Section 7 Esters

As we learned earlier in this section, esters that have only one a hydrogen cannot be converted to j8-keto esters by sodium ethoxide. However, they can be converted to j8-keto esters by reactions that use very strong bases such as lithium diisopropylamide (LDA) (Section 18.4). The strong base converts the ester to its enolate ion in nearly quantitative yield. This allows us to acylate the enolate ion by treating it with an acyl chloride or an ester. An example of this technique using LDA is shown here ... 

In previous sections, ester enolates were used as or carboxyl synthon. Modem techniques allow generation of both mono- and di-anions of carboxylic acids (see the formation of 4.66 in section 4.3.A). These enolate anions undergo C-alkylation and C-condensation reactions. Such compounds are also carboxyl surrogates that have proved to be useful. This section gives examples of these reactions when applied to the synthesis of amino acids. 

Hydroxamic acid formation cf. Section 9, p. 334). To a few drops of an ester, add 0 2 g. of hydroxylamine hydrochloride and about 5 ml. of 10% NaOH solution and gently boil the mixture for 1-2 minutes. Cool and acidify with dil. HCl and then add a few drops of ferric chloride solution. A violet or deep red-brown colour develops immediately. 

Section 15. Esters (pp. 354- 8, 546). Summary of Hydrolytis, Hydrolyse by boiling with 10% aqueous NaOH solution for about 30 minutes ... 

Metallic sodium. This metal is employed for the drying of ethers and of saturated and aromatic hydrocarbons. The bulk of the water should first be removed from the liquid or solution by a preliminary drying with anhydrous calcium chloride or magnesium sulphate. Sodium is most effective in the form of fine wire, which is forced directly into the liquid by means of a sodium press (see under Ether, Section II,47,i) a large surface is thus presented to the liquid. It cannot be used for any compound with which it reacts or which is affected by alkalis or is easily subject to reduction (due to the hydrogen evolved during the dehydration), viz., alcohols, acids, esters, organic halides, ketones, aldehydes, and some amines. 

The reaction with sodium is by no means an infallible practical test for alcohols since, strictly speaking, it is applicable only to pure anhydrous liquids. Traces of water, present as impurities, would give an initial evolution of hydrogen, but reaction would stop after a time if an alcohol is absent furthermore, certain esters and ketones also evolve hydrogen when treated with sodium (compare Section XI,7,6). It may, however, be assumed that if no hydrogen is evolved in the test, the substance is not an alcohol. 

Add 1 ml. of the alcohol-free ether to 0-1-0-15 g. of finely-powdered anhydrous zinc chloride and 0 5 g. of pure 3 5-dinitrobenzoyl chloride (Section 111,27,1) contained in a test-tube attach a small water condenser and reflux gently for 1 hour. Treat the reaction product with 10 ml. of 1-5N sodium carbonate solution, heat and stir the mixture for 1 minute upon a boiling water bath, allow to cool, and filter at the pump. Wash the precipitate with 5 ml. of 1 5N sodium carbonate solution and twice with 6 ml. of ether. Dry on a porous tile or upon a pad of filter paper. Transfer the crude ester to a test-tube and boil it with 10 ml. of chloroform or carbon tetrachloride filter the hot solution, if necessary. If the ester does not separate on cooling, evaporate to dryness on a water bath, and recrystallise the residue from 2-3 ml. of either of the above solvents. Determine the melting point of the resulting 3 5 dinitro benzoate (Section 111,27). 

With higher alcohols appreciable quantities of esters (compare Section 111,82) may be formed. 

The above simple experiments illustrate the more important properties of aliphatic acid chlorides. For characterisation, the general procedure is to hydrolyse the acid chloride by warming with dilute alkali solution, neutralise the resulting solution with dilute hydrochloric acid (phenol-phthalein), and evaporate to dryness on a water bath. The mixture of the sodium salt of the acid and sodium chloride thus obtained may be employed for the preparation of solid esters as detailed under Aliphatic Acids, Section 111,85. The anilide or p-toluidide may be prepared directly from the acid chloride (see (iii) above and Section III,85,i). 

Ethyl maleate of almost equal purity may be obtained by refluxing a mixture of 20 g. of pure maleic a.oid, 37 g. (47 ml.) of absolute ethyl alcohol, 05 ml. of sodium-dried benzene and 4 ml. of concentrated sulphuric acid for 12 hours. The ester is isolated as described for Diethyl Adipate (Section 111,100). The yield of diethyl maleate, b.p. 219-220°, is 26 g. 

Place 200 g, (250 ml.) of rectified spirit in a 1-litre round-bottomed flask fitted with a reflux condenser. Cool in ice and run in, slowly and with frequent shaking, 200 g. (109 ml.) of concentrated sulphuric acid. Add 83 g. (104 ml.) of -butyl cyanide (Section 111,113) to the mixture and reflux the whole for 10 hours. Allow to cool, pour the reaction mixture into ice water, separate the upper layer of ester and alcohol, and dry over anhydrous magnesium or calcium sulphate. Distil through a fractionating column and collect the ethyl n-valerate at 143-146°. A further amovmt of the pure ester may be obtained by redrying the fraction of low boiling point and redistilling. The yield is 110 g. 

Hydrolysis (or saponification) of n-butyl acetate. Boil 4-5 g. of n-butyl acetate (Section 111,95) with 50 ml. of 10 per cent, sodium hydroxide solution under reflux until the odour of the ester can no longer be detected (about 1 hour). Set the condenser for downward distiUation and coUect the first 10 ml. of distillate. Saturate it with potassium carbonate, aUow to stand for 5 minutes, and withdraw all the Uquid into a small pipette or dropper pipette. AUow the lower layer of carbonate solution to run slowly into a test-tube, and place the upper layer into a small test-tube or weighing bottle. Dry the alcohol with about one quarter of its buUr of anhydrous potassium carbonate. Remove the alcohol with a dropper pipette and divide it into two parts use one portion for the determination of the b.p. by the Siwoloboff method (Section 11,12) and convert the other portion into the 3 5-dinitrobenzoate (Section III, 27) and determine the m.p. 

Acidify the residue in the flask with dUute sulphuric acid and distil off 10-15 ml. of the solution. Test a smaU portion of the distillate for acidity, and also observe the odour. Neutralise the main portion with sodium hydroxide solution (add a drop of phenolphthalein to act as indicator), evaporate to smaU bulk, and convert the sodium salt into the p-bromophenacyl ester or into some other suitable derivative (Section 111,85) determine the m.p. of the derivative. 

Drop 1 g. of sodium into 10 ml. of ethyl alcohol in a small flask provided with a small water condenser heat the mixture until all the sodium has dissolved. Cool, and add 1 g. of the ester and 0-5 ml. of water. Frequently the sodium salt of the acid will be deposited either at once or after boiling for a few minutes. If this occurs, filter oflF the solid at once, wash it with a little absolute ethyl alcohol (or absolute methylated spirit), and convert it into the p-bromophenacyl ester, p-nitro-benzyl ester or S-benzyl-tso-thiuronium salt (for experimental details, see Section 111,85). If no solid separates, continue the boiling for 30-60 minutes, boil oflF the alcohol, allow to cool, render the product just neutral to phenolphthalein with dilute sulphuric or hydrochloric acid, convert the sodium salt present in solution into a crystalline derivative (Section 111,85), and determine its melting point. 

P Keto esters (t.g., ethyl ocetoacetate) are soluble in solutions of caustic alkalis but not in sodium carbonate solution. They give colours with freshly prepared ferric chloride solution a little alcohol should be added to bring the ester into solution. Sodium ethoxide solution reacts to yield sodio compounds, which usually crystallise out in the cold. Phenylhydrazine yields pyrazolones. They are hydrolysed by boiling sulphuric acid to the Corresponding ketones, which can be identified as usual (Section 111,74). 

The excess of alkah is then neutralised with dilute hydrochloric acid (phenolphthalein) and the solution is evaporated to dryness on the water bath. The acid may then be characterised as the S-benzyl-tao-thiuronium salt or as the p-bromophenacyl ester (Section 111,85). In many instances the derivative may be prepared directly from the neutralised solution. 

Malonic ester, like acetoacetic ester (Section 111,151), when treated with an equivalent of sodium ethoxide, forms a mono-sodium derivative, which is of great value in synthetical work. The simplest formulation of the reaction is to r rd it as an attack of the basic ethoxide ion on a hydrogen atom in the CH, group the hydrogen atoms in the CHj group are activated by the presence of the two adjacent carbethoxyl groups ... 

Into a 2-litre, three-necked flask, fitted with a separatory funnel, a mechanical stirrer and a reflux condenser, place a hot solution of 200 g. of potassium hydroxide in 200 ml. of water. Stir the solution and add slowly 200 g. of ethyl n-butylmalonate (Section 111,154). A vigorous reaction occurs and the solution refluxes. When all the ester has been added, boil the solution gently for 2-3 hours, i.e., until hydrolysis is complete a test portion should dissolve completely in water. Dilute with 200 ml. of water and distil oflF 200 ml. of liquid in order to ensure the complete removal of the alcohol formed in the hydrolysis (1) it is best to connect the flask by means of a wide delivery tube to a condenser set for downward distillation (compare Fig. II, 41, 1 but with a mercury-sealed stirrer in the centre neck). Replace the separatory funnel and the reflux condenser. 

The ester and catalj st are usually employed in equimoleciilar amounts. With R =CjHs (phenyl propionate), the products are o- and p-propiophenol with R = CH3 (phenyl acetate), o- and p-hydroxyacetophenone are formed. The nature of the product is influenced by the structure of the ester, by the temperature, the solvent and the amount of aluminium chloride used generally, low reaction temperatures favour the formation of p-hydroxy ketones. It is usually possible to separate the two hydroxy ketones by fractional distillation under diminished pressure through an efficient fractionating column or by steam distillation the ortho compounds, being chelated, are more volatile in steam It may be mentioned that Clemmensen reduction (compare Section IV,6) of the hj droxy ketones affords an excellent route to the substituted phenols. 

By the condensation of a nitrile with a phenol or phenol ether in the presence of zinc chloride and hydrogen chloride a hydroxyaryl- or alkoxyaryl-ketone is produced. The procedure is termed the Hoesch reaction and is clearly an extension of the Gattermann aldehyde reaction (Section IV,121). The reaction gives the best results with polyhydric phenols and their ethers with simple monohydric phenols the imino ester hydrochloride is frequently the sole product for example ... 

By the malonic ester synthesis (compare Section 111,165), for example ... 

This product is sufficiently pure for the preparation of phenylacetic acid and its ethyl ester, but it contains some benzyl tso-cyanide and usually develops an appreciable colour on standing. The following procedure removes the iso-cyanide and gives a stable water-white compound. Shake the once-distilled benzyl cyanide vigorously for 5 minutes with an equal volume of warm (60°) 60 per cent, sulphuric acid (prepared by adding 55 ml. of concentrated sulphuric acid to 100 ml. of water). Separate the benzyl cyanide, wash it with an equal volume of sa+urated sodium bicarbonate solution and then with an equal volume of half-saturated sodium chloride solution- Dry with anhydrous magnesium sulphate and distil under reduced pressure. The loss in washing is very small (compare n-Butyl Cyanide, Section 111,113, in which concentrated hydrochloric acid is employed). 

Aromatic esters may be prepared by methods similar to those already described for aliphatic esters (see discussion preceding Section 111,95). These include —... 

By the Schotten-Baumann reaction. Under the usual Schotten-Baumann conditions (compare discussion preceding Section IV,52, also Section IV,100,2and Section IV,114,2), esters are readily formed, forexample ... 

The esters formed with p-nitrobenzoyl chloride and 3 5-dinitrobenzoyl chloride (see Section 111,27,1 and 2 and Section IV,205) must be Includ under this heading. 

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