Organic synthesis via Enolates

1. Acidity of -hydrogens.2. Alkylation of diethylmalonate.3. Synthesis of ethyl acetoacetate by Claisen condensation (with mechanism).4. Keto-enol tautomerism of ethyl acetoacetate.5. Properties and synthetic applications of aceto acetic ester.6. Synthesis of enamines.7. Use of enamines in alkylation and acetylation.

1. Acidity of -hydrogens: The (alpha) - hydrogen is the hydrogen atom that is bound to the carbon (called as -carbon atom) adjacent to the carbonyl carbon. The next carbon is the β-carbon and the hydrogen atoms attached to it are called as β-hydrogen atoms and so on.

Aldehydes and ketones are weak acids and have remarkably low pKa values (between 15 and 20). Hence, they may act as a Bronsted acid in an acid-base reaction with a strong base. But, aldehydes and ketones are much stronger acids than alkanes. Due to the only minor difference in electronegativity between hydrogen and carbon, C-H bonds in alkanes are hardly polarized. Thus, hydrogens of alkanes are in fact not acidic. The pKa values of alkanes are around 50.

The acidity of -hydrogens of aldehydes and ketones is much less than carboxylic acids, which have pKa values around 3 to 4.Reason for acidity: The - hydrogen of carbonyl compounds is acidic, as it is connected with the -carbon that is directly bound to the electron withdrawing carbonyl group.

The relatively high acidity carbonyl compounds (as compared to alkanes) is explained by the resonance stabilization of the conjugate base by the carbonyl group, or, in other words, through the stabilization of the anion formed by deprotonation. This anion is called an enolate anion.The negative charge is mainly distributed among the -carbon and the carbonyl oxygen, by resonance, which leads to the stabilization of the otherwise highly, energized carbanion.

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2. Alkylation of diethylmalonate: With sodium ethoxide, it forms a sodium derivative called as sodiomalonic ester. This reacts with compounds containing a reactive halogen atom, e.g., alkyl halides, acid chlorides, halogen-substituted esters, etc.

The process on repetition produces the disubstituted derivative of malonic ester.

These substituted derivatives of malonic ester can also be readily prepared in one step by treating the ester with two equivalents of sodium ethoxide and then with two equivalents of alkyl halide. This procedure is used only if two identical alkyl groups are to be introduced.

As mentioned earlier, R may be alkyl, acetyl, acyl or halogen substituted ester.

When, R= methyl group i.e. -CH3, then reaction is expressed as-

When, R= acetyl group i.e. CH3CO-, then reaction is expressed as-

3. Synthesis of ethyl acetoacetate by Claisen condensation (with mechanism): Ethyl acetoacetate is the ethyl ester of acetoacetic acid (CH3COOH) and is widely used as a starting material for the synthesis of a variety of ketones and acids. It can be prepared by Claisen condensation of ethyl acetate. The condensation of two molecules of an ester (e.g. ethyl acetate), or of two molecules of different esters, or of one molecule of an ester with one molecule of a ketone under the

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influence of sodium or sodium ethoxide, is termed Claisen condensation (1887), and is one of the best methods for preparing beta-ketonic esters like ethyl acetoacetate. Two molecules of ethyl acetate condense in the presence of sodium ethoxide to produce ethyl acetoacetate. Claisen condensation may also be brought about by sodamide or tri-phenylmethylsodium etc.

Mechanism: It involves following steps. It is similar to aldol condensation.

1) Dissociation of sodium ethoxide

2) Formation of α−carbanion

3) Addition step

4) Elimination step

4. Keto-enol tautomerism of ethyl acetoacetate: Acetic ester or ethyl acetoacetate is the ethyl ester of acetoacetic acid CH3

. CO . CH2 . CO2H, a β-ketonic acid.

Acetoacetic ester was first discovered by Geuther (1863), who prepared it by the action of sodium on ethyl acetate, and gave the formula as CH3

. C(OH) . CH . CO2C2H5 (β-

hydroxycrotonic ester). The same can written as-

In 1865, Frankland and Duppa, also prepared acetoacetic ester by the action of sodium on ethyl acetate,but they proposed a different formula (β-ketobutyric ester).

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β-ketobutyric ester

Which of these is correct?

Evidence in favour of the Geuther formula (reactions of an unsaturated alcohol)

i) When acetoacetic ester is treated with sodium, hydrogen is evolved and the sodium derivative is formed. This showed the presence of a hydroxyl group.

ii) When acetoacetic ester is treated with an ethanolic solution of bromine, it readily decolourises. This indicates the presence of an olefinic double bond.

iii)When acetoacetic ester is treated with ferric chloride, a reddish-violet colour is produced. This is characteristic of compounds containing the enolic group ( -C(OH)=C<) like phenols.

Evidence in favour of the Frandland-Duppa formula(reactions of a ketone).

(i) With sodium hydrogen sulphite, acetoacetic ester forms a bisulphate derivative.(ii) With hydrogen cyanide, acetoacetic ester forms a cyanohydrin.

Thus, evidence for both the structure were there. The controversy continued until about 1910, when chemists came to the conclusion that both formula were correct, and that the two compounds existed together in equilibrium in solution (or in the liquid state):

5. Properties and synthetic applications of aceto acetic ester: On reaction with sodium ethoxide, ethyl acetoacetate forms a sodium derivative called as sodioacetoactic ester. This reacts with compounds containing a reactive halogen atom, e.g., alkyl halides, acid chlorides, halogen-substituted esters, etc. However vinyl and aryl halides do react.

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The process on repetition produces the disubstituted derivative of acetoacetic ester.

As mentioned earlier, R may be alkyl, acetyl, acyl or halogen substituted ester.

When, R= methyl group i.e. -CH3, then reaction is expressed as-

The process on repetition produces the dimethyl derivative of acetoacetic ester

When, R= acetyl group i.e. CH3CO-, then reaction is expressed as-

Acetoacetic ester and its alkyl derivatives can undergo two types of hydrolysis with potassium hydroxide:

(a) Ketonic hydrolysis: It is so called because a ketone is the chief product. It is carried out by boiling with dilute aqueous or ethanolic potassium hydroxide solution, e.g.,

The ketone obtained is acetone or its derivatives, and the latter always contain the group . CH3CO-Mechanism of decarboxylation:

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(b) Acid hydrolysis: It is so called because an acid is the chief product, is carried out by boiling with concentrated ethanolic potassium hydroxide solution, e.g.,

The acid obtained is acetic acid or its derivatives as the potassium salt. The free acid is readily obtained from these salts by treatment with inorganic acids. Mechanism of the cleavage:

Applications: These alkylation reactions followed by ketonic hydrolysis or acidic hydrolysis are used for the synthesis of various ketones and acids.

1.Synthesis of Ketones: The formula of the ketone is written down, and provided it contains the group, the ketone can be synthesized via acetoacetic ester as follows. The acetone nucleus is picked out, and the alkyl groups attached to it are then introduced into acetoacetic ester one at a time; this is followed by ketonic hydrolysis. –CO.CH3 It is usually better to introduce the larger group before the smaller (steric effect).

Reaction type: Nucleophilic substitution, then ester hydrolysis & finally decarboxylation

For example, For Butanone.

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For example, For 3-methylpentan-2-one.

2. Synthesis of fatty acids: Here, the acetic acid nucleus is picked out, and the acetoacetic ester derivatives are subjected to acid hydrolysis. The acetoacetic ester acid synthesis is usually confined to the preparation of straight-chain acids or branched-chain acids where the branching occurs on the α-carbon atom. For example,

For Synthesis of n-Butyric acid

3. Other synthesis: Sodioacetoacetic ester reacts with many other halogen compounds besides alkyl halides, and so may be used to synthesise a variety of compounds. (i) 1, 3-Diketones. Here, the halogen compound used is an acid chloride. As acid chlorides react with ethanol, the reaction is not carried out in this solvent in the usual way. The reaction is thus carried out by treating acetoacetic ester in benzene solution with magnesium and the acid chloride. For example synthesis of pentane-2,4-dione

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(ii) Dicarboxylic acids: These may be prepared by interaction of sodioacetoacetic ester and a halogen derivative of an ester. e.g., preparation of succinic acid from ethyl chloroacetate:

6. Synthesis of enamines: Primary amines react with aldehydes and ketones to produce imines. For example, the reaction of acetophenone with methyl amine.

In this reaction the initially formed tetrahedral intermediate, A, undergoes dehydration. The loss of the OH group in A could be accompanied by loss of a proton from either the NH group or the CH3 group. The former alternative is preferred because the C-N double bond is more stable than the C-C double bond that would be produced via the latter route, i.e. the more stable product is preferred. Also the hydrogen attached to nitrogen is more acidic as compared to carbon and in acid catalysed dehydration, the hydrogen attached to nitrogen gets lost. Note that the amine has to be primary, i.e. have two hydrogen atoms attached to the nitrogen, for the imine to form. On the other hand, reaction of a secondary amine initially follows the same course as that of a primary amine, but now the tetrahedral intermediate, B, cannot form an imine because the nitrogen does not have a second hydrogen atom to lose:

Consequently, intermediate B undergoes dehydration to form an alkene. (Note that the starting material must have at least one hydrogen attached to the α-carbon in order for this reaction to occur.) But this type of alkene is special and is called as an enamine.

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Alkylation of Enamines Enamines are alkylated by treating them with alkyl halide. Benzene is used as a solvent and the water that is formed is removed by azeotropic distillation.

Acylation of Enamines Similar to alkylation, acylation can be done using acetyl chloride. For example,

The alkylated and acylated enamine are hydrolyzed to get alkylated and acylated aldehyde or ketone. Thus sequence of this reactions can shown as

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