Enamine

{{Short description|Class of chemical compounds}} thumb|150px|The general structure of an enamine 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 (-''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. :thumb|center|Resonance structures for an enamine

==Formation== :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 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.<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 dehydrating agents include MgSO4 and Na2SO4.<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 TiCl4<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).<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 imines: :{{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 tautomers of enamines. The enamine-imine tautomerism is analogous to the keto-enol tautomerism.

Protonation of enamines occurs at nitrogen to give enammonium salts, which have been isolated at low temperatures. These salts tend to rearrange to iminium salts:<ref name=Cook/> :{{chem2|R2C\dCH\sNR'2 + H+ -> [R2C\dCH\sN(H)R'2]+}} :{{chem2| [R2C\dCH\sN(H)R'2]+ -> [R2CH\sCH\dNR'2]+}}

==Structure== [[File:EnamineXRD.svg|thumb|110 px|Selected bond distances (picometers) 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 sp2 hybridization of the {{chem2|C\dCN}} core.

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

The great majority of enamine literature focuses on ''tertiary'' enamines, i.e. those lacking an N-H bond. NH-containing enamines are usually unstable, as indicated by the lability of 2-pyrroline.

==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 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 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 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-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}}</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}}</ref> 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.<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}}</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>

===Metallation=== Lithiated enamines, nitrogen analogues to enolates, form by treating imines with strong bases such as LiNR2: :{{chem2|RN\dC(CH2R')R + LiN(iPr)2 -> RN\dC(CHLiR')R + HN(iPr)2}} These ''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> They are alkylated at the β carbon with epoxides 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> :{{chem2|RN\dC(CHLiR')R + CH2CH2O -> RN\dC(CH(CH2CH2OLi)R')R }} :{{chem2|RN\dC(CH(CH2CH2OLi)R')R + HX -> RN\dC(CH(CH2CH2OH)R')R + LiX}} That reaction was used 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> This sequence of reactions (ketone → imine → azaenolate) has allowed for 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) sugars using enzymes called aldolases. 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 }}

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

Category:Functional groups Category:Enamines