2.10. Aldol Reactions
By far the most well-studied section of enol/enolate chemistry are so-called aldol reactions. This class of reactions has been explored for over 150 years. As a result, a large amount of information is available but a large amount of the terminology is classical.
The name for this class of reactions comes from the first observance. Before the mechanism of what was occurring was understood, chemists knew that an aldehyde mixed with base formed a new, larger aldehyde with an alcohol at its beta (β) position (aldol; Scheme 2.25). The reaction was named after this product.
Scheme 2.25 – Classical Example of an Aldol Reaction Highlighting the Origin of the Name “Aldol”.
Because the name “aldol” derives from a specific example rather than something general about the reactivity it is sometimes misleading or confusing. It is still called an aldol reaction even if the carbonyl-containing compound(s) are not aldehydes (Scheme 2.26).
Scheme 2.26 – Examples of Aldol Reactions Highlighting Variability of Carbonyl-Containing Functional Groups.
There are specific names for some combinations/variations. These are typically the name(s) of whoever developed that specific variant. These are still aldol reactions. For historical reasons the overwhelming majority of chemists still refer to the specific variations using the discoverers’ names. As a result, knowing and/or memorizing these is an unfortunate necessity for communication.
Because the name “aldol” derives from a specific example rather than something general about the reactivity it is sometimes misleading or confusing. Molecules with the characteristic β-alcohol to a carbonyl are ALSO called aldols (Scheme 2.27); the product itself is also called an “aldol”. Functionally, a carbonyl with a β-alcohol is called an “aldol” as a slang name for the collection of functional groups (as though it were itself a functional group).
Scheme 2.27 – Examples of Aldol Reactions with their “Aldol” Products.
This text will avoid using the term “aldol” to refer to molecules but as the usage is very common it is extremely likely to be encountered in other sources.
2.10.1. Acid vs. Base Catalysis for Aldol Reactions
There are several different ways of performing aldol reactions. A common approach is to use base-catalysis. Because aldol reactions are a type of enol reaction, this is identical to the standard base-catalysis mechanism of enol reactions (see Scheme 2.12).
As usual, when base catalysis is used the catalyst performs two tasks: it catalyzes keto-enol tautomerism and makes the nucleophile anionic to increase its nucleophilicity (Scheme 2.28).
Scheme 2.28 – Reaction Mechanism for Base-Catalyzed Aldol Reaction with Ethan-1-al (Acetaldehyde) Becoming the Nucleophile and Ethan-1-al (Acetaldehyde) as the Electrophile.
As before, it is important to recognize that using a very strong base such as LDA is not catalysis; while LDA does generate the enolate (viz. it forms the same activated nucleophile) it is not regenerated at the end of the reaction.
When acid catalysis is used the standard acid-catalyzed mechanism of enol reactions occurs (see Scheme 2.11) but then the product undergoes another acid-catalyzed reaction (see Section 2.10.4). The β-hydroxy carbonyl product is not obtained. Acid catalysis is not practical for aldol reactions.
2.10.2. Reaction: Self-Addition (Dimerization)
It is possible to combine two molecules of the same aldehyde in an aldol reaction (Scheme 2.29). There are multiple ways of doing this, though the classical method is to use a base catalyst. This is sometimes referred to as a self-addition aldol reaction or a dimerization aldol reaction. The aldehyde must have at least one alpha (α) hydrogen (it must be able to become an enol/enolate).
Scheme 2.29 – Generalized Reaction Equation for Base-Catalyzed Aldol Self-Addition Reactions of Aldehydes.
This approach will not work with ketones. Although some ketones can undergo self-addition aldol reactions the vast majority instead undergo a second reaction and afford a different product (see Section 2.10.4) even when using base- rather than acid-catalysis.
The mechanism for this reaction follows the standard sequence for base-catalyzed aldol reactions (see Scheme 2.28).
Because only one side of the carbonyl-containing molecule (the aldehyde) has alpha-hydrogens there is only one enol/enolate possible. As a result, only one regioisomer is possible.
For simple cases all stereoselectivity considerations for this reaction are identical to those for alpha-halogenation (see Section 2.7.3.). Assuming there are no pre-existing stereocentres in the starting material, the nucleophilic attack (enolate attacks aldehyde) will not be stereoselective; if a new stereocentre is formed during this step, it will be formed as an equal mixture of both (R) and (S). If another stereocentre (or multiple stereocentres) exists then the resulting products will be diastereomers; the product is a non-one-to-one mixture of diastereomers. Predicting which diastereomer should be favoured is not required.
Many aldol reactions are complicated by the fact that often multiple stereocentres are being formed at the same time (Figure 2.14). Two diastereomers, each a pair of enantiomers, is a common stereochemical possibility. It is possible to predict which diastereomer will be preferred but this requires the use of more complicated drawings/models. This is normally discussed in advanced courses devoted to enol reactions. At an introductory level following the same principles as usual is sufficient: enantiomers are formed as a racemate (both enantiomers are formed the same amount) and diastereomers are formed as a non-one-to-one mixture. Predicting which diastereomer should be favoured is not required.
Figure 2.14 – Examples of Stereochemical Outcomes from a Self-Addition Aldol Reaction.
2.10.3. Crossed-Aldol Reactions
It is possible to combine two different molecules with carbonyl-containing functional groups (Scheme 2.30). These may be two of the same type of functional group (e.g. an aldehyde + a different aldehyde) or two different kinds of functional groups (e.g. an aldehyde and a ketone, an amide and an aldehyde, etc.). There are multiple ways of doing this. These are referred to as crossed-aldol reactions, though some combinations/conditions have specific names.
Scheme 2.30 – Generalized Reaction Equation for Crossed-Aldol Reactions.
In general, crossed-aldol reactions will not work with catalysis. Although there are some (very) specific combinations for which catalysis can work (see Section 2.10.3.3), in the vast majority of cases catalysis affords very poor yields of the desired product (see Section 2.10.3.1).
Often both carbonyl-containing molecules have alpha-hydrogens. This is the primary issue with catalysis in crossed-aldol reactions. Barring a major structural difference between the two, both enolates can be formed and either compound can act as an electrophile for each enolate (Scheme 2.31). A mixture of products is obtained.
Scheme 2.31 – Example of Multiple Aldol Reactions and Products Possible from a Mixture of Two Different Aldehydes and a Base Catalyst.
This introduces a new complication to reactions. Previously, regioisomers were different constitutional isomers as possible products of the same reaction happening to the same functional group of the same molecule. This problem is different. Multiple distinct aldol reactions can occur: two self-addition aldol reactions (blue attacks blue, red attacks red) and two crossed-aldol reactions (blue attacks red, red attacks blue). Some of the products are constitutional isomers of each other but this is coincidental.
For many mixtures of reactants multiple distinct reactions of the same type but involving different functional groups are possible. If the different products are not formed in equal amounts the reaction is described as being chemoselective (selectively forming more of one chemical product over the other(s)).
The majority of early research on crossed-aldol reactions focused on different ways to achieve chemoselectivity.
2.10.3.2 Reaction: Crossed-Aldol Using Stoichiometric LDA
It is possible to chemoselectively combine two different molecules with carbonyl-containing functional groups by quantitatively pre-forming the enolate with one of them (Scheme 2.32). This is the modern approach to solve chemoselectivity. The reaction requires quenching with a weak acid such as ammonium chloride (NH4Cl) to generate the final product. The overall reaction is normally shown as three steps to indicate this.
Scheme 2.32 – Generalized Reaction Equation for Chemoselective Crossed-Aldol Reactions Using LDA.
Quantitatively pre-forming the enolate necessitates that only one compound can act as the nucleophile (enolate) and only one can act as the electrophile. This eliminates three of the four possible pathways and removes all issues with chemoselectivity.
The compound becoming the enolate (nucleophile) may be an aldehyde, a ketone, an ester, or an amide. The compound being the electrophile is almost always an aldehyde.
In practice some ketones may also be used as electrophiles. However, the vast majority do not afford good yields of the desired product. Assume ketones will not work as electrophiles for this reaction unless otherwise indicated. Other functional groups (esters, amides, acid halides) can be used as electrophiles however they undergo a different chemical reaction and afford a different product (see Section 2.10.5 for an example). Assume esters/amides/acid halides will not work as electrophiles for this reaction unless otherwise indicated.
2.10.3.2.1 Mechanism, Stereoselectivity, and Regioselectivity
The mechanism for this reaction follows the standard sequence for irreversible enolate formation followed by nucleophilic attack of the enolate (Scheme 2.33). The strong base (LDA) reacts irreversibly with the acid (carbonyl-containing group) to remove a proton and generate the enolate. This greatly increases its nucleophilicity. Then the enolate (nucleophile) attacks the carbon of the aldehyde (electrophile). This creates a new C-C bond. Finally, the reaction is quenched with the addition of a weak acid.
Scheme 2.33 – Reaction Mechanism for Chemoselective Crossed-Aldol Reaction Using LDA with Propan-2-one (Acetone) Becoming the Nucleophile and Ethan-1-al (Acetaldehyde) as the Electrophile.
All stereoselectivity considerations are identical to those of base-catalyzed self-addition aldol reactions (see Section 2.10.2.3). Barring outside factors, new stereocentres are formed as a mixture of (R) and (S), diastereomers are formed as a non-one-to-one mixture of all possible diastereomers, and many reactions will form products with two new stereocentres as a non-one-to-one mixture of diastereomers (each of which is racemic).
All regioselectivity considerations are identical to those of alpha-alkylation using LDA (see Section 2.9.2). If the compound becoming the enolate has two different sides with alpha-hydrogens (e.g. it is a non-symmetrical ketone) then steric bulk will lead to kinetic control; the new group will be placed on the side with fewer pre-existing groups.
2.10.3.3 Reaction: Claisen-Schmidt
It is possible to chemoselectively combine two different molecules with carbonyl-containing functional groups by using base catalysis with a ketone and an aldehyde with no alpha-hydrogens (Scheme 2.34). This is referred to as a Claisen-Schmidt reaction (Claisen-Schmidt aldol reaction).
Scheme 2.34 – Generalized Reaction Equation for Chemoselective Crossed-Aldol Reactions Using the Claisen-Schmidt Reaction Conditions.
The compound becoming the enolate (nucleophile) must have alpha-hydrogens. Because the aldehyde does not it cannot become the enolate (nucleophile) which eliminates two of the fours possible products (Scheme 2.35). At the same time, the self-addition aldol reaction of a ketone is highly reversible. Overall, this improves chemoselectivity by making two of the potential products impossible and one of the remaining possible products unfavoured.
Scheme 2.35 – Example of Reduction in Possible Products Using Claisen-Schmidt Conditions.
2.10.3.3.1 Mechanism, Stereoselectivity, and Regioselectivity
The mechanism for this reaction follows the standard sequence for base-catalyzed aldol reactions (Scheme 2.36).
Scheme 2.36 – Reaction Mechanism for Base-Catalyzed Claisen-Schmidt Aldol Reaction with Propan-2-one (Acetone) Becoming the Nucleophile and 2,2-Dimethylpropan-1-al (Pivaldehyde) as the Electrophile.
All stereoselectivity considerations are identical to those of base-catalyzed self-addition aldol reactions (see Section 2.10.2.3). Barring outside factors, new stereocentres are formed as a mixture of (R) and (S), diastereomers are formed as a non-one-to-one mixture of all possible diastereomers, and many reactions will form products with two new stereocentres as a non-one-to-one mixture of diastereomers (each of which is racemic).
All regioselectivity considerations are identical to those of alpha-alkylation using LDA (see Section 2.9.2). If the compound becoming the enolate has two different sides with alpha-hydrogens (e.g. it is a non-symmetrical ketone) then steric bulk will lead to kinetic control; the new group will be placed on the side with fewer pre-existing groups.
2.10.3.4 Reaction: Reformatsky
It is possible to chemoselectively combine two different molecules with carbonyl-containing functional groups by using elemental zinc with an alpha-haloester and an aldehyde/ketone (Scheme 2.37). This is referred to as a Reformatsky reaction (Reformatsky aldol reaction). The reaction requires quenching with a weak acid such as ammonium chloride (NH4Cl) to generate the final product. The overall reaction is normally shown as two steps to indicate this.
Scheme 2.37 – Generalized Reaction Equation for Chemoselective Crossed-Aldol Reactions Using the Reformatsky Reaction Conditions.
This approach will not work with fluorine (X = F). The electrophile may be an aldehyde or a ketone. Technically, other metals such as iron or manganese may be used in place of zinc, though these modifications are rare.
This reaction forms a compound analogous to a Grignard but with zinc instead of magnesium (Scheme 2.38). As with the formation of Grignard compounds, the mechanism for how this occurs is beyond the scope of this text.
Scheme 2.38 – Comparison of Formation of Grignard and Reformatsky Compounds.
This is functionally identical to quantitatively pre-forming the enolate. It necessitates that only one compound can act as the nucleophile (enolate) and only one can act as the electrophile. This eliminates three of the four possible pathways and removes all issues with chemoselectivity.
2.10.3.4.1 “Mechanism”, Stereoselectivity, and Regioselectivity
The mechanism for this reaction involves several steps that fall outside the scope of organic chemistry but can be approximated simply (Scheme 2.39). First, the zinc inserts into the carbon-halide bond (no mechanism shown). The zinc and halide migrate between two positions, the carbon and the oxygen, in rapid equilibrium (no mechanism shown). This is functionally identical to keto-enol tautomerism with the zinc halide acting as “a very large hydrogen”. Whether the O-Zn bond is covalent or ionic is debatable. At an introductory level showing it as either covalent or ionic is acceptable. Then the enolate (nucleophile) attacks the carbon of the aldehyde/ketone (electrophile). This creates a new C-C bond. Finally, the reaction is quenched with the addition of a weak acid (no mechanism shown).
Scheme 2.39 – Reaction “Mechanism” for Reformatsky Aldol Reaction with Methyl 2-Bromoacetate Becoming the Nucleophile and Propan-2-one (Acetone) as the Electrophile.
Again, it is important to remember that this is an approximation. Some sources may show other, more complex mechanisms for these reactions.
All stereoselectivity considerations are identical to those of base-catalyzed self-addition aldol reactions (see Section 2.10.2.3). Barring outside factors, new stereocentres are formed as a mixture of (R) and (S), diastereomers are formed as a non-one-to-one mixture of all possible diastereomers, and many reactions will form products with two new stereocentres as a non-one-to-one mixture of diastereomers (each of which is racemic).
There is only one enolate possible. As a result, only one regioisomer is possible.
2.10.4. Reaction: Aldol Condensation
As previously mentioned, under several circumstances the desired aldol reaction will occur followed by a second, different reaction. The name for this combined set of reactions is the aldol condensation. The term “condensation” in named reactions is classical and refers to any reaction where two molecules combine into one larger molecule and release a smaller molecule (usually water or a small alcohol). In this case the two molecules combine in an aldol reaction and then release water in the second stage through an elimination reaction (Scheme 2.40). The overall transformation is called an aldol condensation.
Scheme 2.40 – General Example of an Aldol Condensation Highlighting the Two Reactions Occurring Together.
In general, this is what occurs instead of a simple aldol reaction when ketones are used as electrophiles. This is true for self-addition aldol reactions of ketones (see Section 2.10.2) and crossed-aldol reactions where the electrophile is a ketone (see Section 2.10.3.2). The Reformatsky reaction is functionally identical to an aldol reaction but does not have this issue (see Section 2.10.3.4).
There are several other conditions under which the aldol condensation occurs instead of simply the aldol reaction (see Sections 2.10.4.1 to 2.10.4.3 and subsections therein).
Often the new alkene can exist as E/Z stereoisomers. As with other elimination reactions, there is some stereoselectivity for the formation of alkenes where the largest groups on either end of the alkene are trans relative to each other. However, these reactions are typically not very stereoselective; depending on the exact structure the selectivity can be very close to 1:1 E:Z. The reasons for this are a competition between kinetic and thermodynamic factors, which lies outside the scope of this text. Unless otherwise indicated, assume aldol condensation reactions have the same stereoselectivity as all other reactions that form multiple diastereomers: a non-one-to-one mixture of both will be obtained.
2.10.4.1. Acid Catalysis for Aldol Condensations
Acid catalysis is not practical for aldol reactions because it does not afford the desired β-hydroxy carbonyl product. Instead, when acid catalysis is used the standard acid-catalyzed mechanism of enol reactions occurs (see Scheme 2.11) but then the product undergoes another acid-catalyzed reaction (Scheme 2.41). Acid catalysis causes an aldol condensation to occur rather than just an aldol reaction.
Scheme 2.41 – Generalized Reaction Mechanism for Acid-Catalyzed Aldol Condensation Reactions.
The mechanism for the elimination step is slightly advanced for an introductory level and does not follow the typical patterns (acid-base, nucleophile-electrophile, leaving group, etc.). It is sometimes referred to as a rearrangement. These are common in many complex reactions/mechanisms and are discussed in more detail in advanced texts. For introductory students it may be helpful to think of this step as being equivalent to two steps occurring at the same time: the alcohol (base) removing a proton from the enol (acid) AND THEN a lone pair kicking out a leaving group (Scheme 2.42).
Scheme 2.42 – Rearrangement Elimination in Acid-Catalyzed Aldol Condensation Reactions and a Stepwise Analogue.
2.10.4.2. Base Catalysis for Aldol Condensations
Base catalysis is practical for aldol reactions because it does afford the desired β-hydroxy carbonyl product. However, when elevated temperatures are used the standard base-catalyzed mechanism of enol reactions occurs (see Scheme 2.12) but then the product undergoes another base-catalyzed reaction (Scheme 2.43). Base catalysis WITH HEAT causes an aldol condensation to occur rather than just an aldol reaction. The heat provides enough energy for the elimination to occur.
Scheme 2.43 – Generalized Reaction Mechanism for Base-Catalyzed Aldol Condensation Reactions with Heat.
The elimination mechanism does not follow either of the standard mechanisms, E1 or E2. Although it is similar to an E1 (two steps) the order of steps is different.
Elimination reactions that follow the E1 mechanism have two steps (Scheme 2.44). First the leaving group leaves, generating a carbocation. This greatly increases the acidity of the hydrogen(s) beside it. Then, the base removes a proton, creating a new conjugate acid and forming a new π bond to the adjacent carbon. The old bond to the leaving group breaks before the hydrogen leaves and the new π bond forms.
Scheme 2.44 – Contrasting Order of Steps in Eliminations via E1 and E1cB Mechanisms.
The elimination in the aldol condensation is the opposite order of steps. First the base removes a proton, creating a new conjugate acid and generating a carbanion. This greatly increases the leaving group ability of the group beside it. Then, the lone pair forms a new π bond to the adjacent carbon, ejecting the leaving group. The old bond to the hydrogen breaks before the leaving group leaves and the new π bond forms. Because the mechanism essentially a variation of E1, the name is similar: E1cB (E1 “conjugate base”; the conjugate base is the carbanionic intermediate).
In practice, E1cB eliminations can be complex and have unusual characteristics relative to “simple” E1 and E2 mechanisms. However, because of their rarity memorizing these specific details is not required at an introductory level.
2.10.4.3. Intramolecular Aldol Condensations
All previous examples of aldol reactions (self-addition and crossed-) combined two molecules. These are intermolecular reactions (reactions between different molecules). It is also possible to have intramolecular aldol reactions (reactions between different parts of the same molecule). An example would be aldol reactions between two different carbonyl-containing functional groups in the same molecule. However, in the overwhelming majority of cases this results in aldol condensation rather than just an aldol reaction. Assume all intramolecular aldol reactions instead go through aldol condensations.
Combining two groups in the same molecule forms a ring structure (Scheme 2.45). What is occurring (the mechanism) is identical to the standard acid- or base- catalyzed aldol condensations. The only difference is the formation of the ring.
Scheme 2.45 – Comparison of Simple Intermolecular and Intramolecular Aldol Condensation Reactions.
However, this introduces another problem. Many students have difficulties keeping track of exactly how big the resulting ring should be and/or where any substituents should be. When drawing the product or mechanism of intramolecular reactions it is highly recommended to number all carbons in both the reactant and product to ensure that the correct two atoms have been connected together and that any substituents are drawn at the correct positions.
Often there is only one possible stereochemical outcome for the alkene (Figure 2.15), simplifying predictions of the major product.
Figure 2.15 – Example of Single Stereochemical Outcome from an Intramolecular Aldol Condensation.
2.10.4.3.1. Regioselectivity and Comments on Complexity
In some cases regioselectivity in enol(ate) formation results in multiple possible products with different sizes of rings (Scheme 2.46).
Scheme 2.46 – Example of Multiple Aldol Reactions and Products Possible from a Mixture of Two Different Aldehydes and a Base Catalyst.
There are specific criteria (Baldwin’s Rules) that can be used to determine which should be favoured as the major regioisomer. At an introductory level these rules can be approximated by simply always selecting for a 5- or 6-membered ring over any other size. For example, in the above reaction regioselectivity would (strongly) favour the left six-membered ring over the right four-membered ring.
Technically, this is not always true. Examples with exceptions will not feature in this text. Additionally, it can be challenging to determine which would be favoured if both 5- and 6-membered rings are possible. Examples with both options will not feature in this text.
Finally, intramolecular reactions can quickly become very challenging with regio, chemo-, and stereo-selectivity involved (Scheme 2.47). While examples like these will not feature in this text it is important to remember that even “simple” reactions can quickly pose difficulties.
Scheme 2.47 – Example of Rapid Complexity in Possible Aldol Condensation Products with a Non-Symmetrical Starting Material.
2.10.5. Reaction: Claisen Condensation
All previous examples of aldol reactions (self-addition, crossed-, and intramolecular) involved an aldehyde or ketone as the electrophile. These are the “simple” electrophiles. It is also possible to have other carbonyl-containing functional groups act as electrophiles.
The classic example would be base-catalyzed aldol reactions between esters. This variation is often referred to as a Claisen condensation. The “condensation” label is used because of the side-product: the two esters combine in an aldol reaction and release an alcohol directly (Scheme 2.48).
Scheme 2.48 – General Example of a Claisen Condensation.
What is occurring is identical to standard addition-elimination reactions (see Addition-Elimination Reactions). The only difference is that the nucleophile is an enolate (Scheme 2.49).
Scheme 2.49 – Comparison of Addition-Elimination and Claisen Condensation Reactions.
The catalyst for these reactions is a base. However, using sodium hydroxide (NaOH) in water causes several other reactions to also occur and does not generate the desired product. Instead, the catalyst and solvent are an alkoxide and alcohol that match the group on the ester. For example, if the ester is a methyl ester (Scheme 2.49 bottom right) then the catalyst is sodium methoxide (NaOCH3) and the solvent is methanol (HOCH3).
As with addition-elimination reactions it is possible to use other carbonyl-containing functional groups (amides, acid halides, etc.) as electrophiles. Several other named reactions use variations of these as electrophiles. However, the exact outcome of these reactions is highly dependent on the structure. These alternatives are not explored in this text.
The mechanism for this reaction largely follows the standard sequence for base-catalyzed aldol reactions (Scheme 2.50). However, after the nucleophile (enolate) attacks the electrophile (ester) instead of gaining a proton and regenerating the catalyst a lone pair comes back and reforms the π bond with the carbon, ejecting the leaving group (alkoxide). This regenerates the catalyst and forms the final product.
Scheme 2.50 – Reaction Mechanism for Base-Catalyzed Claisen Condensation of Methyl Ethanoate (Methyl Acetate).
2.10.6. 1,3-Dicarbonyl Compounds and Alpha-Alkylation
A large amount of enolate chemistry, particularly historically, has been performed using so-called 1,3-dicarbonyl compounds (Figure 2.16). These are most often two ketones, a ketone and an ester, or two esters.
Figure 2.16 – Examples of 1,3-Dicarbonyl Compounds.
There are several reasons for this including their increased acidity (additional induction, additional resonance stabilization; Figure 2.17) and ease of synthesis (see Section 2.10.5), both of which made early work simpler. For example, regioselectivity is not an issue because the alpha-hydrogens between the two carbonyls are much more acidic than any other alpha-hydrogens. The enolate will always form with that position being the nucleophile.
Figure 2.17 – Examples of pKa Values for a Ketone and Related 1,3-Dicarbonyl Compounds.
Recall that it is possible to add an alkyl group (R) adjacent to a carbonyl using an enolate nucleophile (alpha-alkylation; see Section 2.9). A particularly common variation of this involves doing the same reaction on a 1,3-dicarbonyl compound (Scheme 2.51). Because of their increased acidity this may be done using LDA or base-catalysis. The diketone is shown as an example but any of the three common 1,3-dicarbonyl compounds may be used.
Scheme 2.51 – Examples of Alpha-Alkylation Highlighting the Difference Between Carbonyl and 1,3-Dicarbonyl Compounds.
As before, the alkyl halide is typically an alkyl bromide or iodide. Some alkyl chlorides work, but many undergo competitive side-reactions. This approach will not work with alkyl fluorides.
As before, in practice this method only works well with some alkyl halides, with many others affording poor-to-acceptable results. However, it is not always intuitive whether a given electrophile will work well or poorly for this reaction. Assume any given alkyl halide will work for this reaction unless otherwise indicated.
The mechanism for this reaction is identical to the standard alpha-alkylation (see Scheme 2.19). When base catalysis is used it follows the normal base-catalyzed enol formation, activation of the nucleophile, nucleophilic attack sequence.
2.10.6.1. Reaction: Adding Two Different Alkyl Groups
After alkylation the product is less reactive than the starting material and does not add a second alkyl group (Scheme 2.52). However, it is possible to use a stronger base such as a tert-butoxide to catalyze the reaction and add another group. Because this can be done in two different steps it is possible to add two different alkyl groups.
Scheme 2.52 – Examples of Single and Sequential Alpha-Alkylation Using Base-Catalysis.
Although this seems trivial, achieving the same results on a single carbonyl group and/or using LDA is not feasible in the majority of cases (Scheme 2.53). Although some newer approaches can also achieve this, in general adding two different alkyl groups to the same position is very challenging without using 1,3-dicarbonyl compounds.
Scheme 2.53 – Examples of Possible/Major Products from Sequential Alpha-Alkylation Using Catalysis or LDA on Propan-2-one (Acetone) and Pentane-2,4-dione.
2.10.6.2. Reaction: Adding Alkyl Group(s) and Removing the Ester
It is possible to add alkyl groups through alpha-alkylation to a 1,3-dicarbonyl compound where one of the carbonyl-containing functional groups is an ester and then remove the ester group (Scheme 2.54).
Scheme 2.54 – General Reaction Sequence for Alpha-Alkylation, Saponification, and Decarboxylation of 1,3-Dicarbonyl Compounds Containing an Ester.
This uses hydrolysis/saponification to convert the ester(s) to carboxylic acids (see Reactions with Ester Electrophiles). Then, decarboxylation occurs. Because of the mechanism for decarboxylation (see Section 2.10.6.2.1) this will only remove one carboxylic acid even if a 1,3-diester was originally used.
The mechanism for this transformation has several stages (Scheme 2.55). The alpha-alkylation(s) follow the standard mechanism (see Scheme 2.19; not shown). Then, converting the ester(s) to carboxylic acid(s) follows the hydrolysis mechanism. The nucleophile (hydroxide) attacks the electrophile (ester). This forms a new bond and adds a lone pair to the oxygen. Then that lone pair comes back and reforms the π bond with the carbon, ejecting the leaving group (alkoxide). The two products then react with each other; the base (alkoxide) removes a proton from the acid (carboxylic acid). After the hydrolysis reaction is complete a strong acid is added to quench, forming the carboxylic acid. Finally, with the energy provided by additional heating decarboxylation occurs.
Scheme 2.55 – Reaction Mechanism for Hydrolysis and Decarboxylation of Methyl 2-Ethyl-2-methyl-3-oxobutanoate.
The mechanism for decarboxylation is another rearrangement, followed by keto-enol tautomerism (no mechanism shown).
2.10.6.3. Reaction: Knoevenagel Condensation
It is possible to use 1,3-dicarbonyl compounds to do aldol reactions. However, in the vast majority of cases the reaction instead continues on to an aldol condensation (Scheme 2.56). This variation is often referred to as a Knoevenagel condensation.
Scheme 2.56 – General Examples of an Aldol Condensation and a Knoevenagel Condensation Highlighting the Similarities.
All considerations for this reaction (mechanism, stereoselectivity, etc.) are identical to those of the aldol condensation (see Sections 2.10.4.1 and 2.10.4.2). The only difference is the use of a 1,3-dicarbonyl.
As with other applications of 1,3-dicarbonyl compounds, the product can be subjected to decarboxylation (see Section 2.10.6.2).
