Imine#Imine synthesis

In imines the five core atoms (C₂C=NX, ketimine; and C(H)C=NX, aldimine; X = H or C) are coplanar. Planarity results from the sp²-hybridization of the mutually double-bonded carbon and the nitrogen atoms. The C=N distance is 1.29–1.31 Å for nonconjugated imines and 1.35 Å for conjugated imines. By contrast, C−N distances in amines and nitriles are 1.47 and 1.16 Å respectively.{{cite book |title=Carbon–Nitrogen Double Bonds |editor=Saul Patai |year=1970 |publisher=John Wiley & Sons |doi=10.1002/9780470771204.ch1 |chapter=General and theoretical aspects |author=C. Sandorfy |series=PATai's Chemistry of Functional Groups |pages=1–60 |isbn=9780470771204}} Rotation about the C=N bond is slow. Using NMR spectroscopy, both E and Z isomers of aldimines have been detected. Owing to steric effects, the E isomer is favored.{{cite journal |doi=10.1039/P29740001081 |title=E–Z-isomerism in Aldimines |year=1974 |last1=Bjørgo |first1=Johannes |last2=Boyd |first2=Derek R. |last3=Watson |first3=Christopher G. |last4=Jennings |first4=W. Brian |last5=Jerina |first5=Donald M. |journal=J. Chem. Soc., Perkin Trans. 2 |issue=9 |pages=1081–1084}}

The term "imine" was coined in 1883 by the German chemist Albert Ladenburg.{{cite journal |last=Ladenburg |first=A. |year=1883 |title=Ueber die Imine |trans-title=About imines |url=https://babel.hathitrust.org/cgi/pt?id=osu.32435060218708;view=1up;seq=31 |journal= Berichte der Deutschen Chemischen Gesellschaft|language=de |volume=16 |pages=1149–1152 |doi=10.1002/cber.188301601259 |quote=From p. 1150: Denn offenbar gehört auch das Piperidin in die Klasse der von mir gesuchten Verbindungen, für welche der Name Imine durch die bestehende Nomenklatur angezeigt ist. |trans-quote=For obviously piperidine also belongs in the class of compounds that are sought by me, for which the name "imines" is indicated by the prevailing nomenclature.}}

Usually imines refer to compounds with the general formula R₂C=NR, as discussed below.{{Cite book|url=https://books.google.com/books?id=xQrwAAAAMAAJ|title=Nomenclature of Organic Compounds|year=1974|isbn=9780841201910|series=Advances in Chemistry|volume=126|pages=180–188|chapter=Amines and Imines|publisher=American Chemical Society |doi=10.1021/ba-1974-0126.ch023|oclc=922539}} In the older literature, imine refers to the aza-analogue of an epoxide. Thus, ethylenimine is the three-membered ring species aziridine C₂H₄NH.{{Cite journal |year=1950 |title=Ethylenimine |url=http://orgsyn.org/demo.aspx?prep=CV4P0433 |journal=Organic Syntheses |volume=30 |page=38 |doi=10.15227/orgsyn.030.0038|url-access=subscription }} The relationship of imines to amines having double and single bonds can be correlated with imides and amides, as in succinimide vs acetamide.

Imines are related to ketones and aldehydes by replacement of the oxygen with an NR group. When R = H, the compound is a primary imine, when R is hydrocarbyl, the compound is a secondary imine. If this group is not a hydrogen atom, then the compound can sometimes be referred to as a Schiff base.{{GoldBookRef|title=Schiff base|file=S05498}} When R³ is OH, the imine is called an oxime, and when R³ is NH₂ the imine is called a hydrazone.

A primary imine in which C is attached to both a hydrocarbyl and a H (derived from an aldehyde) is called a primary aldimine; a secondary imine with such groups is called a secondary aldimine.{{goldbookref|file=A00209.html|title=aldimines}} A primary imine in which C is attached to two hydrocarbyls (derived from a ketone) is called a primary ketimine; a secondary imine with such groups is called a secondary ketimine.{{goldbookref|file=K03381.html|title=ketimines}}

File:Aldimine-(primary)-skeletal.svg|Primary aldimine, E-isomer

File:Aldimine-(secondary)-skeletal.svg|Secondary aldimine, E-isomer

File:Imine-(primary)-skeletal.svg|Primary ketimine

File:Imine-(secondary)-skeletal.svg|Secondary ketimine

{{clear}}

N-Sulfinyl imines are a special class of imines having a sulfinyl group attached to the nitrogen atom.

:File:Imine-synthesis.svg

{{Main|Alkylimino-de-oxo-bisubstitution}}

Imines are typically prepared by the condensation of primary amines and aldehydes.{{cite journal|doi=10.15227/orgsyn.050.0066|title=Directed Aldol Condensations:b-Phenylcinnamaldehyde|journal=Organic Syntheses|year=1970|volume=50|page=66|author=G. Wittig, A. Hesse}}{{cite journal|last1=Bigelow|first1=Lucius A.|last2=Eatough|first2=Harry|doi=10.15227/orgsyn.008.0022|title=Benzalaniline|journal=Organic Syntheses|year=1928|volume=8|page=22}} Ketones undergo similar reactions, but less commonly than aldehydes. In terms of mechanism, such reactions proceed via the nucleophilic addition giving a hemiaminal {{chem2|\sC(OH)(NR2)\s}} intermediate, followed by an elimination of water to yield the imine (see alkylimino-de-oxo-bisubstitution for a detailed mechanism). The equilibrium in this reaction usually favors the carbonyl compound and amine, so that azeotropic distillation or use of a dehydrating agent, such as molecular sieves or magnesium sulfate, is required to favor of imine formation. In recent years, several reagents such as Tris(2,2,2-trifluoroethyl)borate [B(OCH₂CF₃)₃],{{Cite journal|last1=Reeves|first1=Jonathan T.|last2=Visco|first2=Michael D.|last3=Marsini|first3=Maurice A.|last4=Grinberg|first4=Nelu|last5=Busacca|first5=Carl A.|last6=Mattson|first6=Anita E.|last7=Senanayake|first7=Chris H.|date=2015-05-15|title=A General Method for Imine Formation Using B(OCH₂CF₃)₃|journal=Organic Letters|volume=17|issue=10|pages=2442–2445|doi=10.1021/acs.orglett.5b00949|issn=1523-7060|pmid=25906082}} pyrrolidine{{Cite journal|last1=Morales|first1=Sara|last2=Guijarro|first2=Fernando G.|last3=García Ruano|first3=José Luis|last4=Cid|first4=M. Belén|date=2014-01-22|title=A General Aminocatalytic Method for the Synthesis of Aldimines|journal=Journal of the American Chemical Society|volume=136|issue=3|pages=1082–1089|doi=10.1021/ja4111418|issn=0002-7863|pmid=24359453}} or titanium ethoxide [Ti(OEt)₄]{{Cite journal|last1=Collados|first1=Juan F.|last2=Toledano|first2=Estefanía|last3=Guijarro|first3=David|last4=Yus|first4=Miguel|date=2012-07-06|title=Microwave-Assisted Solvent-Free Synthesis of Enantiomerically Pure N-(tert-Butylsulfinyl)imines|journal=The Journal of Organic Chemistry|volume=77|issue=13|pages=5744–5750|doi=10.1021/jo300919x|issn=0022-3263|pmid=22694241}} have been shown to catalyse imine formation.

Rarer than primary amines is the use of ammonia to give a primary imine.{{Cite journal|author1=Verardo, G.|author2=Giumanini, A. G.|author3=Strazzolini, P.|author4=Poiana, M.|title=Ketimines From Ketones and Ammonia|journal=Synthetic Communications|volume=18|issue=13|pages=1501–1511|doi=10.1080/00397918808081307|year=1988}} In the case of hexafluoroacetone, the hemiaminal intermediate can be isolated.{{cite journal|first1= W. J.|last1=Middleton|first2=H. D.|last2=Carlson|title=Hexafluoroacetone imine|journal=Org. Syntheses|volume=50|year=1970|pages=81–3|doi=10.15227/orgsyn.050.0081}}

Primary ketimines can be synthesized via a Grignard reaction with a nitrile. This method is known as Moureu-Mignonac ketimine synthesis.{{Cite book|date=2010-09-15|chapter=Moureau-Mignonac Ketimine Synthesis|title=Comprehensive Organic Name Reactions and Reagents|language=en|location=Hoboken, NJ, USA|publisher=John Wiley & Sons, Inc.|pages=1988–1990|doi=10.1002/9780470638859.conrr446|isbn=9780470638859}}{{cite journal|last1=Koos|first1=Miroslav|last2=Mosher|first2=Harry S.|title=α-Amino-α-trifluoromethyl-phenylacetonitrile: A potential reagent for NMR determination of enantiomeric purity of acids|journal=Tetrahedron|date=1993|volume=49|issue=8|pages=1541–1546|doi=10.1016/S0040-4020(01)80341-0}}{{cite journal|last1=Moureu|first1=Charles|last2=Mignonac|first2=Georges|title=Les Cetimines|journal=Annales de Chimie|date=1920|volume=9|issue=13|pages=322–359|url=http://babel.hathitrust.org/cgi/pt?id=uc1.b3816273;view=1up;seq=682|access-date=18 June 2014}} For example, benzophenone imine can also be synthesized by addition of phenylmagnesium bromide to benzonitrile followed by careful hydrolysis (lest the imine be hydrolyzed):{{Cite journal|last1=Pickard|first1=P. L.|last2=Tolbert|first2=T. L.|date=December 1961|title=An Improved Method of Ketimine Synthesis|journal=The Journal of Organic Chemistry|language=EN|volume=26|issue=12|pages=4886–4888|doi=10.1021/jo01070a025|issn=0022-3263}}

:C₆H₅CN + C₆H₅MgBr → (C₆H₅)₂C=NMgBr

:(C₆H₅)₂C=NMgBr + H₂O → (C₆H₅)₂C=NH + MgBr(OH)

Several other methods exist for the synthesis of imines.

• Reaction of organic azides with metal carbenoids (produced from diazocarbonyl compounds).{{cite journal|last1=Mandler|first1=Michael|last2=Truong|first2=Phong|last3=Zavalij|first3=Peter|last4=Doyle|first4=Michael|title=Catalytic Conversion of Diazocarbonyl Compounds to Imines: Applications to the Synthesis of Tetrahydropyrimidines and β-Lactams|journal=Organic Letters|date=Jan 14, 2014|volume=16|issue=3|pages=740–743|doi=10.1021/ol403427s|pmid=24423056}}
• The reaction of iminophosphoranes and organic azides in an Aza-Wittig-reaction.
• Condensation of carbon acids with nitroso compounds.
• The rearrangement of trityl N-haloamines in the Stieglitz rearrangement.
• By reaction of alkenes with hydrazoic acid in the Schmidt reaction.
• By reaction of a nitrile, hydrochloric acid, and an arene in the Hoesch reaction.
• Multicomponent synthesis of 3-thiazolines in the Asinger reaction.
• Thermal decomposition of oximes.{{cite journal |doi=10.15227/orgsyn.010.0028|title=Diphenylmethane Imine Hydrochloride|journal=Organic Syntheses|year=1930|volume=10|page=28|author=Arthur Lachman}}

==Reactions==

File:Hexafluoroacetone imine.svg

The chief reaction of imines, often undesirable, is their hydrolysis back to the amine and the carbonyl precursor.

:R₂C=NR' + H₂O {{Eqm}} R₂C=O + R'NH₂

Imines are widely used as intermediates in the synthesis of heterocycles.

• Aromatic imines react with an enol ether to a quinoline in the Povarov reaction.
• Imines react, thermally, with ketenes in [2+2] cycloadditions to form β-lactams in the Staudinger synthesis.{{cite journal |doi=10.15227/orgsyn.072.0014|title=(3S,4S)-3-Amino-1-(3,4-Dimethoxybenzyl)-4-[(R)-2,2-Dimethyl-1,3-Dioxolan-4-Yl]-2-Azetidinone|journal=Organic Syntheses|year=1995|volume=72|page=14|first1=Christian|last1=Hubschwerlen|first2=Jean-Luc|last2=Specklin}} Several variants have been described.{{cite journal|doi=10.15227/orgsyn.065.0140|title=1,3-Dimethyl-3-Methoxy-4-Phenylazetidinone|journal=Organic Syntheses|year=1987|volume=65|page=140|first1= Lous S.|last1=Hegedus|first2=Michael A.|last2=McGuire|first3=Lisa M.|last3=Schultze}}{{cite journal|doi=10.15227/orgsyn.088.0138|title=PHOSPHINE-CATALYZED [3 + 2] ANNULATION: SYNTHESIS OF ETHYL 5-(tert-BUTYL)-2-PHENYL-1-TOSYL-3-PYRROLINE-3-CARBOXYLATE|journal=Organic Syntheses|year=2011|volume=88|page=138|author= Ian P. Andrews and Ohyun Kwon|doi-access=free}}
• Imine react with dienes in the Imine Diels-Alder reaction to a tetrahydropyridine.
• tosylimines react with α,β-unsaturated carbonyl compound to give allylic amines in the Aza-Baylis–Hillman reaction.

Somewhat like the parent amines, imines are mildly basic and reversibly protonate to give iminium salts:

:R₂C=NR' + H⁺ {{EqmR}} [R₂C=NHR']⁺

Alternatively, primary imines are sufficiently acidic to allow N-alkylation, as illustrated with benzophenone imine:{{cite journal|doi=10.15227/orgsyn.095.0374|title=Trimethylsilyldiazo[13C]methane: A Versatile ¹³C-Labelling Reagent|year=2018|journal=Organic Syntheses|volume=95|pages=374–402|first1=Chris|last1=Nottingham|first2=Guy C.|last2=Lloyd-Jones|doi-access=free|hdl=20.500.11820/c801073c-6b4b-4a85-be68-2c4313b6e53d|hdl-access=free}}

:(C₆H₅)₂C=NH + CH₃Li → (C₆H₅)₂C=NLi + CH₄

:(C₆H₅)₂C=NLi + CH₃I → (C₆H₅)₂C=NCH₃ + LiI

Imines are common ligands in coordination chemistry. Particularly popular examples are found with Schiff base ligands derived from salicylaldehyde, the salen ligands. Metal-catalyzed reactions of imines proceed through such complexes. In classical coordination complexes, imines bind metals through nitrogen. For low-valent metals, η²-imine ligands are observed.

Very analogous to ketones and aldehydes, primary imines are susceptible to attack by carbanion equivalents. The method allows for the synthesis of secondary amines:{{cite journal |doi=10.15227/orgsyn.097.0262|title=Stereoselective Synthesis of Chiral Sulfinamide Monophosphine Ligands (Ming-Phos)(S, Rs)-M|year=2020|journal=Organic Syntheses|volume=97|pages=262–273|s2cid=235020219|first1=Anjing|last1=Hu|first2=Zhan-Ming|last2=Zhang|first3=Yuanjing|last3= Xiao|first4=Junliang|last4=Zhang

|doi-access=free}}{{cite journal |doi=10.15227/orgsyn.084.0306|title= Chiral Lithium Amide Base Desymmetrization of a Ring Fused Imide: Formation of (3aS,7aS)-2[2-(3,4-Dimethoxyphenyl)-ethyl]-1,3-dioxo-octahydro-isoindole-3a-Carboxylic Acid Methyl Ester |journal=Organic Syntheses|year=2007|volume=84|page=306|author= Vincent Rodeschini, Nigel S. Simpkins, and Fengzhi Zhang }}

:R₂C=NR' + R"Li → R₂R"CN(Li)R'

:R₂R"CN(Li)R' + H₂O → R₂R"CNHR' + LiOH

This can be expanded to include enolisable carbons in the Mannich reaction, which is a straightforward and commonly used approach for producing β-amino-carbonyl compounds.{{cite journal |last1=Arend |first1=Michael |last2=Westermann |first2=Bernhard |last3=Risch |first3=Nikolaus |title=Modern Variants of the Mannich Reaction |journal=Angewandte Chemie International Edition |date=4 May 1998 |volume=37 |issue=8 |pages=1044–1070 |doi=10.1002/(SICI)1521-3773(19980504)37:8<1044::AID-ANIE1044>3.0.CO;2-E}}

File:Mannich.png

{{Main article|Hydrogenation of carbon-nitrogen double bonds}}

Imines are reduced via reductive amination. An imine can be reduced to an amine via hydrogenation for example in a synthesis of m-tolylbenzylamine:{{OrgSynth | collvol = 3 | pages = 827 | title = m-Tolylbenzylamine | year = 1955 | prep = cv3p0827 | author = C. F. H. Allen and James VanAllan}}

:Image:ImineReduction.svg

Other reducing agents are lithium aluminium hydride and sodium borohydride.For example: {{OrgSynth | collvol = 6 | collvolpages = 905 | year = 1988 | prep = cv6p0905 | title = Aldehydes from 2-Benzyl-4,4,6-trimethyl-5,6-dihydro-1,3(4H)-oxazine: 1-Phenylcyclopentanecarboxaldehyde | author = Ieva R. Politzer and A. I. Meyers}}

The asymmetric reduction of imines has been achieved by hydrosilylation using a rhodium-DIOP catalyst.{{cite journal | doi = 10.1016/S0040-4039(01)87358-5 | title = Synthese asymetrique d'amines par hydrosilylation d'imines catalysee par un complexe chiral du rhodium | year = 1973 | last1 = Langlois | first1 = N | journal = Tetrahedron Lett. | volume = 14 | pages = 4865–4868 | issue = 49}} Many systems have since been investigated.{{cite journal | doi = 10.1021/cr980414z | title = Catalytic Enantioselective Addition to Imines | year = 1999 | last1 = Kobayashi | first1 = Shū | last2 = Ishitani | first2 = Haruro | journal = Chem. Rev. | volume = 99 | pages = 1069–94 | issue = 5| pmid = 11749440 }}J. Martens: Reduction of Imino Groups (C=N) in (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann) Houben-Weyl Stereoselective Synthesis, Workbench Edition E21 Volume 7, S. 4199-4238, Thieme Verlag Stuttgart, 1996, {{ISBN|3-13-106124-3}}.

Owing to their enhanced electrophilicity, iminium derivatives are particularly susceptible to reduction to the amines. Such reductions can be achieved by transfer hydrogenation or by the stoichiometric action of sodium cyanoborohydride. Since imines derived from unsymmetrical ketones are prochiral, their reduction defines a route to chiral amines.

Unhindered aldimines tend to cyclize, as illustrated by the condensation of methylamine and formaldehyde, which gives the hexahydro-1,3,5-triazine.

Imine polymers (polyimines) can be synthesised from multivalent aldehydes and amines.{{Cite journal| last = Schoustra| first = Sybren K.| author2 = Groeneveld, Timo| author3 = Smulders, Maarten M. J.| title = The effect of polarity on the molecular exchange dynamics in imine-based covalent adaptable networks | journal = Polymer Chemistry | year = 2021| volume = 12 | issue = 11| pages = 1635–1642 | doi = 10.1039/D0PY01555E| doi-access = free}} The polymerisation reaction proceeds directly when the aldehyde and amine monomers are mixed together at room temperature. In most cases, (small) amounts of solvent may still be required. Polyimines are particularly interesting materials because of their application as vitrimers. Owing to the dynamic covalent nature of the imine bonds, polyimines can be recycled relatively easily. Furthermore, polyimines are known for their self-healing behaviour.{{Cite journal|last=Schoustra|first=Sybren K.|author2=Dijksman, Joshua A.|author3=Zuilhof, Han|author4=Smulders, Maarten M. J.|title=Molecular control over vitrimer-like mechanics – tuneable dynamic motifs based on the Hammett equation in polyimine materials|journal=Chemical Science|year=2021|volume=12|issue=1|pages=293–302|doi=10.1039/d0sc05458e|issn=2041-6520|pmid=34163597|pmc=8178953}}{{Cite journal|last=Zhu|first=Jiaqi| title=A self-healing transparent polydimethylsiloxane elastomer based on imine bonds|journal=European Polymer Journal|year=2020|volume=123|page=109382|doi=10.1016/j.eurpolymj.2019.109382|bibcode=2020EurPJ.12309382W |s2cid=214199868|url=https://doi.org/10.1016/j.eurpolymj.2019.109382|url-access=subscription}}

Akin to pinacol couplings, imines are susceptible to reductive coupling leading to 1,2-diamines.

{{cite journal|doi=10.15227/orgsyn.076.0023|title=(R,R)- and (S,S)-N,N'-Dimethyl-1,2-Diphenylethylene-1,2-Diamine|journal=Organic Syntheses|year=1999|volume=76|page=23|first1=Alex|last1=Alexakis|first2=Isabelle|last2=Aujard|first3=Tonis|last3=Kanger|first4=Pierre|last4=Mangeney}}

Imine are oxidized with meta-chloroperoxybenzoic acid (mCPBA) to give an oxaziridines.

Imines are intermediates in the alkylation of amines with formic acid in the Eschweiler–Clarke reaction.

A rearrangement in carbohydrate chemistry involving an imine is the Amadori rearrangement.

A methylene transfer reaction of an imine by an unstabilised sulphonium ylide can give an aziridine system.

Imine react with dialkylphosphite in the Pudovik reaction and Kabachnik–Fields reaction

Imines are common in nature.{{Cite web|title=Researchers look to nature to unearth the secrets of cyclic imine cleavage|url=https://www.eurekalert.org/pub_releases/2019-03/uot-rlt030719.php|access-date=2021-07-22|website=EurekAlert!|language=en}}{{Cite journal|last1=Borchert|first1=Andrew J.|last2=Ernst|first2=Dustin C.|last3=Downs|first3=Diana M.|date=2019|title=Reactive Enamines and Imines in vivo: Lessons from the RidA Paradigm|journal=Trends in Biochemical Sciences|volume=44|issue=10|pages=849–860|doi=10.1016/j.tibs.2019.04.011|issn=0968-0004|pmc=6760865|pmid=31103411}} The pyridoxal phosphate-dependent enzymes (PLP enzymes) catalyze myriad reactions involving aldimines (or Schiff bases).{{cite journal|doi=10.1146/annurev.biochem.73.011303.074021|title=Pyridoxal Phosphate Enzymes: Mechanistic, Structural, and Evolutionary Considerations|year=2004|last1= Eliot|first1=Andrew C.|last2=Kirsch|first2=Jack F.|journal=Annual Review of Biochemistry|volume=73|pages= 383–415|pmid=15189147}} Cyclic imines are also substrates for many imine reductase enzymes.{{Cite journal |last1=Mangas-Sanchez |first1=Juan |last2=France |first2=Scott P |last3=Montgomery |first3=Sarah L |last4=Aleku |first4=Godwin A |last5=Man |first5=Henry |last6=Sharma |first6=Mahima |last7=Ramsden |first7=Jeremy I |last8=Grogan |first8=Gideon |last9=Turner |first9=Nicholas J |date=2017 |title=Imine reductases (IREDs) |url=https://linkinghub.elsevier.com/retrieve/pii/S1367593116301880 |journal=Current Opinion in Chemical Biology |language=en |volume=37 |pages=19–25 |doi=10.1016/j.cbpa.2016.11.022|pmid=28038349 }}

File:PLP mechanism.svg and cysteine, illustrating one biological role for aldimines.]]

• Enamine
• Schiff base
• Carboximidate
• Oxazolidine
• Other functional groups with a C=N double bond: oximes, hydrazones
• Other functional groups with a C N triple bond: nitriles, isonitriles

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Category:Functional groups