What is tautomerism in organic chemistry


12. The carbonyl group: reactions in the α-position

In Chapters 10 and 11 it was shown that the carbonyl group is attacked by electrophiles on oxygen and by nucleophiles on carbon. Two other types of reactivity occur at the carbon atom adjacent to the carbonyl group (in the α position).

12.1 Keto-enol tautomerism

When a hydrogen atom is on an α-carbon atom, a Tautomerization enter:

The two isomers are called Tautomersbecause they can be rapidly converted into one another through a proton transfer reaction.

When you're in water at pH7 works, typical aldehydes and ketones only contain traces of the enol tautomer:

In the case of carboxylic acids, esters and amides, the percentage of the enol form is even smaller. Enol tautomers cannot be isolated under these conditions, but their chemical properties are important nonetheless.

Keto-enol tautomerization is through Acids and Bases catalyzed.

With Acid catalysis the carbonyl-O-atom is protonated first, and finally a proton of Cα split off:

Mechanism:

In the base-catalyzed tautomerization will the Cα-Atom simply deprotonated: i.e. the protons in the α-position are somewhat acidic (we will examine their exact acidity soon). This creates a Enolate anion which can again take up a proton from the solvent to form the enol form:

Mechanism:

Only protons in the α position are acidic. Protons in other places cannot be split off because the resulting anions cannot be stabilized by a neighboring carbonyl group:

12.2 α-substitution reactions; The reaction of enols with halogens

Enols are electron-rich and react as nucleophiles. But they are much more reactive than alkenes. In an acid catalyzed substitution, the enol reacts very rapidly with an electrophile by the following mechanism:

Aldehydes and ketones react with halogens on the α-carbon with acid or base catalysis. The extent of halogenation depends on whether acid or base catalysis was used. The halogenation in acid catalysis comes to a standstill as soon as the first halogen atom has been introduced, e.g .:

12.3 The acidity of the α-hydrogen atoms: the formation of enolate anions

We found that relatively strong bases formed a resonance-stabilized Enolate ions can split off an α-hydrogen atom:

The pKa of acetone is about 19:

In order to understand the acidity of this hydrogen atom, it is necessary to explain the particular stability of the enolate anion. This can best be achieved with an orbital image:

The C-H σ bond must be perpendicular to the p orbitals so that the electrons (i.e. the negative charge) can be delocalized onto the most electronegative atom (i.e. oxygen). These Resonance stabilization can be described by the two resonance structures:

It is then also understandable why simple alkanes and alkenes are not sour Contain hydrogen atom. In such cases there would be no resonance stabilization.

But compared to carboxylic acids (R-COOH), the α-hydrogen atoms in carbonyl compounds are only very weakly acidic. That means in the following equilibrium:

a relatively strong base must be used to shift the equilibrium towards the enolate ion.

Where a C-H bond is linked to two carbonyl groups, some special carbonyl compounds form particularly stable enolate anions. examples are ß-diketones such as 2,4-pentanedione, 1,3-ß-ketoester such as ethyl acetoacetate, and 1,3-diester such as ethyl malonate. The enolate anions of such ß-dicarbonyl compounds are particularly stable because the negative charge can be delocalized over both carbonyl oxygen atoms.

Acidity constants for some organic compounds

12.4 The reactions of enolate anions with electrophiles

The enol form of carbonyl compounds is only present in very low concentrations and only reacts quickly with strong electrophiles such as bromine. On the other hand, enolate anions can be formed almost quantitatively from carbonyl compounds if one has an equivalent of a strong base such as NaH or NaNH2 begins. Since they carry a negative charge, they are also stronger nucleophiles:

Enolate anions can react with electrophiles either on carbon or on oxygen. Both processes are possible, but the reaction on carbon is more common. The two main types of response are Alkylation reactions and Condensation reactions.

12.5 Alkylation reactions: the malonic ester synthesis and the acetoacetic ester synthesis

Enolate anions can be linked to haloalkanes via an SN2 reaction are alkylated. The rules and limits of SN2-reactions naturally also apply to such alkylation reactions. The anions can be reacted with methyl or primary haloalkanes in good yields. However, tertiary haloalkanes give elimination products.

The Malonic ester synthesis is one of the best-known carbonyl alkylation reactions, which is particularly suitable for the synthesis of substituted acetic acids. Diethyl malonate is treated with Na+EtO- converted into its enolate anion. This enolate anion can be reacted with a haloalkane. This creates an α-substituted malonic acid ester:

The product of this first alkylation reaction still contains an acidic hydrogen atom at Cα. If necessary, a second alkylation reaction can be carried out:

The alkylated malonic acid esters can now be hydrolyzed, and by heating with HCl they lose CO2 in a decarboxylation reaction:

It is a special property of 1,3-keto-carboxylic acids and 1,3-dicarboxylic acids that they lose carbon dioxide when they are heated with HCl. Such decarboxylation reactions do not take place with simple carboxylic acids.

The Acetoacetic ester synthesis forms a method for the production of α-substituted acetone derivatives (methyl ketone derivatives):

Ethyl 3-oxobutanate (ethyl acetoacetate) contains two acidic hydrogen atoms, at C.α between the two carbonyl groups.

By treatment with base and haloalkane, first monoalkylated and then dialkylated acetoacetic acid esters can be formed:

The synthetic significance of the alkylation reactions of 3-ketoesters is that they easily decarboxylate after hydrolysis, resulting in ketones:

An example :

12.6 Attack of Enolates on Carbonyl Groups: The Aldol Condensation

We have seen that carbonyl compounds can behave either as nucleophiles or as electrophiles:

Electrophilic carbonyl group Nucleophilic enolate anions
Nucleophilic addition and substitution reactions Enolate Alkylation and Condensations

The fourth and final major category of carbonyl group reactions is based on both types of reactivity. Enolates can attack carbonyl compounds with the formation of ß-hydroxycarbonyl compounds: the Aldol reaction (or aldol addition).

A general mechanism is:

When an aldehyde or ketone is treated with a base, a rapid addition takes place, e.g .:

If there are no α-H atoms, no condensation takes place! This reaction is reversible and the equilibrium position is strongly dependent on the reaction conditions.

The Aldol product does not react further if the reaction occurs at low temperature (5thOC - RT) is executed. At elevated temperature, the aldol product (β-hydroxy-aldehyde / ketone) reacts further with elimination of water and formation of a conjugated enone (α, β-unsaturated carbonyl compound) (Aldol condensation).

Most Alcohols are unreactive to the elimination of water, however one Hydroxyl group in β-position to a carbonyl group is easily eliminated in the presence of acid or base. The aldol product is converted into its enolate anion, which splits off a hydroxide ion to form the end product:

If aldol condensations are carried out at elevated temperatures, such α, β-unsaturated carbonyl groups are isolated directly. A conjugated enone system is thermodynamically much more stable than the corresponding non-conjugated system:

The synthetic utility of aldol condensation is that a new C-C bond is formed, either forming a β-hydroxycarbonyl moiety or an α, β-unsaturated carbonyl compound.

12.7 The Claisen condensation of the esters

The acidity of the α-hydrogen in esters is still large enough to result in the formation of Ester enolates respectively. Ester enolates react like enolates of aldehydes and ketones. For example, they enter into alkylations and condensations.

Ester enolates also attack the carbonyl group of esters. In this implementation, the Claisen condensation is known, the enolate ion reacts with the ester function via an addition-elimination mechanism, resulting in a 3-ketoester, e.g .:

General mechanism:

Both the alkoxide and the ester should be derived from the same alcohol in order to prevent side reactions due to transesterification.

12.8 Examples from biological chemistry

Carbonyl condensation reactions occur frequently in nature. An important step in glycolysis is one Retro aldol reaction:

We saw how in Chapter 11.13 Acetyl-CoA can act as an acetyl donor. Acetyl-CoA is also involved in other important reactions in biochemistry, which should actually be viewed as Claisen reactions. The enol or enolate anion form of acetyl-CoA can then attack other carbonyl compounds. Two examples follow: