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22.7: Alkylation of Enolate Ions

  • Page ID
    36418
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    Objectives

    After completing this section, you should be able to

    1. write a general mechanism for the attack of an enolate anion on an alkyl halide.
    2. write a reaction sequence to illustrate the preparation of carboxylic acids via the malonic ester synthesis.
    3. identify the product formed, and all the intermediates, in a given malonic ester synthesis.
    4. identify all of the compounds needed to prepare a given carboxylic acid by a malonic ester synthesis.
    5. write a detailed mechanism for each of the steps involved in a malonic ester synthesis.
    6. write a reaction sequence to illustrate the preparation of ketones through the acetoacetic ester synthesis.
    7. identify the product formed, and all the intermediates, in a given acetoacetic ester synthesis.
    8. identify all of the compounds needed to prepare a given ketone by an acetoacetic ester synthesis.
    9. write a detailed mechanism for each of the steps involved in an acetoacetic ester synthesis.
    10. identify the product or products formed when a given lactone, ester, nitrile or ketone is treated with lithium diisopropylamide followed by an alkyl halide.
    11. identify the compounds needed to prepare a given α‑substituted ketone, ester, lactone or nitrile by a method involving the alkylation of an enolate anion.
    Key Terms

    Make certain that you can define, and use in context, the key terms below.

    • alkylation
    • malonic ester synthesis
    Study Notes

    The two syntheses discussed in this section provide routes to a wide variety of carboxylic acids and methyl ketones. You may wish to review the factors influencing SN2 reactions (Section 11.3) in conjunction with this section.

    You should try to memorize the structures of malonic ester and ethyl acetoacetate. The IUPAC names of these compounds are shown in the table below.

    Structure Common name IUPAC name
    propanedioic acid malonic acid propanedioic acid
    diethyl propanedioate malonic ester or
    diethyl malonate
    diethyl propanedioate
    3-oxobutanoic acid acetoacetic acid 3‑oxobutanoic acid
    ethyl 3-oxobutanoate ethyl acetoacetate or
    acetoacetic ester
    ethyl 3‑oxobutanoate

    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 directly alkylated 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 carbonyl condensation reactions. In addition, the acidic hydrogen on carboxylic acids inhibits the formation of an enolate, making direct alkylations difficult. Esters, including lactones, and symmetrical ketones readily undergo direct alkylation. However, direct alkylations, like all enolate-based reactions, will form a racemic mixture if the alkylated alpha carbon is chiral.

    General Reaction

    Mechanism

    1) Enolate formation

    2) SN2 attack

    Examples

    When an unsymmetrical ketone with two sets of nonequivalent alpha 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 (equilibrium) control. Although there can be a predominant product, a mixture of products is usually formed, reducing product yield.

    Thermodynamic Enolates

    The thermodynamic enolate is formed when the more substituted alpha hydrogen is removed. This leads to the more alkyl substituted, therefore the more stable, enolate. Formation of the thermodynamic enolate is sterically hindered due to increased sterics and is kinetically slow, especially with a bulky base like LDA. Thermodynamic enolates are favored by conditions which allow for equilibration between the possible enolates. When there is a slight excess of ketone, equilibrium between the enolates and the alpha 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 promote the formation of the thermodynamic enolate, such as higher reaction temperature, or 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, also allowing for enolate equilibrium.

    Example of enolate equilibration

    Kinetic Enolates

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

    Ideally, an enolate of an asymmetric ketone is stabilized through resonance. There is no competition between possible enolates despite kinetics or thermodynamics. The formation of unwanted alkylated side-products is minimal.

    Example

    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 alpha 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 alpha 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.

    General Reaction

    Predicting the Product of a Malonic Ester Synthesis

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

    22.7 Predicting malonic ester synth product.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.

    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.

    4) Decarboxylation & Tautomerization

    Monoalkyl malonic acids decarboxylate when heated, forming an alpha 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 beta-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.

    Example

    Dialkylation

    The presence of two alpha 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.

    Examples

    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.

    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 alpha 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 using sodium ethoxide.

    General Reaction

    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.

    Reaction Steps

    1) Formation of the enolate

    As previously described, the alpha hydrogens of acetoacetic ester are rather acidic (pKa = 10.7) allowing the enolate to form easily when reacting with sodium ethoxide as a base.

    2) Alkylation via an SN2 Reaction

    Subsequent reaction with an alkyl halide produces a monoalkylacetoacetic ester.

    3) Ester hydrolysis and decarboxylation

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

    Examples

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

    The reaction steps of the acetoacetic ester synthesis can also be applied to other beta-keto esters with acidic alpha hydrogens. Because the alpha 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 alpha alkylated cyclic ketone.

    Examples

    Direct Alkylation of Nitriles

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

    General Reaction

    Mechanism

    Example

    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 alpha carbon and the beta 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.

    Worked out example:

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

    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 alpha-beta 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.

    Possible Synthesis

    Exercises

    Questions

    1) Propose a synthesis for each of the following molecules from this malonic ester.

    22.10 Solution Reference.png

    (a)22.10 Problem A.png

    (b) 22.10 Problem B.png

    (c)22.10 Problem C.png

    2) Why can't you prepare tri substituted acetic acids from a malonic ester?

    3) Propose a synthesis for the following molecule via a malonic ester.

    22.12 Problem.png

    4) How might you prepare the following compounds from an alkylation reaction?

    (a)22.16 Problem A.png

    (b)22.16 Problem B.png

    (c)22.16 Problem C.png

    (d)22.16 Problem D.png

    (e)22.16 Problem E.png

    (f)22.16 Problem F.png

    Solutions

    1

    (a) 1) Malonic Ester, NaOEt, 2) 4-Methylbenzyl Bromide, 3) Base, 4) Acid, Heat

    (b) 1) Malonic Ester, NaOEt, 2) 3-bromohexane, 3) Base, 4) Acid, Eat

    (c) 1) Malonic Ester, NaOEt, 2) 1-Bromo-2,3,3-trimethylbutane, 3) Base, 4) Acid, Heat

    2

    Malonic esters only contain two acid protons.

    3

    22.12 Solution.png

    4

    (a)22.16 Solution A.png

    (b)22.16 Solution B.png

    (c)22.16 Solution C.png

    (d)22.16 Solution D.png

    (e)22.16 Solution E.png

    (f)22.16 Solution F.png


    22.7: 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.