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Enolate

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Resonance structures of an enolate anion.

In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl (RR'C=O) compounds. Rarely isolated, they are widely used as reagents in the synthesis of organic compounds.[1][2][3][4]

Bonding and structure

Molecular orbitals of an enolate, showing the occupancy corresponding to the anion.
Molecular orbitals of an enolate, showing the occupancy corresponding to the anion.

Enolate anions are electronically related to allyl anions. The anionic charge is delocalized over the oxygen and the two carbon sites. Thus they have the character of both an alkoxide and a carbanion.[5]

Although they are often drawn as being simple salts, in fact they adopt complicated structures often featuring aggregates.[6]

Structure of the lithium enolate PhC(OLi)=CMe2(tmeda) dimer. H atoms omitted on the diamine.[7]

Preparation

Deprotonation of enolizable ketones, aromatic alcohols, aldehydes, and esters gives enolates.[8][9] With strong bases, the deprotonation is quantitative. Typically enolates are generated from using lithium diisopropylamide (LDA).[10]

Often, as in conventional Claisen condensations, Mannich reactions, and aldol condensations, enolates are generated in low concentrations with alkoxide bases. Under such conditions, they exist in low concentrations, but they still undergo reactions with electrophiles. Many factors affect the behavior of enolates, especially the solvent, additives (e.g. diamines), and the countercation (Li+ vs Na+, etc.). For unsymmetrical ketones, methods exist to control the regiochemistry of the deprotonation.[11]

Deprotonation using LDA.[12]

The deprotonation of carbon acids can proceed with either kinetic or thermodynamic reaction control. For example, in the case of phenylacetone, deprotonation can produce two different enolates. LDA has been shown to deprotonate the methyl group, which is the kinetic course of the deprotonation. To ensure the production of the kinetic product, a slight excess (1.1 equiv) of lithium diisopropylamide is used, and the ketone is added to the base at −78 °C. Because the ketone is quickly and quantitatively converted to the enolate and base is present in excess at all times, the ketone is unable to act as a proton shuttle to catalyze the gradual formation of the thermodynamic product. A weaker base such as an alkoxide, which reversibly deprotonates the substrate, affords the more thermodynamically stable benzylic enolate.

Enolates can be trapped by acylation and silylation, which occur at oxygen. Silyl enol ethers are common reagents in organic synthesis as illustrated by the Mukaiyama aldol reaction:[13]

vereinfachte Übersicht mit einem Stereozentrum
vereinfachte Übersicht mit einem Stereozentrum

Reactions

As powerful nucleophiles, enolates react readily with a variety of electrophiles. These reactions generate new C-C bonds and often new stereocenters. The stereoselectivity and regioselectivity is influenced by additives, solvent, counterions, etc. One important class of electrophiles are alkyl halides, and in this case a classic problem arises: O-alkylation vs C-alkylation. Controlling this selectivity has drawn much attention. The negative charge in enolates is concentrated on the oxygen, but that center is also highly solvated, which leads to C-alkylation.[14]


Other important electrophiles are aldehydes/ketones and Michael acceptors. [15]

Sample aldol reaction with lithium enolate
Sample aldol reaction with lithium enolate

Aza enolates

Aza enolates (also known as imine anions, enamides, metallated Schiff bases, and metalloenamines) are nitrogen analogous to enolates.[16] When imines get treated with strong bases such as LDA, highly nucleophilic aza enolates are generated.

Formation of Aza enolate With LDA by deprotonation of the alpha-carbon hydrogen and the creation of an alpha-beta unsaturated bond

The major benefit of using aza enolates is that they don't undergo self-condensation (i.e. aldol reaction for aldehydes) in a basic or neutral solution, but rather they favor alkylation on the alpha-carbon.[17] This is mainly because imines contain carbon-nitrogen double bonds unlike aldehydes, which contain oxygen-carbon double bonds. Since oxygen is more electronegative than nitrogen, it withdraws more electron density from the carbonyl carbon, inducing a greater partially positive charge on the carbon. Therefore, with more electrophilic carbon, aldehydes allow for better nucleophilic addition to the carbon on the carbon-oxygen double bond.

On the other hand, imine has less electronegative nitrogen which induces a weaker partially positive charge on the carbonyl-carbon. As a result, while imines can still react with organolithiums, they don't react with other nucleophiles (including aza enolates) to undergo nucleophilic additions.[18]

Instead, aza enolates react similarly to enolates, forming SN2 alkylated products.[17] Through nitrogen lone pair conjugation, β-carbon becomes a nucleophilic site, permitting aza enolates to undergo alkylation reactions.[19] Thus, aza enolates can react with numerous electrophiles like epoxides and alkyl halides to form a new carbon-carbon bond on β-carbon.[16]

Two potential reaction mechanisms are shown below:

Alkylation of aza enolates via epoxide ring opening of oxetane [20]

Since epoxide is a three-membered ring molecule, it has a high degree of ring strain. Although the carbons in the ring system are tetrahedral, preferring 109.5 degrees between each atom, epoxide strains the ring angles into 60 degrees. To counter this effect, the nucleophilic aza enolates easily react with epoxides to reduce their ring strains.

Alkylation of aza enolates via allyl halide to generate Oulema melanopus [21]

Besides reacting with epoxides, aza enolates can also react with alkyl halides (or allyl halides as depicted above) to form a new carbon-carbon sigma bond. This reaction is one of the key steps in the synthesis of the male aggression pheromone, Oulema melanopus.[21] Aza enolate is generated by LDA reacting with pivaldehyde, which then reacts with an alkyl halide to form an Oulema melanopus intermediate.

Aza enolates can also be formed with Grignard reagents and react with other soft electrophiles, including Michael receptors.[16]

See also

References

  1. ^ Stolz, Daniel; Kazmaier, Uli (2010). "Metal Enolates as Synthons in Organic Chemistry". PATai's Chemistry of Functional Groups. doi:10.1002/9780470682531.pat0423. ISBN 9780470682531.
  2. ^ Hart, David J.; Ha, Deok Chan (1989). "The ester enolate-imine condensation route to .beta.-lactams". Chemical Reviews. 89 (7): 1447–1465. doi:10.1021/cr00097a003.
  3. ^ Wu, George; Huang, Mingsheng (2006). "Organolithium Reagents in Pharmaceutical Asymmetric Processes". Chemical Reviews. 106 (7): 2596–2616. doi:10.1021/cr040694k. PMID 16836294.
  4. ^ Curti, Claudio; Battistini, Lucia; Sartori, Andrea; Zanardi, Franca (2020). "New Developments of the Principle of Vinylogy as Applied to π-Extended Enolate-Type Donor Systems". Chemical Reviews. 120 (5): 2448–2612. doi:10.1021/acs.chemrev.9b00481. PMC 7993750. PMID 32040305.
  5. ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) "Enolates". doi:10.1351/goldbook.E02123
  6. ^ Reich, Hans J. (2013). "Role of Organolithium Aggregates and Mixed Aggregates in Organolithium Mechanisms". Chemical Reviews. 113 (9): 7130–7178. doi:10.1021/cr400187u. PMID 23941648.
  7. ^ Nichols, Michael A.; Leposa, Christina M.; Hunter, Allen D.; Zeller, Matthias (2007). "Crystal Structures of Hexameric and Dimeric Complexes of Lithioisobutyrophenone". Journal of Chemical Crystallography. 37 (12): 825–829. doi:10.1007/s10870-007-9255-0. S2CID 97183362.
  8. ^ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, ISBN 978-0-471-72091-1
  9. ^ Manfred Braun (2015). Modern Enolate Chemistry: From Preparation to Applications in Asymmetric Synthesis. Wiley‐VCH. doi:10.1002/9783527671069. ISBN 9783527671069.
  10. ^ "Synthesis of Β-lactones By Aldolization of Ketones with Phenyl Ester Enolates: 3,3-Dimethyl-1-oxaspiro[3.5]nonan-2-one". Org. Synth. 75: 116. 1998. doi:10.15227/orgsyn.075.0116. {{cite journal}}: Unknown parameter |authors= ignored (help)
  11. ^ "The Formation and Alkylation of Specific Enolate Anions from an Unsymmetrical Ketone: 2-Benzyl-2-methylcyclohexanone and 2-Benzyl-6-methylcyclohexanone". Org. Synth. 52: 39. 1972. doi:10.15227/orgsyn.052.0039. {{cite journal}}: Unknown parameter |authors= ignored (help)
  12. ^ Kong, Jianshe; Meng, Tao; Ting, Pauline and Wong, Jesse (2010). "Preparation of Ethyl 1-Benzyl-4-Fluoropiperidine-4-Carboxylate". Organic Syntheses. 87: 137. doi:10.15227/orgsyn.087.0137.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Mukaiyama, Teruaki; Kobayashi, Shū (1994). "Tin(II) Enolates in the Aldol, Michael, and Related Reactions". Organic Reactions. pp. 1–103. doi:10.1002/0471264180.or046.01. ISBN 0471264180.
  14. ^ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, p. 551, ISBN 978-0-471-72091-1
  15. ^ Seebach, Dieter (1988). "Structure and Reactivity of Lithium Enolates. From Pinacolone to SelectiveC-Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures". Angewandte Chemie International Edition in English. 27 (12): 1624–1654. doi:10.1002/anie.198816241.
  16. ^ a b c Aslam, O. (28 September 2012). Development of catalytic aza enolate reactions (Doctoral). UCL (University College London).
  17. ^ a b Clayden, Jonathan (2012). Organic chemistry (2nd ed.). Oxford: Oxford University Press. pp. 465, 593–594. ISBN 9780199270293.
  18. ^ Cranwell, Philippa. "Enamines/aza-enolates – Mechanism Mordor". sites.google.com. Archived from the original on 2021-09-03. Retrieved 2020-11-28.
  19. ^ Carey, Francis A. (2007). Advanced organic chemistry. Part B, Reactions and synthesis (5th ed.). New York, NY: Springer. pp. 46–47. ISBN 978-0-387-68350-8.
  20. ^ Hudrlik, Paul F.; Wan, Chung-Nan (October 1975). "Reactions of oxetane with imine salts derived from cyclohexanone". The Journal of Organic Chemistry. 40 (20): 2963–2965. doi:10.1021/jo00908a027.
  21. ^ a b Chevalley, Alice; Férézou, Jean-Pierre (2012). "One-pot formation of aza-enolates from secondary amines and condensation to esters and alkyl bromides". Tetrahedron. 68 (29): 5882–5889. doi:10.1016/j.tet.2012.04.105.
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