Imine

An imine (/ɪˈmiːn/ or /ˈɪmɪn/) is a functional group or chemical compound containing a carbon–nitrogen double bond. The nitrogen atom can be attached to a hydrogen (H) or an organic group (R). If this group is not a hydrogen atom, then the compound can sometimes be referred to as a Schiff base.[1] The carbon atom has two additional single bonds.[2][3][4] The term "imine" was coined in 1883 by the German chemist Albert Ladenburg.[5]

The general structure of an imine

Nomenclature and classification

Usually imines refer to compounds with the connectivity R2C=NR, as discussed below. In the older literature, imine refers to the aza analogue of an epoxide. Thus, ethyleneimine is the three-membered ring species C2H4NH.[6]

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. Imines exhibit diverse reactivity and are commonly encountered throughout chemistry.[4] 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 is called a primary aldimine; a secondary imine with such groups is called a secondary aldimine.[7] A primary imine in which C is attached to two hydrocarbyls is called a primary ketimine; a secondary imine with such groups is called a secondary ketimine.[8]

  • Primary aldimine
  • Secondary aldimine
  • Primary ketimine
  • Secondary ketimine
  • Aziridine and its derivatives are sometimes referred to as imines.

One way of naming aldimines is to take the name of the radical, remove final "e", and add "-imine", for example ethanimine. Alternately, an imine is named as a derivative of a carbonyl, adding the word "imine" to the name of a carbonyl compound whose oxo group is replaced by an imino group, for example sydnone imine and acetone imine (an intermediate in the synthesis of acetone azine).

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

An iminium cation is a related functional group in which the nitrogen has a fourth bond, giving it a positive charge.

Aldimine

An aldimine is an imine that is an analog of an aldehyde.[9] As such, aldimines have the general formula R–CH=N–R'. Aldimines are similar to ketimines, which are analogs of ketones.

An important subset of aldimines are the Schiff bases, in which the substituent on the nitrogen atom (R') is an alkyl or aryl group (i.e. not a hydrogen atom).[10]

Nomenclature CH3–CH2–CH2–CH=NH CH3–CH=N–CH3
1 butanimine N-methylethanimine
2 butylideneazane ethylidene(methyl)azane
3 butylideneamine N-methylethylideneamine
common usage butyraldehyde imine acetaldehyde N-methylimine

Aldimines may be named in three different manners:[11]

  1. by replacing the final -e of the parent hydride, R–CH3, with the suffix "-imine";
  2. as alkylidene derivatives of azane;
  3. (rare) as alkylidene derivatives of "amine".

An obsolete nomenclature treats aldimines as derivatives of a parent aldehyde.

Synthesis of imines
Imine synthesis from a primary amine and a carbonyl compound.

Imines are typically prepared by the condensation of primary amines and aldehydes and less commonly ketones. In terms of mechanism, such reactions proceed via the nucleophilic addition giving a hemiaminal -C(OH)(NHR)- 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 push the reaction in favor of imine formation. In recent years, several reagents such as Tris(2,2,2-trifluoroethyl)borate [B(OCH2CF3)3],[12] pyrrolidine[13] or titanium ethoxide [Ti(OEt)4][14] have been shown to catalyse imine formation.

More specialized methods

Several other methods exist for the synthesis of imines.

Imine reactions
Hexafluoroacetone imine is an unusual primary ketimine that is readily isolable.[16]

Imines are susceptible to hydrolysis to the corresponding amine and carbonyl compound.

Imines participate in many reactions that are analogous to the reactions of aldehydes and ketones:

Precursors to heterocycles

Unhindered imines tend to oligomerize. This behavior is common for imines derived from formaldehyde, such as CH3N=CH2, which trimerizes to the hexahydrotriazine.

Imines are widely used as intermediates in the synthesis of heterocycles. Aromatic imines reacts with an enol ether to a quinoline in the Povarov reaction. The C=N bond in imines is reactive toward cycloadditions. Imines react, thermally, with ketenes in [2+2] cycloadditions to form β-lactams in the Staudinger synthesis. An imine can be oxidized with meta-chloroperoxybenzoic acid (mCPBA) to give an oxaziridine

A tosylimine reacts with an α,β-unsaturated carbonyl compound to an allylic amine in the Aza-Baylis–Hillman reaction.

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

Acid-base reactions

Somewhat like the parent amines, imines are mildly basic and reversibly protonate to give iminium salts. Iminium derivatives are particularly susceptible to reduction to the amines using transfer hydrogenation or by the stoichiometric action of sodium cyanoborohydride. Since imines derived from unsymmetrical ketones are prochiral, their reduction is a useful method for the synthesis of chiral amines.

As ligands

Imines are common ligands in coordination chemistry. The condensation of salicylaldehyde and ethylenediamine give families of imine-containing chelating agents such as salen.

Imine reductions
Main article: Hydrogenation of carbon-nitrogen double bonds

An imine can be reduced to an amine via hydrogenation for example in a synthesis of m-tolylbenzylamine:[19]

Other reducing agents are lithium aluminium hydride and sodium borohydride.[20]

The first asymmetric imine reduction was reported in 1973 by Kagan using Ph(Me)C=NBn and PhSiH2 in a hydrosilylation with chiral ligand DIOP and rhodium catalyst (RhCl(CH2CH2)2)2.[21] Many systems have since been investigated.[22][23]

Biological role

Imines are common in nature. Vitamin B6 promotes the deamination of amino acids via the formation of imines, for example.

See also

References
  1. IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "Schiff base". doi:10.1351/goldbook.S05498
  2. IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "imines". doi:10.1351/goldbook.I02957
  3. March Jerry; (1985). Advanced Organic Chemistry reactions, mechanisms and structure (3rd ed.). New York: John Wiley & Sons, inc. ISBN 0-471-85472-7
  4. Fletcher, Dermer, Fox, Nomenclature of Organic Compounds (1974) doi:10.1021/ba-1974-0126.ch023
  5. Ladenburg, A. (1883) "Ueber die Imine" (About imines), Berichte der Deutschen Chemischen Gesellschaft, 16 : 1149–1152 ; see p. 1150. 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." (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.)
  6. C. F. H. Allen, F. W. Spangler, and E. R. Webster "Ethyleneimine" Org. Synth. 1950, volume 30, 38. doi:10.15227/orgsyn.030.0038.
  7. IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "aldimines". doi:10.1351/goldbook.A00209.html
  8. IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "ketimines". doi:10.1351/goldbook.K03381.html
  9. IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "aldimines". doi:10.1351/goldbook.A00209
  10. IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "Schiff bases (Schiff's bases)". doi:10.1351/goldbook.S05498
  11. Panico R, Powell WH, Richer JC, eds. (1993). "Recommendation R-5.4.3". A Guide to IUPAC Nomenclature of Organic Compounds. IUPAC/Blackwell Science. pp. 89–90. ISBN 0-632-03488-2.
  12. Reeves, Jonathan T.; Visco, Michael D.; Marsini, Maurice A.; Grinberg, Nelu; Busacca, Carl A.; Mattson, Anita E.; Senanayake, Chris H. (2015-05-15). "A General Method for Imine Formation Using B(OCH2CF3)3". Organic Letters. 17 (10): 2442–2445. doi:10.1021/acs.orglett.5b00949. ISSN 1523-7060. PMID 25906082.
  13. Morales, Sara; Guijarro, Fernando G.; García Ruano, José Luis; Cid, M. Belén (2014-01-22). "A General Aminocatalytic Method for the Synthesis of Aldimines". Journal of the American Chemical Society. 136 (3): 1082–1089. doi:10.1021/ja4111418. ISSN 0002-7863. PMID 24359453.
  14. Collados, Juan F.; Toledano, Estefanía; Guijarro, David; Yus, Miguel (2012-07-06). "Microwave-Assisted Solvent-Free Synthesis of Enantiomerically Pure N-(tert-Butylsulfinyl)imines". The Journal of Organic Chemistry. 77 (13): 5744–5750. doi:10.1021/jo300919x. ISSN 0022-3263. PMID 22694241.
  15. Mandler, Michael; Truong, Phong; Zavalij, Peter; Doyle, Michael (Jan 14, 2014). "Catalytic Conversion of Diazocarbonyl Compounds to Imines: Applications to the Synthesis of Tetrahydropyrimidines and β-Lactams". Organic Letters. 16 (3): 740–743. doi:10.1021/ol403427s. PMID 24423056.
  16. Middleton, W. J.; Carlson, H. D. (1970). "Hexafluoroacetone imine". Org. Syntheses. 50: 81–3. doi:10.15227/orgsyn.050.0081..
  17. Koos, Miroslav; Mosher, Harry S. (1993). "α-Amino-α-trifluoromethyl-phenylacetonitrile: A potential reagent for NMR determination of enantiomeric purity of acids". Tetrahedron. 49 (8): 1541–1546. doi:10.1016/S0040-4020(01)80341-0.
  18. Moureu, Charles; Mignonac, Georges (1920). "Les Cetimines". Annales de Chimie. 9 (13): 322–359. Retrieved 18 June 2014.
  19. C. F. H. Allen and James VanAllan (1955). "m-Tolylbenzylamine". Organic Syntheses: 827.; Collective Volume, 3
  20. For example: Ieva R. Politzer and A. I. Meyers (1988). "Aldehydes from 2-Benzyl-4,4,6-trimethyl-5,6-dihydro-1,3(4H)-oxazine: 1-Phenylcyclopentanecarboxaldehyde". Organic Syntheses.; Collective Volume, 6, p. 905
  21. Langlois, N (1973). "Synthese asymetrique d'amines par hydrosilylation d'imines catalysee par un complexe chiral du rhodium". Tetrahedron Lett. 14 (49): 4865–4868. doi:10.1016/S0040-4039(01)87358-5.
  22. Kobayashi, Shū; Ishitani, Haruro (1999). "Catalytic Enantioselective Addition to Imines". Chem. Rev. 99 (5): 1069. doi:10.1021/cr980414z..
  23. 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.
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