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5.5: Alkylation of Enolate Ions

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    Alkylation of Enolates

    Enolates can be alkylated in the alpha position through an SN2 reaction with alkyl halides. During this reaction an α-hydrogen is replaced with an alkyl group and a new C-C bond is formed. The limitations of SN2 reactions still apply. This includes preferring a good primary or secondary leaving group, X = chloride, bromide, iodide, tosylate. Tertiary leaving groups cannot be used in this reaction and typically give undesired E2 elimination products. A very strong base, such as LDA, is often used because of its ability to form the enolate completely. Removal of the carbonyl starting material from the reaction mixture makes it unavailable for nucleophilic addition by the enolate. Aldehydes are usually not directly alkylated because their enolates prefer to undergo the carbonyl condensation reactions discussed later. In addition, the acidic hydrogen on carboxylic acids inhibits the formation of an enolate, and makes their direct alkylation difficult. Esters, including lactones, and symmetrical ketones readily undergo direct alkylation. However, direct alkylations, like all enolate-based reactions, can form a racemic mixture if the alkylated α-carbon produced is chiral.

    General Reaction

    General Reaction Enolate Alkylation.svg


    1) Enolate formation

    Mechanism Enolate Alkylation Step 1.svg

    2) SN2 attack

    Mechanism Enolate Alkylation Step 2.svg


    Example Enolate Alkylation A.svg

    Example Enolate Alkylation B.svg

    Example Enolate Alkylation C.svg

    When an unsymmetrical ketone with two sets of non-equivalent α-hydrogens is treated with a base, two possible enolates can form. Regioselective enolate formation is possible under the proper conditions. The main determinant is whether the reaction is under kinetic control (rate) or thermodynamic control (equilibrium). Although a predominant product can be produced, a mixture of products is usually formed causing a reduction in product yield.

    Thermodynamic & Kinetic Enolate.svg

    Thermodynamic Enolates

    The thermodynamic enolate is formed when the more substituted α-hydrogen is removed. This leads to the more alkyl substituted, therefore the more stable, enolate to be formed. The presence of additional alkyl groups causes the formation of the thermodynamic enolate to be sterically hindered and kinetically slow, especially when a bulky base like LDA is used. Thermodynamic enolates are favored by conditions which allow for equilibration between the possible enolates. When the ketone starting material is not completely deprotonated, equilibrium between the possible enolates and the α-hydrogens of the ketone can occur. During equilibrium, interconversion between the enolates allows the lower energy of the thermodynamic enolate to dominate. Other conditions can also promote the formation of the thermodynamic enolate, such as higher reaction temperatures, or the use of a smaller less sterically hindered base such as sodium hydride (NaH). Weaker bases, such as sodium ethoxide, do not completely deprotonate the ketone starting material which also allows for enolate equilibrium to occur.

    Example of enolate equilibration

    Enolate Equilibrium.svg

    Thermodynamic Enolate.svg

    Kinetic Enolates

    Kinetic enolates are favored under conditions which do not allow for equilibration between the enolates, such as the use of a strong bulky base, like LDA, in a molar equivalent to the ketone starting material. Kinetic enolates are formed when the less substituted α-hydrogen is deprotonated. Being less sterically hindered allows this α-hydrogen to be deprotonated faster even though it forms a less thermodynamically stable enolate. Using a molar equivalent of LDA completely converts the ketone starting material to an enolate, removing it from the reaction mixture and preventing equilibration between the possible enolates. Low reaction temperatures (-78 oC) prevent enolate equilibration and promote the formation of the kinetic enolate.

    Kinetic Enolate.svg

    When and enolate of an asymmetric ketone is stabilized through additional resonance forms there is no competition between possible enolates despite kinetic or thermodynamics conditions. The resonance stabilized enolate will be preferentially alkylated to the point that formation of the alkylated products of other possible enolates will be minimal.


    Example Phenylpropanone.svg

    Malonic Ester Synthesis

    The malonic ester synthesis is a series of reactions which converts an alkyl halide to a carboxylic acid with two additional carbons. One important use of this synthesis pathway is that it allows for the creation of α-alkylated carboxylic acids which cannot be created by direct alkylation.

    The starting material of this reaction is a malonic ester: a diester derivative of malonic acid. Diethyl propanedioate, also known as diethyl malonate, is the malonic ester most commonly used in pathway. Since it is a 1,3-dicarbonyl compound, diethyl malonate has relatively acidic α-hydrogens (pKa = 12.6) and can be transformed to its enolate using sodium ethoxide as a base. Other alkoxide bases are not typically used given the possibility of a transesterification reaction.

    Example Malonic Ester.svg

    General Reaction

    General Reaction Malonic Ester.svg

    Predicting the Product of a Malonic Ester Synthesis

    The product of a Malonic Ester Synthesis can be created by simply replacing the halogen on the alkyl halide with a -CH2CO2H group.

    Malonic Ester Summary.svg

    Malonic ester synthesis takes place in four steps:

    1) Enolate Formation

    Reacting diethyl malonate with sodium ethoxide (NaOEt) forms a resonance-stabilized enolate.

    2) Alkylation

    The enolate is alkylated via an SN2 reaction to form an monoalkylmalonic ester.

    Mechanism Malonic Ester Step 2.svg

    3) Ester hydrolysis and protonation

    After alkylation, the diester undergoes hydrolysis with sodium hydroxide to form a dicarboxylate. Subsequent protonation with acid forms a monoalkyl malonic acid.

    Mechanism Malonic Ester Step 3.svg

    4) Decarboxylation & Tautomerization

    Monoalkyl malonic acids decarboxylate when heated, forming an α-alkyl carboxylic acid and carbon dioxide (CO2). Decarboxylation can only occur in compounds with a second carbonyl group two atoms away from carboxylic acid such as in malonic acids and β-keto acids. The mechanism occurs via a concerted mechanism involving a proton transfer between the carboxyl acid hydrogen and the nearby carbonyl group to form the enol of a carboxylic acid and CO2. The enol undergoes tautomerization to form the carboxylic acid.

    Mechanism Malonic Ester Step 4.svg


    Example Malonic Ester Synthesis.svg


    The presence of two α-hydrogens in malonic esters allows for a second alkylation to be performed prior to decarboxylation. This leads to dialkylated carboxylic acids. Due to the lack of stereochemical control inherent in enolate based reactions, if the two added alkyl groups are different, a racemic mixture of products will result.


    Example Dialkyation.svg

    In a variation of the dialkylation reaction - if one molar equivalent of malonic ester is reacted with one molar equivalent of a dihaloalkane and two molar equivalents of sodium ethoxide, a cyclization reaction occurs. By changing the dihaloalkane, three, four, five, and six-membered rings can be created.

    Example Ring Formaiton.svg

    The Acetoacetic Ester Synthesis

    The acetoacetic ester synthesis is a series of reactions which converts alkyl halides into a methyl ketone with three additional carbons. This reaction creates an α-substituted methyl ketone without side-products. The starting reagent for this pathway is ethyl 3-oxobutanoate, also called ethyl acetoacetate, or acetoacetic ester. Like other 1,3-dicarbonyl compounds, ethyl acetoacetate is more acidic than ordinary esters being almost completely converted to an enolate by sodium ethoxide.

    General Reaction

    General Reaction Acetoester.svg

    Predicting the Product of an Acetoacetic Ester Synthesis

    The product of a acetoacetic ester synthesis can be created by replacing halogen on the alkyl halide with a -CH2COCH3 group.

    Acetoacetic Ester Summary.svg

    Reaction Steps

    1) Formation of the enolate

    As previously described, the α-hydrogens of acetoacetic ester are rather acidic (pKa = 10.7) allowing the enolate to be easily formed when sodium ethoxide is used as a base.

    Mechanism Acetoester Step 1.svg

    2) Alkylation via an SN2 Reaction

    Subsequent reaction with an alkyl halide produces a monoalkylacetoacetic ester.

    Mechanism Acetoester Step 2.svg

    3) Ester hydrolysis and decarboxylation

    Hydrolysis with NaOH followed by protonation produces an alkylated beta-ketoacid. β-ketoacids are easily decoboxylated to form an α-alkyl substituted methyl ketone and carbon dioxide (CO2) using a similar mechanism as the malonic ester synthesis.

    Mechanism Acetoester Step 3.svg


    Example Acetoester Synthesis.svg

    Much like the malonic ester synthesis, a second alkyl group can added before the decarboxylation step.

    Example Dialkyation Acetoester.svg

    The reaction steps of the acetoacetic ester synthesis can also be applied to other β-keto esters with acidic α-hydrogens. Because the α-hydrogens between the two carbonyls are the most acidic, they are preferentially deprotonated allowing for a single enolate to be formed. Even cyclic beta-keto esters can be alkylated and subsequently decarboxylated to give an α-alkylated cyclic ketone.


    Example Cyclopentanone.svg

    Direct Alkylation of Nitriles

    The presence of acidic α-hydrogens in nitriles gives them the ability to form an enolate equivalent which can be also be directly alkylated.

    General Reaction

    General Reaction Nitrile Alkylation.svg


    Mechanism Nitrile Alkylation.svg


    Example Nitrile Alkylation.svg

    Planning a Synthesis Using Enolate Alkylations

    When planning a synthesis that could involve enolates, the key is to recognize the functionality which can form an enolate. During retrosynthetic analysis a C-C bond is broken between the α-carbon and the β-carbon away from this functionality. It is also important to be able to identify specific groups of atoms which indicate if a malonic ester or an acetoacetic ester synthesis can be used. Having multiple C-C bonds which can be broken allows for multiple synthetic pathways.

    After retrosynthetically breaking the C-C bond, the fragment with the functionality will gain a hydrogen and the other fragment will gain a halogen. Sometimes the fragment with the functionality will become diethyl malonate or acetoacetic ester.

    Planning a Synthesis A.svg

    Planning a Synthesis B.svg

    Planning a Synthesis C.svg

    Planning a Synthesis D.svg

    Worked out example:

    Plan a synthesis of the following molecule using an alkylation of an enolate. Consider multiple pathways and explain which is preferable.

    Worked Out Example A.svg

    The target molecule does not contain the appropriate fragments to utilize either the malonic ester or acetoacetic acid synthesis so direct alkylation of a ketone will likely be used. When analyzing this molecule, there are three α-β C-C bonds which could be cleaved to create a possible starting material. When looking at the possible starting materials, A and C are asymmetrical ketones and therefore can create multiple products during alkylation. B is a symmetrical ketone and should be the most likely to create the target molecule in high yield.

    Worked Out Example B.svg

    Possible Synthesis

    Worked Out Example C.svg

    5.5: Alkylation of Enolate Ions is shared under a CC BY-SA 4.0 license and was authored, remixed, and/or curated by Steven Farmer, Dietmar Kennepohl, Layne Morsch, William Reusch, & William Reusch.