The influence of various carbonyl and related functional groups on the equilibrium acidity of alpha-hydrogen atoms colored red is summarized in the following table.
For common reference, these acidity values have all been extrapolated to water solution, even though the conjugate bases of those compounds having pK a s greater than 18 will not have a significant concentration in water solution.
To illustrate the general nucleophilic reactivity of di-activated enolate anions, two examples of S N 2 alkylation reactions are shown below. Malonic acid esters and acetoacetic acid esters are commonly used starting materials, and their usefulness in synthesis will be demonstrated later in this chapter.
Note that each of these compounds has two acidic alpha-hydrogen atoms colored red. In the equations written here only one of these hydrogens is substituted; however, the second is also acidic and a second alkyl substitution may be carried out in a similar fashion.
The aldol reaction , is a remarkable and useful reaction of aldehydes and ketones in which the carbonyl group serves both as an electrophilic reactant and the source of a nucleophilic enol species. Esters undergo a similar transformation called the Claisen Condensation.
Four examples of this base-induced reaction, which usually forms beta-ketoester products, are shown in the following diagram. Greek letter assignments for the ester products are given in blue. Equation 1 presents the synthesis of the important reagent ethyl acetoacetate, and 2 illustrates the general form of the Claisen condensation. Intramolecular reactions, such as 3, lead to rings usually five or six-membered and are referred to as Dieckmann Condensations.
The last equation shows a mixed condensation between two esters, one of which has no alpha-hydrogens. The product in this case is a phenyl substituted malonic ester rather than a ketoester. By clicking the " Structural Analysis " button below the diagram, a display showing the nucleophilic enolic donor molecule and the electrophilic acceptor molecule together with the newly formed carbon-carbon bond will be displayed.
A stepwise mechanism for the reaction will be shown by clicking the " Reaction Mechanism " button. In a similar mode to the aldol reaction, the fundamental event in the Claisen condensation is a dimerization of two esters by an alpha C—H addition of one reactant to the carbonyl group of a second reactant.
This bonding is followed by alcohol elimination from the resulting hemiacetal. The eventual formation of a resonance stabilized beta-ketoester enolate anion, as shown on the third row of the mechanism, provides a thermodynamic driving force for the condensation. Note that this stabilization is only possible if the donor has two reactive alpha-hydrogens. The Claisen condensation differs from the aldol reaction in several important ways.
The extra base is needed because beta-ketoesters having acidic hydrogens at the alpha-carbon are stronger acids by about 5 powers of ten than the alcohol co-product. Consequently, the alkoxide base released after carbon-carbon bond formation upper right structure in the mechanism diagram immediately removes an alpha proton from the beta-ketoester product.
As noted above, formation of this doubly-stabilized enolate anion provides a thermodynamic driving force for the condensation. The specific alkoxide base used should match the alcohol component of the ester to avoid ester exchange reactions. Very strong bases such as LDA may also be used in this reaction. Transformations similar to the Claisen condensation may be effected with mixed carbonyl reactants, which may include ketones and nitriles as well as esters.
Esters usually serve as the electrophilic acceptor component of the condensation. Acyl chlorides and anhydrides would also be good electrophilic acceptors, but they are more expensive than esters and do not tolerate the alcohol solvents often used for Claisen condensations. In the case of mixed condensations , complex product mixtures are commonly avoided by using an acceptor ester that has no alpha-hydrogens.
The 2-formylcyclohexanone product from reaction 3 exists predominantly as its hydrogen-bonded enol. Most beta-ketoesters have significant enol concentrations , but the formyl group has an exceptional bias for this tautomer. Equation 1 shows a condensation in which both reactants might serve either as donors or acceptors.
Protonation of this anion gives the product. The last equation 5 presents an interesting example of selectivity. There are three ester functions, each of which has at least one alpha-hydrogen. Only one of these, that on the left, has two alpha-hydrogens and will yield an enolizable beta-ketoester by functioning as the donor in a Dieckmann cyclization.
Strained four-membered rings are not favored by reversible condensation reactions, so ring closure to the ester drawn below the horizontal chain does not occur. The only reasonable product is the five-membered cyclic ketoester. Selecting fixed-charge groups for electron-based peptide dissociations. International Journal of Mass Spectrometry , , Holm , Mikkel K.
Leib , William A. Donald , Evan R. Electron capture, femtosecond electron transfer and theory: A study of noncovalent crown ether 1,n-diammonium alkane complexes. Polce , Chrys Wesdemiotis. Cytosine neutral molecules and cation—radicals in the gas-phase. Studies on the Reactivity of Noncyclic Nickel Enolates. Organometallics , 26 23 , Proton and hydrogen atom adducts to cytosine. An experimental and computational study.
Journal of the American Chemical Society , 25 , The Journal of Physical Chemistry A , 20 , Quantifying resonance through a Lewis Valence Bond approach: application to haloallyl and carbonylcations. Faraday Discuss. Journal of the American Chemical Society , 38 , M Harrison. Studies of structure and dynamics in a nominally symmetric twisted amide by NMR and electronic structure calculations.
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Please reconnect. This website uses cookies to improve your user experience. By continuing to use the site, you are accepting our use of cookies. 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. Other alkoxide bases are not typically used given the possibility of a transesterification reaction.
Reacting diethyl malonate with sodium ethoxide NaOEt forms a resonance-stabilized enolate. The enolate is alkylated via an S N 2 reaction to form an monoalkylmalonic ester. After alkylation, the diester undergoes hydrolysis with sodium hydroxide to form a dicarboxylate.
Subsequent protonation with acid forms a monoalkyl malonic acid. Monoalkyl malonic acids decarboxylate when heated, forming an alpha alkyl carboxylic acid and carbon dioxide CO 2.
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 CO 2. The enol undergoes tautomerization to form the carboxylic acid. 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. 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 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. The product of a acetoacetic ester synthesis can be created by replacing halogen on the alkyl halide with a -CH 2 COCH 3 group.
Subsequent reaction with an alkyl halide produces a monoalkylacetoacetic ester. 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 CO 2 using a similar mechanism as the malonic ester synthesis.
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.
The presence of acidic alpha hydrogens in nitriles gives them the ability to form an enolate equivalent which can be also be directly alkylated. 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.
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