ORGANIC SYNTHESIS VIA ENOLATES

Transcription

1 1 ORGANIC SYNTHESIS VIA ENOLATES Aldehydes and ketones undergo nucleophilic addition reaction at the carbonyl group. Further, α-hydrogen containing compounds are acidic in nature. In addition to carbonyl group, other strongly electron withdrawing group also enhance the acidity of α-hydrogen. For eg.. CN, - COOR, -NO 2 etc. The effect of α-substituent on the pk a value is roughly additive. For eg. Thus enolates derived from dicarbonyl compounds such as malonic ester (pk a =13), acetoacetic ester (pk a =11) are extremely important in organic synthesis as their enolate anions can act as good nucleophile. Alkylation of Diethyl malonate: Malonic ester synthesis Diethyl malonate or malonic ester are commonly known as active methylene compound as α-hydrogen present on CH 2 group are sufficiently acidic due to presence of two electron withdrawing ester groups. Synthetic utility of malonic ester depends upon following three reactions: (i) Formation of enolate anion: Malonic ester on treated with ethoxide ion is quantitatively converted into enolate anion. This enolate anion is stabilized by resonance in which negative charge is delocalized over two carbonyl groups.

2 2 (ii) Alkylation of enolate anion (S N 2 reaction): enolate anion readily undergoes S N 2 reaction with unhindered primary alkyl halides to give high yields of alkylation product. With secondary alkyl halides, the yields are however low. Tertiary alkyl halides undergo elimination rather than substitution to give alkenes. Since the product of alkylation, i.e. monoalkyl malonic ester still contains an acidic hydrogen, it can further react with sodium ethoxide to form corresponding enolate anion. This in turn can react with an alkyl halide to form a dialkylmalonic ester. Besides primary and secondary alkyl halides, α-haloketones and α- haloesters can also be used for alkylation of malonic ester (iii) Hydrolysis and decarboxylation: The monoalkyl and dialkylmalonic esters obtained above upon hydrolysis with aqueous alkali followed by acidification gives corresponding dicarboxylic acids. These acids are thermally unstable and hence on heating above their melting points (usually K) readily undergo decarboxylation to give monocarboxylic acids Synthesis of monocarboxylic acids 1. Synthesis of monoalkylacetic acids: The process involves conversion of malonic ester into enolate anion. This is then alkylated with a suitable alkyl halide. The monoalkyl malonic ester thus obtained is subjected to hydrolysis followed by decarboxylation. (i) n-butyric acid CH 3 CH 2 CH 2 COOH:

3 3 (ii) Isovaleric acid: 2. Synthesis of dialkyl acetic acids: The process involves conversion of malonic ester into its enolate anion. The enolate ion is alkylated with a suitable alkyl halide to give monoalkylated malonic ester. The monoalkylated malonic ester is once again converted into its enolate anion and then reacted with another alkyl halide to give the dialkyl substituted malonic ester. This upon hydrolysis and subsequent decarboxylation gives the desired dialkyl substituted acetic acid. (i) 2-methyl propanoic acid:

4 4 (ii) 2-methylbutanoic acid 3. Synthesis of cycloalkane dicarboxylic acids: If enolate anion of malonic ester is alkylated once with an α,ω-dihalide, the resulting product has one acidic hydrogen and one halogen atom. These undergo an intramolecular S N 2 reaction in presence of sodium ethoxide to form a cyclic ester. Hydrolysis and subsequent decarboxylation yields the corresponding cycloalkanecarboxylic acid. Depending upon nature of α,ω-dihalide, cycloalkanecarboxylic acids with ring size 3-6 can be easily synthesized. Syntheis of β-ketoacids, RCOCH 2 COOH and ketones RCOCH 3 Synthesis of dicarboxylic acids (i) 1,3-dicarboxylic acids. Carboxylic acids in which the two carboxyl groups are attached to the same carbon atom can be easily prepared by the mono and dialkylation of malonic ester followed by hydrolysis. For example, synthesis of 2-ethylmalonic acid has already been described under synthesis of n-butyric acid and that of 2-ethyl-2-malonic acid has been described under the

5 5 synthesis of isovaleric acid. (ii) 1,4-dicarboxylic acids. Such acids are prepared by treating enolate anion of malonic ester with a suitable α-haloester such as ethyl α-bromoacetate. Hydrolysis is followed by decarboxylation of the resulting triester which yields the desired dicarboxylic acid. For example succinic acid is prepared as follows: (iii) 1,5-dicarboxylic acids. These acids may be prepared by 1,4-addition (Michael addition) of the enolate anion of malonic ester or its alkyl derivative to an α,β-unsaturated ester. The resulting triester on hydrolysis and decarboxylation gives 1,5-dicarboxylic acid. For example, glutaric acid may be prepared as :

6 6 (iv) 1,6-dicarboxylic acids: These acids are prepared by treating enolate anion of malonic ester or its monoalkyl derivative (two molecules) with 1,2-dibromoethane. The resulting tetraester on hydrolysis and decarboxylation gives 1,6-dicarboxylic acids. For example, adipic acid may be prepared as follows: ALKYLATION OF ETHYL ACETOACETATE: ACETOACETATE ESTER SYNTHESIS Ethyl acetoacetate or acetoacetic ester is commonly called as β-ketoester. Like malonic ester, it is also an active methylene compound, i.e. α-hydrogen present on the CH 2 group are sufficiently acidic due to presence of a keto group on one side and the ester on the other side. Its synthetic utility depends on the following three reactions. (i) Formation of an enolate anion:

7 7 (ii) Alkylation of enolate anion (S N 2 reaction): (iii) Hydrolysis and decarboxylation: The mono and dialkylacetoacetic esters obtained above can undergo hydrolysis in the following two different ways: (a) Ketonic hydrolysis: When mono and dialkylacetoacetic esters are hydrolyzed with a dilute aqueous alkali (or acid), the ester group get hydrolyzed to form the corresponding acids after acidification. These acids being β-ketoacids are thermally unstable and hence readily undergoes decarboxylation on heating to yield ketones. Since ketones are the final products of this hydrolysis, therefore, it is commonly called ketonic hydrolysis. The decarboxylation of mono or dialkylacetoacetic acid occurs even more readily than malonic acid. It probably occurs through transfer of carboxylic hydrogen either before or simultaneously with the loss of CO 2.

8 8 (b) Acid hydrolysis: When the hydrolysis of mono- and dialkylacetoacetic esters is carried out with concnetrated alkali nucleophilic attack by hydroxide ion occurs both at the keto group as well as at the ester group leading to formation of sodium salts of two carboxylic acids one of which is always sodium acetate. This type of hydrolysis is called acid or acidic hydrolysis because it leads to the formation of acids. SYNTHESIS OF KETONES AND CARBOXYLIC ACIDS USING ACETOACETIC ESTER SYNTHESIS 1. Synthesis of Ketones (i) Synthesis of mono-substituted methyl ketones Synthesis of 4-methyl-2-pentanone (ii) Synthesis of 1,1-disubstituted methyl ketones Synthesis of 3-methyl-2-pentanone

9 9 (iii) Synthesis of diketones (a) Synthesis of 1,3-diketones (b) Synthesis of 1,4-diketones Alternatively,

10 10 2. Synthesis of carboxylic acids (i) Synthesis of monoalkyl and dialkyl acetic acids (a) Synthesis of n-valeric acid (ii) Active valeric acid, 2-methylbutanoic acid (iii) Synthesis of dicarboxylic acids

11 11 SYNTHESIS OF ETHYL ACETOACETATE: THE CLAISEN CONDENSATION Ethyl acetoacetate (EAA) can be prepared by condensation of two molecules of ethyl acetate in presence of sodium ethoxide. The initially formed sodium salt upon acidification gives ethyl acetoacetate. This reaction is called Claisen condensation. Mechanism: Step 1: In presence of sodium ethoxide, the acidic α-hydrogen is lost and a resonance stabilized enolate anion is formed. Since ethanol is stronger acid (pk a ~16) than ethyl acetate (pk a ~25), therefore, this step is reversible and the position of equilibrium lies far in favour of the reactants rather than the products, i.e. only a low yield of enolate ion is formed. Step 2: The enolate anion being a strong nucleophile attacks the carbonyl group of the second molecule of ethyl acetate to form an addition product which subsequently eliminates an ethoxide ion to form ethyl acetoacetate.

12 12 Step 3: The driving force for elimination of ethoxide ion is the formation of ethyl acetoacetate. Since ethyl acetoacetate is a stronger acid (pk a ~11) than ethanol, it immediately reacts with ethoxide ion forming its resonance stabilized enolate ion. Evidences in favour of the above mechanism (i) Esters containing acidic α-hydrogens on treatment with C 2 H 5 O - in C 2 H 5 OD readily undergoes deuterium exchange (ii) Due to reversible formation of enolate ions, optically active esters of type R 1 R 2 CHCOOC 2 H 5 undergo racemization during Claisen condensation. KETO-ENOL TAUTOMERISM OF ETHYL ACETOACETATE Keto-enol tautomerism is exhibited by carbonyl compounds having either a methylene group (-CH 2 -) or methine group (-C 1 C 2 H-) adjacent to a carbonyl group. Ethyl acetoacetate is most extensively studied classical example of keto-enol tautomerism.

13 13 The presence of keto- and enol forms in ethyl acetoacetate is supported by two sets of reaction listed below: (a) Reactions supporting keto-form: 1. It forms (i) crystalline sodium bisulphite addition compound with conc. solution of NaHSO 3, (ii) a cyanohydrin with HCN, (iii) oxime with hydroxylamine, and (iv) phenylhydrazone with phenylhydrazine 2. Ethyl acetoacetate on hydrolysis with aq. or alcoholic KOH followed by acidification and subsequent heating to K yield ketone. (b) Reactions supporting enol form: The presence of enol form in ethyl acetoacetate is supported by the following reasons: (i) It reacts with sodium metal to evolve H 2 gas, (ii) reacts with PCl 5 to form β-chlorocrotonate, (iii) discharges the orange colour of Br 2 rapidly, (iv) produces reddish violet coloration with FeCl 3 and (v) forms acetyl derivative with CH 3 COCl.

14 14 Evidence for existence of dynamic equilibrium: When a reagent such as NH 2 OH which reacts with keto-form is added, equilibrium shifts to produce more of keto form instantaneously from the enol form. This process continues till whole of enol form is converted into keto form and entire amount of ethyl acetoacetate reacts as if it consisted only of keto form. Similarly, if sufficient bromine is added, enol form reacts and equilibrium shifts to produce more of enol from keto form. In this way, whole of ethyl acetoacetate reacts as if it consisted only of enol form. Factors affecting relative amounts of keto and enol forms in keto-enol tautomerism The following two factors affect the position of equilibrium in keto-enol tautomerism. 1. Stability of enol form: Generally speaking, keto-form is more stable than enol-form (C=O: 364 KJ mol -1 & C=C: 251 KJ mol -1 ). Therefore, in simple aldehydes and ketones such as acetaldehyde, acetone, cyclohexanone, the amount of enol is negligibly small (<1%). However if the enolic form is stabilized by some special factors, amount of enol content increases. Two such factors are: (i) conjugation of ethylenic double bond with a second carbonyl group (ii) formation of intramolecular hydrogen bond (chelation) between enolic hydroxyl group and second carbonyl group Thus, High enol content in acetylacetone is due to the reason that keto group is a much better electron-withdrawing group than ester group. 2. Effect of polarity of solvent on the enol content: Any solvent that can form H-bonds with carbonyl group will stabilize keto

15 15 form relative to enol form (which cannot form H-bond with solvent since it is already involved in intramolecular H-bond). As a result equilibrium will shift in favour of keto-form and hence enolic form will decrease. In general, polar protic solvents such as water, methanol, ethanol, acetic acid etc. which tend to stabilize keto-form relative to enol-form will reduce enol content. On the other hand, non-polar solvents such as hexane, benzene etc. tend to increase enol content. ALKYLATION OF 1,3-DITHIANE 1,3-DITHIANE or 1,3-dithiacyclohexane is an alicyclic heterocyclic compound. It is prepared by reaction of formaldehyde with 1,3-propanedithiol in presence of trace of an acid. The two hydrogen atoms of C-2 attached to two sulphur atoms are acidic (pk a =32). Thus it can be converted to anion on treatment with strong base such as n-butyllithium. Alkylation of 1,3-Dithiane Synthetic utility (i) Preparation of aldehydes and ketones: The mono and dialkyl derivative of 1,3-dithiane can be hydrolyzed either with mercuric chloride (HgCl 2 ) in methanol or aqueous acetonitrile (CH 3 CN) to give aldehydes and ketones.

16 16 (ii) Conversion of aldehydes into ketones: An aldehyde can be converted into a ketone by first making it thioacetal with 1,3- propanedithiol in presence of a trace of an acid. The dithiane thus formed on alkylation with a suitable alkyl halide in presence of n-buli gives a thioketal which upon hydrolysis with HgCl 2 in aqueous methanol gives corresponding ketone. ALKYLATION AND ACYLATION OF ENAMINES Enamines are α,β-unsaturated amines (ene+amine). These are formed when an aldehyde or ketone containing α-hydrogen atom/s react with a secondary amine in presence of a trace amount of an acid such as p-toluenesulphonic acid (PTS). The equilibrium is shifted in the forward direction by removing H 2 O as an azeotrope with benzene. Enamines derived from aldehydes are less stable than those from ketones and both types derived from acyclic 2 0 amines are far less stable than acyclic 2 0 amines. The commonly used 2 0 amines are pyrrolidine, piperidine and morpholine. ALKYLATION OF ENAMINES Enamines are regarded as resonance hybrid of following structures: Since β-carbon has sufficient carbanion character, therefore, enamines, act as moderately strong nucleophiles. Therefore, they undergo alkylation by S N 2 mechanism when treated with some primary alkyl halide or some other active alkyl halides such as allylic, benzylic, propargyl etc. α-haloethers and α-haloesters are also used as alkylating agents.

17 17 The hydrolysis of imine salt thus formed gives alkylated aldehyde or ketone. Synthetic utility Acylation of enamines can be used to prepare,13-dicarbonyl compounds by following sequence of reactions: (i) Preparation of enamine from the given ketone (ii) Acylation of enamine with suitable acid chloride (iii) Hydrolysis of acylated enamine For example: 2-acetylcyclopentanone may be prepared as follows: