Reactions of enamines and enolates

An enamine is an unsaturated compound derived by the reaction of an aldehyde or ketone with a secondary amine followed by loss of H2O.
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).

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This article is about a class of chemical compounds. For the chemical company, see Enamine Ltd.
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.[1][2] Enamines are versatile intermediates.[3][4]

Condensation to give an enamine.[5]

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 considered to be nitrogen analogs of enols.[6]

If one of the nitrogen substituents is a hydrogen atom, H, it is the tautomeric 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.

EnamineResStructures.png

Contents

  • 1 Reactions with Enamines
  • 2 Enamine Reactivity
  • 3 Enamine Transition States
  • 4 See also
  • 5 References

Reactions with Enamines

Enamine Formation Enamines are labile and therefore chemically useful moieties which can be easily produced from commercially available starting reagents. A common route for enamine production is via an acid-catalyzed nucleophilic reaction of ketone or aldehyde species containing an α-hydrogen with secondary amines. Primary amines are usually not used for enamine synthesis due to the preferential formation of the more thermodynamically stable imine species.[7] An example of this reaction, proceeding through a carbinolamine intermediate, is as follows:

Enamine Alkylation Even though enamines are more nucleophilic than their enol counterparts, they can still react selectively, in particular 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. 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.[8]

Enamine Acylation 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.[9]

Enamine Reactivity

Enamines act as nucleophiles that require less acid/base activation for reactivity than their enolate counterparts. They have also been shown to offer a greater selectivity with less side reactions. There is a gradient of reactivity among different enamine types, with a greater reactivity offered by ketone enamines than their aldehyde counterparts. Cyclic ketone enamines follow a trend of reactivity where the five membered ring is the most reactive with 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.[10] 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.[11]

Enamine Transition States

Proline Catalyzed Aldol Reactions Proline-catalyzed aldol additions undergo a six-membered enamine transition state according to the Zimmerman-Traxler model. Addition of 20-30 mol% proline to acetone or hydroxyacetone catalyzes their addition to a diverse set of aldehydes with high (>99%) enantioselectivity yielding syn-diol products.[12] [13] [14]

See also

  • Thorpe reaction

References

  1. ^ Clayden, Jonathan (2001). Organic chemistry. Oxford, Oxfordshire: Oxford University Press. ISBN 0-19-850346-6. 
  2. ^ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, ISBN 0-471-72091-7 
  3. ^ Enamines: Synthesis: Structure, and Reactions, Second Edition, Gilbert Cook (Editor). 1988, Marcel Dekker, NY. ISBN 0-8247-7764-6
  4. ^ R. B. Woodward, I. J. Pachter, and M. L. Scheinbaum (1974), 2,2- (Trimethylenedithio)cyclohexanone, Org. Synth. 54: 39 ; Coll. Vol. 5: 1014 
  5. ^ R. D. Burpitt and J. G. Thweatt (1968), Cyclodecanone, Org. Synth. 48: 56 ; Coll. Vol. 5: 277 
  6. ^ Imines and Enamines | PharmaXChange.info
  7. ^ Farmer, Steven. "Enamine Reactions". http://chemwiki.ucdavis.edu/Organic_Chemistry/Reactivity_of_Alpha_Hydrogens/Enamine_Reactions. UC Davis Chem Wiki. 
  8. ^ Wade, L.G. (1999). Organic Chemistry. Saddle River, NJ: Prentice Hall. p. 1019. 
  9. ^ Farmer, Steven. "Enamine Reactions". http://chemwiki.ucdavis.edu/Organic_Chemistry/Reactivity_of_Alpha_Hydrogens/Enamine_Reactions. UC Davis Chem Wiki. 
  10. ^ Mayr, H. (2003). "Structure-Nucleophilicity Relationships for Enamines". Chem Eur. J. 9: 2209. 
  11. ^ Lockner, James. "Stoichiometric Enamine Chemistry". Baran Group, The Scripps Research Institute. Retrieved 26 November 2014. 
  12. ^ Garcia, Jesus; Oiarbide, Mikel; Palomo, Claudio (15 July 2005). "Current Progress in the asymmetric aldol addition reaction". Chem. Soc. Rev. 33: 65–75. 
  13. ^ Notz, W; List, B. (2000). Journal of the American Chemical Society 122: 2395. 
  14. ^ Sakthivel, K.; Notz, W; Bui, T; Barbas, C (2000). Journal of the American Chemical Society 122: 5260. 

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