enolate

Examples of enolate in the following topics:

• Diastereoselection in Reactions with Chiral Enolates

  • Note that the enolate in equation 1 is racemic, whereas that in equation 2 is the S-enantiomer.
  • Three examples of reactions involving E-enolates are shown in the first diagram below.
  • The E- and Z-enolate reactants are both derived from the same syn-disubstituted ethyl ketone.
  • Both enolates react with excellent but complementary facial selectivity.
  • This is pronounced for the E- enolate, but very poor in the Z-isomer reaction.

• The Aldol Reaction

  • Techniques for generating the E and Z isomers of designated enolate species have been developed, and the diastereoselectivity of each in the aldol reaction established.
  • As a general rule for reactions involving cyclic transition states, E-enolates produce anti-aldols, and Z-enolates the syn-diastereomer, a tendency that reflects the facial selectivities of the transition states.
  • Thus the reaction of E-enolates with aldehydes proceeds preferentially by the re (or si) face of the carbonyl reactant bonding to the same prochiral face of the enolate.
  • Conversely, similar reactions of Z-enolates occur by preferential bonding of the re (or si) face of the aldehyde to the si (or re) face of the enolate.
  • The Mukaiyama aldol reaction of silyl enol ethers takes place by way of an open transition state, in which both enolate configurations are biased to bond to the opposite prochiral face of the aldehyde, giving syn-diastereomers as the major product.

• Irreversible Substitution Reactions

  • Modestly electrophilic reactants such as alkyl halides are not sufficiently reactive to combine with neutral enol tautomers, but the increased nucleophilicity of the enolate anion conjugate base permits such reactions to take place.
  • Ether solvents like tetrahydrofuran (THF) are commonly used for enolate anion formation.
  • Because of its solubility in THF, LDA is a widely used base for enolate anion formation.
  • Characteristics that influence direct substitution of enolate anions to C or O 2
  • examples of electrophilic substitution at both carbon and oxygen for the enolate anion

• Mechanism of Electrophilic α-Substitution

  • (ii) The carbon-carbon double bond of an enol is planar, so any chirality that existed at the α carbon is lost on enolization.
  • If chiral products are obtained from enol intermediates they will necessarily be racemic.
  • Reactions that involve enol reactants will therefore be limited in rate by the enol concentration.
  • These catalysts will therefore catalyze reactions proceeding via enol intermediates.
  • These are the enol tautomer itself and its conjugate base (common with that of the keto tautomer), usually referred to as an enolate anion.

• Reactions at the α-Carbon

  • These reactions, which included halogenation, isotope exchange and the aldol reaction, take place by way of enol tautomer or enolate anion intermediates, a characteristic that requires at least one hydrogen on the α-carbon atom.
  • Formulas for the corresponding enol and enolate anion species that may be generated from these derivatives are drawn in the following diagram.
  • This may reflect the smaller equilibrium enol concentrations found in these carboxylic acid derivatives.
  • Acyl halides and anhydrides are more easily halogenated than esters and nitriles, probably because of their higher enol concentration.
  • The enol concentration of malonic acid (about 0.01%) is roughly ten thousand times greater than that of acetic acid.

• Enolate Intermediates

  • Many of the most useful alpha-substitution reactions of ketones proceeded by way of enolate anion conjugate bases.
  • Since simple ketones are weaker acids than water, their enolate anions are necessarily prepared by reaction with exceptionally strong bases in non-hydroxylic solvents.
  • Esters and nitriles are even weaker alpha-carbon acids than ketones (by over ten thousand times), nevertheless their enolate anions may be prepared and used in a similar fashion.
  • The presence of additional activating carbonyl functions increases the acidity of the alpha-hydrogens substantially, so that less stringent conditions may be used for enolate anion formation.
  • To illustrate the general nucleophilic reactivity of di-activated enolate anions, two examples of SN2 alkylation reactions are shown below.

• Enantioselective Aldol Reactions

  • In this example the re-face of the enolate bonds to the si-face of the aldehyde.
  • The change in selectivity relative to the siloxy substituent is due to its chelation effect in the lithium enolate and non-chelated polar effect in the boron enolate.
  • As a result, the bulky t-butyl group serves to direct bonding from the re-face of the enolate to the si-face of the carbonyl group in the lithium enolate, but changes the facial selectivity of both reactants in the enol borinate.
  • Pure E-enolates are more difficult to generate, and the discovery that the magnesium salt from reaction of 2,2,6,6-tetramethylpiperidine with ethylmagnesium bromide enolized the starting ketone selectively in this manner was crucial.
  • Alternative routes to E-enolate intermediates are possible.

• 1:3-Diastereoselection in Reactions with Chiral Aldehydes

  • First, these are all Mukaiyama aldol reactions of silyl enol ethers.
  • The R = tert-butyl enolate forms the 1,2-syn,1,3-anti-diastereomer C with high selectivity, but the R = methyl enolate is much less selective and actually favors the 1,2-anti,1,3-anti-diastereomer D when P = PMB.
  • It is interesting to see what happens to the selectivity described here when E and Z-enolate donors replace the methyl ketone enolates used above.
  • In all but the last Z-enolate reaction Felkin-Ahn facial selectivity dominates, with β:γ being syn in products A through D.
  • Reactions of aldehydes I and II with comparable E-enolborinates and Z-chlorotitanium enolates

• Supporting and Conflicting Substituent Effects

  • These include the nature of the reaction (cyclic or open transition state), the configuration of the enolate donor (E or Z), the presence of stereogenic centers α to the carbonyl acceptor and/or the enolate donor, as well as a β-polar substituent on the aldehyde.
  • The second diagram below shows corresponding reactions of the Z-titanium chloride enolate.
  • All the reactions of the E-enolate give anti-aldol products (light blue asterisks).
  • Thus Felkin-Ahn selectivity in which the re-face of the enolate bonds to the si-face of the carbonyl predominates.
  • Most of the Z-enolate reactions shown in the second diagram above give syn-aldol products, as expected (light blue asterisks).

• Aldehydes and Ketones

  • Ketones have alpha-hydrogens which participate in keto-enol tautomerism.
  • In the presence of a strong base, enolate formation and subsequent deprotonation of the enolate will occur.
  • Like ketones, aldehydes are sp2 hybridized and can exist in the keto or enol tautomer.
  • Both aldehydes and ketones exist in an equilibrium with their enol forms; the enol form is defined as an alkene with a hydroxyl group affixed to one of the carbon atoms composing the double bond.
  • However, the enol form is important for some reactions because the deprotonated enolate form is a strong nucleophile.