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{{Short description|Class of chemical compounds}}
{{Short description|Class of chemical compounds}}
[[File:Enamine-2D-skeletal.svg|thumb|150px|The general structure of an enamine]]
[[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>
An '''enamine''' is a [[functional group]] with the formula {{chem2|R2N\sC(R′)\dCR″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 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>
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>
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.
Enamines are both good nucleophiles and good bases. Their behavior as carbon-based nucleophiles is explained with reference to the following resonance structures.
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==Formation==
==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>]]
:[[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:
Enamines can be easily produced from commercially available starting reagents. Commonly enamines are produced by [[Carbonyl condensation|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:
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|access-date=2014-11-26|archive-date=2016-01-24|archive-url=https://web.archive.org/web/20160124133428/http://chemwiki.ucdavis.edu/Organic_Chemistry/Reactivity_of_Alpha_Hydrogens/Enamine_Reactions|url-status=dead}}</ref> Instead, such reactions give [[imine]]s:
Imines are [[tautomer]]s of enamines. The enamine-imine tautomerism is analogous to the [[keto-enol tautomerism]].
==Structure==
==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>]]
[[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> [[hybridization]] of the {{chem2|C\dCN}} core.
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==
==Reactions==
===Alkylation===
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>
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>
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\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)
:{{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>
===Acylation===
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"/>
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\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)
:{{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===
===Halogenation===
[[Chlorination reaction|Chlorination]] of enamines followed by hydrolysis gives α-halo derivatives:
[[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|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)
:{{chem2|[R2N+\dCH\sCHR'Cl]Cl- + H2O -> R2NH + R'CH(Cl)CHO}} (hydrolysis of chloroiminium, giving a chloroaldehyde)
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===Oxidative coupling===
===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>
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===
===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>
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==
==Metalloenamines==
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>
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>]]:
They can also be formed with [[Grignard reagents]] and react with other soft electrophiles, including [[Michael reaction|Michael receptors]].<ref name="uk" />
[[File:Modulating Enamine Nucleophilicity via Stereoelectronicand Inductive Effects.png|center|500px|Modulating enamine nucleophilicity via stereoelectronicand inductive Effects]]
''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>
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"/>
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==
==Biochemistry==
[[File:FructoseP2Split.svg|thumb|Role of iminium and enamines in splitting of [[fructose 2,6-bisphosphate]].]]
[[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>
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 }}
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 (-ol). Enamines are nitrogen analogs of enols.[4]
Enamines are both good nucleophiles and good bases. Their behavior as carbon-based nucleophiles is explained with reference to the following resonance structures.
Enamines can be easily produced from commercially available starting reagents. Commonly enamines are produced by condensation of secondary amines with ketones and aldehydes..[3][6] The condensing ketone and aldehyde must contain an α-hydrogen. The associated equations for enamine formation follow:
In some cases, acid-catalysts are employed. Acid catalysis is not always required, if the pKaH of the reacting amine is sufficiently high (for example, pyrrolidine, which has a pKaH of 11.26). If the pKaH of the reacting amine is low, however, then acid catalysis is required through both the addition and the dehydration steps.[7] Common dehydrating agents include MgSO4 and Na2SO4.[8]
Methyl ketone self-condensation is a side-reaction which can be avoided through the addition of TiCl4[9] into the reaction mixture (to act as a water scavenger).[8][10]
Primary amines are usually not used for enamine synthesis.[11] Instead, such reactions give imines:
E vs Z geometry affects the reactivity of enamines.[8]
Reactions
Enamines are nucleophiles. Ketone enamines are more nucleophilic than their aldehyde counterparts.[13]
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 pyramidalize) and compromise donation into the adjacent π C-C bond.[14]
Alkylation and acylation
Alkylation is the predominant reaction sought with enamines. When treated with alkyl halides enamines give the alkylated iminium salts, which then can be hydrolyzes to regenerate a ketone (a starting material in enamine synthesis):
Template:Chem2 (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.[15]
Similar to their alkylation, enamines can be acylated. Hydrolysis of this acylated imine forms a 1,3-dicarbonyl.[16][11]
Template:Chem2 (hydrolysis of chloroiminium, giving a chloroaldehyde)
In addition to chlorination, bromination and even iodination have been demonstrated.[17]
Oxidative coupling
Enamines can be efficiently cross-coupled with enol silanes through treatment with ceric ammonium nitrate.[18] Oxidative dimerization of aldehydes in the presence of amines proceeds through the formation of an enamine followed by a final pyrrole formation.[19] 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.[20]
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.[21] This is important, in particular in the field of natural product synthesis, for example, for the synthesis of the Wieland-Miescher ketone – a vital building block for more complex biologically active molecules.[22][23]
Metalloenamines
Lithiated enamines (also known as aza enolates, imine anions, enamides, or metallated Schiff bases) are nitrogen analogues to enolates,[24] formed when imines get treated with strong bases such as LiNR2:
Most prominently, these reactions have allowed for asymmetric alkylations of ketones through transformation to chiral intermediate metalloenamines.[31]
