View source for Enamine

{{Short description|Class of chemical compounds}}
[[File:Enamine-2D-skeletal.svg|thumb|150px|The general structure of an enamine]]
An '''enamine''' is a [[functional group]] with the formula {{chem2|R2N\sC(R&prime;)\dCR&Prime;2}}.<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 reagents used in [[organic synthesis]] and are intermediates in some enzyme-catalyzed reactions.<ref name=Cook>{{cite book |editor-first1=Gilbert |editor-last1=Cook |title=Enamines: Synthesis: Structure, and Reactions |date=1988 |doi=10.1201/9780203758014 |isbn=978-1-351-45251-9|publisher=CRC Press|location=Boca Raton }}</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 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>

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 [[condensation]] of secondary amines with ketones and aldehydes..<ref name=Cook/><ref>{{OrgSynth|author=R. B. Woodward, I. J. Pachter, M. L. Scheinbaum |year=1974|title=2,2- (Trimethylenedithio)cyclohexanone|volume=54|page=39|doi=10.15227/orgsyn.054.0039}}</ref> The condensing ketone and aldehyde must contain an [[α-hydrogen]]. The associated equations for enamine formation follow:
:{{chem2|R2NH  +  R'CH2CHO  <->  R2NC(OH)(H)CH2R'}} ([[carbonolamine]] formation)
:{{chem2|R2NC(OH)(H)CH2R' <->  R2NCH\dCHR' + H2O}} (enamine formation)

In some cases, acid-catalysts are employed.  [[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> 

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> 

Primary amines are usually not used for enamine synthesis.<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> Instead, such reactions give [[imine]]s:
:{{chem2|RNH2  +  R'CH2CHO  <->  R(H)NC(OH)(H)CH2R'}} (carbonolamine formation)
:{{chem2|R(H)NC(OH)(H)CH2R' <->  RN\dC(H)CH2R' + H2O}} (imine formation)
Imines are [[tautomer]]s of enamines. The enamine-imine tautomerism is analogous to the [[keto-enol tautomerism]].

==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 |bibcode=1978HChAc..61.3108B }}</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> [[Orbital hybridization|hybridization]] of the {{chem2|C\dCN}} core.

E vs Z geometry affects the reactivity of enamines.<ref name="scripps_Lockner_Nov_07"/>

==Reactions==
Enamines are nucleophiles. Ketone enamines are more nucleophilic than their aldehyde counterparts.<ref>{{cite book|last1=Zvi Rappoport|first1=Zvi|editor-first1=Zvi |editor-last1=Rappoport |title=Enamines|series=PATAI'S Chemistry of Functional Groups|date=May 1994|isbn= 9780470024768 |doi=10.1002/0470024763}}</ref>

Compared to their enolate counterparts, their alkylations often proceed with fewer side reactions.  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 |bibcode=2003ChEuJ...9.2209K }}</ref>

===Alkylation and acylation ===
[[Alkylation]] is the predominant reaction sought with enamines. When treated with [[haloalkanes|alkyl halides]] enamines give the alkylated [[iminium]] salts, which then can be hydrolyzes to regenerate a ketone (a starting material in enamine synthesis):
:{{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)
Owing to the pioneering work by [[Gilbert Stork]], this reaction  is sometimes referred to as 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>

Similar to their alkylation, enamines can be acylated.  Hydrolysis of this acylated imine forms a 1,3-[[dicarbonyl]].<ref>{{cite journal |doi=10.15227/orgsyn.043.0034 |title=Docosanedioic Acid |journal=Organic Syntheses |date=1963 |volume=43 |page=34|author=S. Hunig, E. Lucke, W. Brenninger
 }}</ref><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)

===Halogenation===
[[Chlorination reaction|Chlorination]] of enamines followed by hydrolysis gives α-halo ketones and aldehydes:
:{{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|bibcode=2007JAChS.129.7004J |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>

==Metalloenamines==
Lithiated enamines (also known as ''aza'' enolates, imine anions, enamides, or metallated Schiff bases) are nitrogen analogues to enolates,<ref name="uk">{{cite thesis |last1=Aslam |first1=O. |title=Development of catalytic aza enolate reactions |url=https://discovery.ucl.ac.uk/id/eprint/1363094 |publisher=UCL (University College London) |date=28 September 2012|type=Doctoral }}</ref> formed when imines get treated with strong bases such as [[Lithium amide#Other lithium amides|LiNR<sub>2</sub>]]:
[[File:Aza enolate formation2.tif|600px|frameless|center]]
They can also be formed with [[Grignard reagents]] and react with other soft electrophiles, including [[Michael reaction|Michael receptors]].<ref name="uk" />  

''Aza'' enolates are highly nucleophilic at the β carbon,<ref>{{cite web |last1=Cranwell |first1=Philippa |title=Enamines/aza-enolates – Mechanism Mordor |url=https://sites.google.com/site/mechanismmordor/3rd-4th-year-mechanisms/retrosynthesis/carbonyls/enamines |archive-url=https://web.archive.org/web/20210903151137/https://sites.google.com/site/mechanismmordor/3rd-4th-year-mechanisms/retrosynthesis/carbonyls/enamines |archive-date=2021-09-03 |access-date=2020-11-28 |website=sites.google.com}}</ref><ref>{{cite book |last1=Carey |first1=Francis A. |title=Advanced organic chemistry. Part B, Reactions and synthesis |date=2007 |publisher=Springer |isbn=978-0-387-68350-8 |edition=5th |location=New York, NY |pages=46–47}}</ref><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> but scarcely electrophilic.  They do not undergo [[self-condensation]] in a basic or neutral solution (where [[aldehydes]] would undergo the [[aldol reaction]]).<ref name="Clayden">{{cite book |last1=Clayden |first1=Jonathan |title=Organic chemistry |date=2012 |publisher=Oxford University Press |location=Oxford |isbn=978-0-19-927029-3 |pages=465, 593–594 |edition=2nd}}</ref>  Thus, ''aza'' enolates are convenient to alkylate the β carbon with [[epoxide]]s and [[alkyl halides]]:<ref>{{cite journal |last1=Hudrlik |first1=Paul F. |last2=Wan |first2=Chung-Nan |date=October 1975 |title=Reactions of oxetane with imine salts derived from cyclohexanone |journal=The Journal of Organic Chemistry |volume=40 |issue=20 |pages=2963–2965 |doi=10.1021/jo00908a027}}</ref>
[[File:Epoxide ring opening via aza enolate.tif|650px|frameless|center]]
That reaction is one of the key steps in the synthesis of the ''[[Oulema melanopus]]''<nowiki/>' male aggression pheromone:<ref name= 'hormone'>{{cite journal |last1=Chevalley |first1=Alice |last2=Férézou |first2=Jean-Pierre |title=One-pot formation of aza-enolates from secondary amines and condensation to esters and alkyl bromides |journal=Tetrahedron |date=2012 |volume=68 |issue=29 |pages=5882–5889 |doi=10.1016/j.tet.2012.04.105 }}</ref>
[[File:Aza enolate allyl halide.tif|700px|frameless|center]]

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>

==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>

==Further reading==
Early literature of historic interest:
*the term "enamine" is coined: {{cite journal |last1=Wittig |first1=Georg |last2=Blumenthal |first2=Hermann |title=Über die Einwirkung von Ammoniak und Ammoniak-Derivaten auf ''o'' -Acetylaceto-phenole |journal=Berichte der Deutschen Chemischen Gesellschaft (A and B Series) |date=1927 |volume=60 |issue=5 |pages=1085–1094 |doi=10.1002/cber.19270600515}}
*{{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|url-access=subscription }}
*{{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 }}

==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}}

{{Authority control}}

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