Enolates

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An enolate is the anion of the enol form of a carbonyl compound . Enolates are formed by the deprotonation of a CH-acidic hydrogen in the α-position to the carbonyl function . Two boundary structures can be formulated, so enolates are ambident anions . Enolates are good nucleophiles that react with soft electrophiles (especially carbon electrophiles) preferentially at the α-position.

generation

Deprotonation of a carbonyl compound with strong bases . Hydroxides or alcoholates are sufficient for incomplete deprotonation in equilibrium (pK a of ketones is approx. 20, of esters approx. 25). With stronger bases, complete deprotonation is achieved. Lithium diisopropylamide (LDA), but also lithium hexamethyl disilazide (LHMDS), potassium hexamethyl disilazide (KHMDS) or lithium tetramethyl piperidide (LTMP) are used most frequently for this purpose . However, the bases used must not themselves be nucleophilic, since otherwise they attack the carbonyl compound on the electrophilic carbonyl carbon and do not deprotonate. Therefore, for example, lithium alkyl compounds such as butyllithium are not suitable.

Enolate1.svg

structure

Regioselectivity

In the case of asymmetric ketones , two regioisomers are often conceivable, which arise during the deprotonation .

Under kinetic control (strong bases such as LDA , low temperatures), the sterically more accessible proton is preferably removed; the less substituted enolate double bond is created (kinetic enolate, 1 ).

Enolate2.svg

Under thermodynamic control (weak base, higher temperature), however, deprotonation is preferred at the point where the more highly substituted double bond can arise with electrophiles (thermodynamic enolate, 2 ).

Enolate Acidity Control.png

The figure above shows another example of thermodynamic control of enolate formation. The more stable product is the more highly substituted enolate. The acidity of the hydrogen substituents is indicated here by different colors, since sodium ethanolate is a relatively weak base, more acidic hydrogen substituents are preferably abstracted. The orange-colored hydrogen substituents have a pk a value of approx. 20, the red-colored hydrogen substituents have a pk a value of approx. 12.

Regioselectivity of the formation of enolates from ketones:

Thermodynamic enolates Kinetic enolates
are more heavily substituted are less heavily substituted
are more stable are less stable
are favored by a higher concentration of the ketone, high temperatures and long reaction times are favored by strong, sterically hindered bases (e.g. LDA), low temperatures and short reaction times.

Stereoselectivity

The geometry of the enolate double bond (if R> methyl) is determined by the size of the substituent R ′. There are two ways of doing this: ( O ) - ( Z ) -enolates and ( O ) - ( E ) -enolates. The addition ( O ) in front of the E / Z indication is intended to make it clear that only the relative configuration between the enolate oxygen and the substituent of the enolate double bond is considered, which does not have to agree with the IUPAC nomenclature for double bonds. Large substituents R ′ prefer the ( O ) - ( Z ) -enolate, small substituents the ( O ) - ( E ) -enolate. Tertiary alkyl substituents and –NR 2 are suitable as large substituents . Small substituents include primary alkyl substituents as well as –OR and –SR.

Enolate3.svg     ( O ) - ( Z ) -enolate, R ′ = tertiary alkyl, –NR 2
Enolate4.svg     ( O ) - ( E ) -enolate, R ′ = primarily alkyl, -OR, -SR

In organic synthesis, chiral auxiliaries are used for stereoselective reaction management and the like. a. used by enolates.

The Ireland model

The stereoselectivity of enolate formation can be explained sufficiently well by the Ireland model.

The stereoselective formation of enolates according to the Ireland model.

In the Ireland model, deprotonation is described as a six-membered transition state. The larger of the two substituents of the electrophile (in the upper case the methyl group is larger than the hydrogen substituent) prefers the equatorial alignment in the transition state in order to avoid energetically unfavorable interactions with the substituents of the base. The ( E ) -enolate is therefore preferred here.

The model fails at many points (e.g. when the solvent is changed from THF to 23% HMPA-THF), but it offers a good opportunity to estimate the stereoselectivity.

Reactions

As good nucleophiles , enolates can be reacted with a large number of electrophiles . Possible electrophiles include alkyl halides ( alkylation ), carboxylic acid chlorides ( acylation ), carbonyl compounds ( aldol reaction ), Michael acceptors , epoxides , vinyl and aryl halides. All of these electrophiles only attack the carbon atom of the enolate. An attack on the enolate oxygen is rare and only occurs through hard electrophiles ( HSAB principle ) such as silyl chlorides or sulfonic acid derivatives .

Enolate5.svg

literature

  • Reinhard Brückner: reaction mechanisms . 3rd edition, Spektrum Akademischer Verlag, Munich 2004, pp. 516 ff., ISBN 3-8274-1579-9 .

Individual evidence

  1. a b c Jonathan Clayden, Nich Greeves, Stuart Warren: Organic Chemistry . 2nd Edition. Springer Spectrum, Berlin / Heidelberg 2013, ISBN 978-3-642-34715-3 , p. 659 ff .