modulate enamine reactivity in addition to altering the steric/electronics at the nitrogen center including changing temperature, solvent, amounts of other reagents, and type of electrophile. Tuning these parameters allows for the preferential formation of E/Z enamines and also affects the formation of the more/less substituted enamine from the ketone starting material.<ref name="scripps_Lockner_Nov_07"/>

==Biochemistry==
[[File:FructoseP2Split.svg|thumb|Role of iminium and enamines in splitting of [[fructose 2,6-bisphosphate]].]]
Nature processes (makes and degrades) [[sugar]]s using enzymes called [[aldolase]]s.  These enzymes act by reversible formation of enamines.<ref>{{cite journal |doi=10.1021/ar0300468 |title=Enamine-Based Organocatalysis with Proline and Diamines: The Development of Direct Catalytic Asymmetric Aldol, Mannich, Michael, and Diels−Alder Reactions |date=2004 |last1=Notz |first1=Wolfgang |last2=Tanaka |first2=Fujie |last3=Barbas |first3=Carlos F. |journal=Accounts of Chemical Research |volume=37 |issue=8 |pages=580–591 |pmid=15311957 }}</ref><ref>{{cite journal |doi=10.1021/cr0684016 |title=Asymmetric Enamine Catalysis |date=2007 |last1=Mukherjee |first1=Santanu |last2=Yang |first2=Jung Woon |last3=Hoffmann |first3=Sebastian |last4=List |first4=Benjamin |journal=Chemical Reviews |volume=107 |issue=12 |pages=5471–5569 |pmid=18072803 }}</ref>

==See also==
*[[Enders SAMP/RAMP hydrazone-alkylation reaction]]
*[[Hajos–Parrish–Eder–Sauer–Wiechert reaction]]
*[[Michael Addition]]
*[[Nenitzescu indole synthesis]]
*[[Organocatalysis]]
*[[Robinson annulation]]
*[[Thorpe reaction]]
*[[Fluoxymesterone]]

==References==
{{reflist|2}}

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[[Category:Functional groups]]
[[Category:Enamines| ]]