1. Structure and Formation of Enols and Enolate ions
2. Halogenation and Alkylation of Enolates and Enols (a-substitution)
2b. Hell-Volhard-Zelinsky Reaction
2c. Alkylation of aldehydes and ketones using LDA
4a. The Dieckman Cyclization- Claisen Cyclization Process
5. The Acetoacetic Ester Synthesis
6. The Malonate Ester Synthesis
6a. Variations on the Malonate ester synthesis
7a. Synthetic Strategy for Aldol Condensations (Synthesis of b-Hydroxy Aldehydes and Ketones and a,b-Unsaturated Aldehydes and Ketones)
7b. Synthetic Strategy for Claisen Condensations (Synthesis of b-keto Esters)
7c. Synthetic Strategy for Malonate Ester Synthesis (Acetic Acid Synthesis)
8. Conjugate Additions- The Michael Reaction
10. Active Methylene Compounds
1. Structure and Formation of Enols and Enolate ions
1a. Enols and Tautomerization
Tautomers – special type of constitutional isomers that are easily interconverted:
Keto-enol tautomerization is an equilibrium process. The keto form predominates. (The keto form refers to the aldehyde (R=H) and the ketone, i.e., the carbon-oxygen double bond form.)
A hydrogen atom on an a carbon is said to be enolizable.
Without any acid or base present, two molecules may undergo tautomerization:
Tautomerization is catalyzed by acids …
… and catalyzed by bases:
Enolate ions are produced under basic conditions:
Be sure to distinguish between enols and enolates …
Most carbonyl reactions involve enolate ions although many of these mechanism can also be catalyzed by acid, in which case, the enol is involved, not the enolate ion.
2. Halogenation and Alkylation of Enolates and Enols (a-substitution)
Strong bases can deprotonate carbonyl compounds:
Although the concentration of enolate may be small, as the enolate reacts with an electrophile, the equilibrium shifts to the right.
Sometimes the base reacts with the electrophile faster than the enolate. In these cases, a stronger base is needed to quantitatively form the enolate.
BuLi cannot be used as a strong base since it will attack the carbonyl carbon; but BuLi is used to generate a common base, LDA
LDA is a very common base:
Enolate ions behave like C=C double bonds in that they react with electrophiles; the net reaction is alpha-substitution.
Usually, the enolate is preferred as the nucleophile instead of the enol form since the enol is part of an equilibrium, whereas, the enolate can be quantitatively formed using LDA.
Therefore, most a-substitution reactions are base-promoted.
The reaction is base-promoted, not base-catalyzed, since a full equivalent of base is required.
Also, base-promoted halogenation usually does not stop with mono-substitution as shown for the Haloform Reaction.
Acid-Catalyzed alpha halogenation of Ketones- enol intermediate
Depending on the amount of halogen used, one or more alpha hydrogens can be replaced. Acetic acid serves as the solvent and the catalyst:
b.__Hell-Volhard-Zelinsky_Reaction2b. Hell-Volhard-Zelinsky Reaction
Acyl bromide forms first then enolizes, followed by bromine addition:
Aldehydes do not under go alpha halogenation but instead are easily oxidized to the acid. Halogens are oxidizing agents.
2c. Alkylation of aldehydes and ketones using LDA
The Aldol Reaction is a carbonyl condensation reaction in which the electrophile is a second equivalent of the carbonyl compound, instead of a halogen or an alkyl group.
When the electrophile is an aldehyde or ketone- the enolate adds to the carbonyl of the second equivalent.
When the substitution is followed by elimination (of water), the process is called the Aldol Condensation.
Aldol products are easily recognized as b-hydroxy ketones (and b-hydroxy aldehydes):
A mixed Aldol (or crossed Aldol) refers to a reaction between two different carbonyl compounds:
Notice that in a mixed Aldol, one carbonyl compound is non-enolizable, i.e., one compound does not contain alpha hydrogen atoms. This ensures that only one compound will form an enolate (the nucleophile) and the other compound will be the electrophile.
The Aldol cyclization is an intramolecular Aldol reaction.
Diketones can undergo a cyclization process using an Aldol reaction:
4. Claisen Ester Condensation
The Claisen is used for the synthesis of b-ketoesters.
Analogous to the Aldol reaction, the Claisen condensation is a reaction between the alpha carbon of one molecule with the carbonyl group of another molecule. Generally, the Claisen condensation refers to condensation reactions using esters.
Overall, one ester loses an a-hydrogen and the other ester loses the alkoxide group:
Mechanism
Esters must have at least two a-hydrogen atoms to undergo the Claisen condensation; one hydrogen is removed to form the enolate, a second hydrogen is removed from the b-ketoester. The second proton abstraction is the driving force step.
When ethyl acetate condenses with itself, the product is ethyl acetoacetate, commonly called acetoacetic ester.
4a. The Dieckman Cyclization- Claisen Cyclization Process
The intramolecular version is a cyclization process. In this reaction, the a-carbon and the ester group are in the same molecule.
Analogous to the mixed Aldol, this reaction works best when one ester does not have any alpha-hydrogen atoms.
Ketone enolates also react with esters in reactions that resemble mixed Claisen condensations.
The ketone enolate forms easier than the ester enolate since their a-hydrogens are more acidic. Thus, the ketone will act as the nucleophile and the ester will behave as the electrophile.
These ketone-ester condensations work even better if the ester does not have alpha hydrogens. This includes formates, carbonates and oxalates as the ester component.
5. The Acetoacetic Ester Synthesis
Synthesis of Methyl Ketones (Substituted Acetones)
Starting with a b-ketoester, such as acetoacetic ester (from condensation of ethyl acetate), the methylene protons can be substituted in a reaction that is essentially an SN2 reaction using the enolate as the nucleophile:
To prepare a mono-substituted acetone, the ester group is saponified and the resulting carboxylate is acidified then decarboxylated:
The overall process is:
1) alkylation
2) saponification
3) decarboylation
Notice, the product is a substituted methyl ketone; in this example, a mono-substituted acetone.
To prepare a di-substituted acetone, two successive alkylations are done, then the ester group is saponified to the corresponding acid which is then removed by decarboxylation. The second alkylation usually requires a stronger base; potassium t-butoxide is commonly used:
5a. Decarboxylation Mechanism
Either monosubstituted or disubstituted b-ketoesters can be saponified and decarboxylated.
6. The Malonate Ester Synthesis
Synthesis of Substituted Acetic Acids
Malonate esters can be substituted in a fashion that resembles the acetoacetic ester synthesis:
Similar to the acetoacetic ester synthesis, the substituted malonate ester can be saponified …
… and decaboxylated to give a substituted acetic acid compound:
The overall process is:
1) alkylation
2) saponification
3) decarboylation
Notice, the product is a substituted acetic acid.
Malonate esters can be disubstituted to give disubstituted acetic acids. Again, the stronger base, potassium t-butoxide is used for the second alkylation:
6a. Variations on the Malonate ester synthesis
A dihaloalkane can react with one equivalent of a malonate ester to give a cyclized product:
Removal of one carboxyl group can be done using the common methods of saponification and decarboxylation:
The dialkyl malonate enolate is a synthetic equivalent to the acetic acid anion:
The Knoevenagel Condensation resembles the Aldol condensation. This is a reaction of an malonate ester with an aldehyde or ketone.
Retrosynthetic analysis is a technique used to solve synthesis problems. This is a hypothetical process in which a target molecule is broken apart into two simpler molecules. The molecule is broken apart using a bond disconnection. One or more covalent bonds are broken and the resulting “pieces” are considered to be the precursors to the target molecule. The precursors themselves are disconnected in the same manner until one arrives at a simple molecule from which to begin the synthesis. The idea is that a bond disconnection yields two structures that can undergo a reaction to form the target molecule from which they were generated. The precursors are called synthons, a term which means synthetic equivalents. Synthons may be actual molecules but often represent hypothetical structures which embody the correct polarity or functional group needed to perform the actual reaction. Following is a simple example to elucidate the process of retrosynthetic analysis.
Consider the trisubstituted alkene as the target molecule. Working backwards, a reasonable retrosynthetic analysis could be written as:
A special retrosynthetic arrow is used to indicate the retro analysis (working backwards). The alcohol is the synthon needed to form the alkene. In this case, the synthon is an actual molecule, the secondary alcohol. Similarly, the ketone is the synthon needed to form the alcohol. Once the retrosynthetic analysis yields a reasonably simple starting material, a series of actual organic reactions are written to synthesize the target.
The reactions needed are:
A retrosynthetic analysis does not imply that there is only one set of reactions for a particular target. An alternative, one-step analysis involves base-promoted dehydrohalogenation:
And the reaction is:
Here is a retrosynthetic analysis in which the synthons are not real molecules:
If we could actually obtain these precursors, the reaction would undoubtedly work since the polarity is correct. But, obviously the acyl anion and the alkyl cation are not real molecules. So we need synthons for each species. We can envision the following as synthons for each:
Being able to identify a synthon comes from experience. You may recall that dithiane can be deprotonated, alkylated and hydrolyzed to the carbonyl. So dithiane is a logical synthon for an acyl anion equivalent and an alkyl halide is one of many synthons for a carbocation. Thus, the actual reactions are:
Retrosynthetic analysis is readily applied to carbonyl condensations.
7a. Synthetic Strategy for Aldol Condensations (Synthesis of b-Hydroxy Aldehydes and Ketones and a,b-Unsaturated Aldehydes and Ketones)
If your target molecule contains a b-hydroxy ketone (b-hydroxy aldehyde) or an a,b-unsaturated ketone (a,b-unsaturated aldehyde), then consider an Aldol reaction or Aldol Condensation.
The bond disconnection for Aldol products is between the a and b carbon atoms …
Now you can recognize the ketone and aldehyde partners…
And the reaction is …
For cyclic targets:
And the reaction is …
7b. Synthetic Strategy for Claisen Condensations (Synthesis of b-keto Esters)
The b-ketoester anion is a synthetic equivalent to the ketone enolate:
Although a ketone can be alkylated directly, alkylation of the b-ketoester occurs under milder conditions since it is more acidic than a ketone. Treating the b-ketoester with alkoxide will form the corresponding enolate, whereas, treating the ketone with alkoxide will promote an Aldol reaction.
If the target molecule contains a b-ketoester, the bond disconnection is between the a and b carbon atoms, counting from the ester carbonyl:
The acyl cation is a synthon for an ester and the carbanion is simply the enolate of a ester. This is a mixed Clasien and the reaction would be:
7c. Synthetic Strategy for Malonate Ester Synthesis (Acetic Acid Synthesis)
The dialkyl malonate enolate is a synthetic equivalent to the acetic acid anion:
If the target molecule is a carboxylic acid, the bond disconnection is between the a and b carbon atoms.
The carbocation synthon is another ester and the carbanion is the enolate of the corresponding ester:
8. Conjugate Additions- The Michael Reaction
There are two modes of attack of nucleophiles to an a,b-unsaturated compound, addition to the carbonyl carbon and addition to the b-carbon atom. Resonance structures illustrate the polarity in these systems:
Addition to the carbonyl carbon followed by protonation of the carbonyl oxygen gives the 1,2-addition product.
Addition of a nucleophile to the b-carbon atom is called conjugate addition and the product is called the conjugate addition product. Addition to the b-carbon atom followed by protonation of the carbonyl oxygen gives the 1,4-addition product.
1,4-Addition gives the enol which will tautomerize to the ketone:
The a,b-unsaturated system is called a Michael acceptor and a wide range of nucleophiles that add in a conjugate fashion are referred to as Michael donors.
Another example of conjugate addition is the addition of malonic ester enolate to methyl vinyl ketone.
The resulting enolate produced by nucleophilic attack is quickly protonated …
The Michael product can be saponified and decarboxylated to give a d-keto acid …
There are other Michael acceptors such as a,b-unsaturated esters:
One of the most interesting series of reactions involves conjugate addition followed by an Aldol cyclization, the Robinson Annulation.
Conjugate addition of the cyclohexanone enolate produces another enolate …
The thermodynamic enolate initially produced isomerizes to the kinetic enolate …
The kinetic enolate adds to the carbonyl of the cyclohexanone producing a bicyclic system.
The bicyclic ring system can dehydrate to give a cyclohexenone, an a,b-unsaturated product.
10. Active Methylene Compounds
Compounds that contain two electron withdrawing groups in a 1,3-relationship are called active hydrogen compounds or active methylene compounds. This terminology refers to the enhanced acidity of hydrogen atoms bonded to a carbon situated between two electron-withdrawing groups.
The pKa values for active methylene compounds ranges from about 5 to 13.
Active methylene compounds include b-keto esters, malonate esters and several others such as the following:
Notice that conjugated double bonds between the Z groups has the same effect on acidity.
The malonic ester synthesis, the Knoevenagel Condensation and the Michael reaction are essentially reactions of active methylene compounds.
Enolizable aldehydes and ketones react with formaldehyde and amines in a reaction known as the Mannich reaction. The product is a b-amino ketone (or b-amino aldehyde) which is also called a Mannich base.
The aldehyde or ketone must contain alpha hydrogens since it is the enol form which serves as a nucleophile.
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