Imine

The general structure of an imine

An imine (/ᵻˈmiːn/ 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]

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.^[5]

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.^[6] 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 .^[7]

• 
  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. See the aldimine article for other naming conventions. 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.

Synthesis of imines

Imines are typically prepared by the condensation of primary amines and aldehydes and less commonly ketones:

RNH₂ + R'C(O)R → RN=C(R')(R) + H₂O

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],^[8] pyrrolidine^[9] or Titanium Ethoxide [Ti(OEt)₄]^[10] have been shown to catalyse imine formation.

More specialized methods

Several other methods exist for the synthesis of imines.

• Reaction of organic azides with metal carbenoids (produced from diazocarbonyl compounds).^[11]
• Condensation of carbon acids with nitroso compounds.
• The rearrangement of trityl N-haloamines in the Stieglitz rearrangement.
• Dehydration of hemiaminals.^[12]
• 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.
• Primary ketimines can be synthesized via a Grignard reaction with a nitrile.^[13][14]

Imine reactions

The most important reactions of imines are their hydrolysis to the corresponding amine and carbonyl compound. Otherwise this functional group participates in many other reactions, many of which are analogous to the reactions of aldehydes and ketones.

• An imine is reduced in reductive amination.
• An imine reacts with an amine to an aminal, see for example the synthesis of cucurbituril.
• An imine reacts with dienes in the Aza Diels-Alder reaction to a tetrahydropyridine.
• An imine can be oxidized with meta-chloroperoxybenzoic acid (mCPBA) to give an oxaziridine
• An aromatic imine reacts with an enol ether to a quinoline in the Povarov reaction.
• 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.
• Imines react, thermally, with ketenes in [2+2] cycloadditions to form β-lactams in the Staudinger synthesis.

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

An imine can be reduced to an amine via hydrogenation for example in a synthesis of m-tolylbenzylamine:^[15]

Other reducing agents are lithium aluminium hydride and sodium borohydride.^[16]

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.^[17] Many systems have since been investigated.^[18][19]

Biological role

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

See also

• Enamine
• Schiff base
• Carboximidate
• Oxime
• Other functional groups with a CN double bond: oximes, hydrazones
• Other functional groups with a CN triple bond: nitriles, isonitriles

References

1. IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "Schiff base".
2. IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "imines".
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. C. F. H. Allen, F. W. Spangler, and E. R. Webster "Ethyleneimine" Org. Synth. 1950, volume 30, 38. doi:10.15227/orgsyn.030.0038.
6. IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "aldimines".
7. IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "ketimines".
8. 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.
9. 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.
10. 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.
11. 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: 740–743. doi:10.1021/ol403427s.
12. W. J. Middleton and H. D. Carlson (1988). "Hexafluoroacetone imine". Org. Synth.; Coll. Vol., 6, p. 664.
13. 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.
14. Moureu, Charles; Mignonac, Georges (1920). "Les Cetimines". Annales de chimie. 9 (13): 322–359. Retrieved 18 June 2014.
15. C. F. H. Allen and James VanAllan (1955). "m-Tolylbenzylamine". Org. Synth.: 827.; Coll. Vol., 3
16. 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". Org. Synth.; Coll. Vol., 6, p. 905
17. Langlois, N (1973). "Synthese asymetrique d'amines par hydrosilylation d'imines catalysee par un complexe chiral du rhodium". Tet. Lett. 14 (49): 4865. doi:10.1016/S0040-4039(01)87358-5.
18. Kobayashi, Shū; Ishitani, Haruro (1999). "Catalytic Enantioselective Addition to Imines". Chem. Rev. 99 (5): 1069. doi:10.1021/cr980414z..
19. 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.