Section 5 Ketones

The direct synthesis of a, unsaturated nitriles occurs in high yields at 40 to 50 °C from aldehydes and acetonitrile or benzyl cyanide in the presence of catalytic amounts of lb or 9b [125]. These reactions take place in both polar protic and non-polar aprotic solvents. Pro-azaphosphatrane 9b, which is a stronger base than lb, effidently catalyzes the condensation/dehydration of aromatic aldehydes and tertiary aliphatic aldehydes. The use of 9b in these reactions gave rise to products with imusuahy high E/Z ratios. With either lb or 9b, ahphatic aldehydes gave aldol products, and secondary aldehydes led to novel Michael addition products which are described in the next section. Ketones do not condense wiA either benzyl cyanide or acetonitrile under our conditions. 

In the case discussed in the previous section ketone hydrogenation was combined with kinetic resolution. In fact it can be combined with dynamic kinetic resolution using two heterogeneous catalysts, one for hydrogenation and another for racemization (Fig. 8.40). 

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 ketone may be 83mthesiseavailable commercially. The latter should first be dried, redistilled, and the fraction, b.p. 150-162°, collected. 

Use the apparatus detailed in Section 111,20. Dissolve 100 g. (123 ml.) of methyl n-butyl ketone (2-hexanone) (Section 111,152) in 750 ml. of ether and add 150 ml. of water. Introduce 69 g. of clean sodium in the form of wire (or small pieces) as rapidly as possible the reaction must be kept under control and, if necessary, the flask must be cooled in ice or in running water. When all the sodium has reacted, separate the ethereal layer, wash it with 25 ml. of dilute hydrochloric acid (1 1), then with water, dry with anhydrous potassium carbonate or with anhydrous calcium sulphate, and distil through a fractionating column. Collect the fraction of b.p. 136-138°. The yield of methyl n-butyl carbinol (2-hexanol) is 97 g. 

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. 

The following reactions are characteristic of aliphatic aldehydes those which are shared by ketones, due to the presence of the carbonyl group, are given under Aliphatic Ketones (Section 111,74). 

Dinitrophenylhydrazones. Small quantities may be prepared with the class reagent described in Section XI,7,4. A more satisfactory procedure is given under Aliphatic Ketones, Section 111,74,7. 

Semicarbazones. For experimental details, see under Aliphatic Ketones, Section 111,74,2. 

Thus if R = n-propyl (ethyl n-propylacetoacetate), methyl n-butyl ketone is produced. The preparation of this ketone is described in Section 111,152 under Ethyl Aceioacetate. 

For the preparation of methyl n butyl ketone and methyl n amyl ketone by another method, see Section 111,152. 

Methyl n-hexyl ketoxime. From methyl n hexyl ketone (Section 111,71) ill 90 per cent, yield. B.p. 106-108°/12 mm. 

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 formation of ethyl isopropylidene cyanoacetate is an example of the Knoevenagel reaction (see Discussion before Section IV,123). With higher ketones a mixture of ammonium acetate and acetic acid is an effective catalyst the water formed is removed by azeotropic distillation with benzene. The essential step in the reaction with aqueous potassium cyanide is the addition of the cyanide ion to the p-end of the ap-double bond ... 

The ketones are readily prepared, for example, acetophenone from benzene, acetyl chloride (or acetic anhydride) and aluminium chloride by the Friedel and Crafts reaction ethyl benzyl ketones by passing a mixture of phenylacetic acid and propionic acid over thoria at 450° and n-propyl- p-phenylethylketone by circulating a mixture of hydrocinnamic acid and n-butyric acid over thoria (for further details, see under Aromatic Ketones, Sections IV,136, IV,137 and IV,141). 

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. 

Oximes (compare Section III,74,B). The following procedure has wide application. Dissolve 0-5 g. of hydroxylamine hydrochloride in 2 ml. of water, add 2 ml. of 10 per cent, sodium hydroxide solution and 0-2 g. of the aldehyde (or ketone). If the latter is insoluble, add just sufficient alcohol to the mixture to give a clear solution. Heat the mixture under reflux for 10-15 minutes, and then cool in ice. If crystals separate, filter these off, and recrystallise from alcohol, dilute alcohol, benzene or light petroleum (b.p. 60-80°). If no solid separates on cooling, dilute with 2-3 volumes of water, filter the precipitated sohd, and recrystallise. 

Phenylhydrazones (compare Section III,74,C). Dissolve 0-5 g, of colourless phenylhydrazine hydrochloride and 0 8 g. of sodium acetate in 5 ml. of water, and add a solution of 0-2-0-4 g. of the aldehyde (or ketone) in a little alcohol (free from aldehydes and ketones). Shake the mixture until a clear solution is obtained and add a little more alcohol, if necessary. Warm on a water bath for 10-15 minutes and cool. Filter ofiF the crystalline derivative, and recrystalhse it from dilute alcohol or water sometimes benzene or light petroleum (b.p. 60-80°) may be used. 

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 ... 

Aromatic ketones usually have relatively high boiling points, but distil with little or no decomposition. Many are solids. The vapours generally burn with a smoky flame. They react with the 2 4-dinitrophenyll hydrazine reagent (Section 111,74,/) or with the phenylhydrazine reagent... 

Prepare a solution containing about 100 g, of potassium hypochlorite from commercial calcium hypochlorite ( H.T.H. ) as detailed under -Dimethylacrylic Acid, Section 111,142, Note 1, and place it in a 1500 ml. three-necked flask provided with a thermometer, a mechanical stirrer and a reflux condenser. Warm the solution to 55° and add through the condenser 85 g, of p-acetonaphthalene (methyl p-naphthyl ketone) (1). Stir the mixture vigorously and, after the exothermic reaction commences, maintain the temperature at 60-70° by frequent cooling in an ice bath until the temperature no longer tends to rise (ca. 30 minutes). Stir the mixture for a further 30 minutes, and destroy the excess of hypochlorite completely by adding a solution of 25 g. of sodium bisulphite in 100 ml. of water make sure that no hypochlorite remains by testing the solution with acidified potassium iodide solution. Cool the solution, transfer the reaction mixture to a 2-litre beaker and cautiously acidify with 100 ml. of concentrated hydrochloric acid. Filter the crude acid at the pump. 

The commercial product, m.p. 53-55°, may be used. Alternatively the methyl -naphthyl ketone may be prepared from naphthalene as described in Section IV,136. The Friedel - Crafts reaction in nitrobenzene solution yields about 90 per cent, of the p-ketone and 10 per cent, of the a-ketone in carbon disulphide solution at — 15°, the proportions ore 65 per cent, of the a- and 35 per cent, of the p-isomer. With chlorobenzene ns the reaction medium, a high proportion of the a-ketone is also formed. Separation of the liquid a-isomer from the solid p-isomer in Such mixtures (which remain liquid at the ordinary temp>erature) is readily effected through the picrates the picrate of the liquid a-aceto compound is less soluble and the higher melting. 

The mechanism, of the base-catalysed acylation of ketones by esters probably involves several steps (compare acetoacetlc ester condensation see discussion prloi to Section 111,151) —... 

The preparation of benzoylacctone Is another example of the acylation of a ketone (acetophenone) by ethyl acetate to a p diketone (Claisen condensation compare preceding Section) ... 

Secondary alcohols may be oxidised to the corresponding ketones with aluminium ferf.-butoxlde (or tsopropoxlde) In the presence of a large excess of acetone. This reaction Is known as the Oppenauer oxidation and Is the reverse of the Meerweln - Ponndorf - Verley reduction (previous Section) it may bo expressed ... 

Naphthylacetic acid. In a conical or round-bottomed flask, fitted with a reflux condenser by means of a ground glass joint, place a mixture of 128 g. of )3-naphthyl methyl ketone (Section IV,136), 35 g. of sulphur and... 

If an unknown compound gives a positive test with the 2 4-dinitrophenylhydrazine reagent, it then becomes necessary to decide whether it is an aldehyde or a ketone. Although the dimedone reagent (Section 111,70,2) reacts only with aldehydes, it is hardly satisfactory for routine use in class reactions. It is much simpler to make use of three other reagents given below, the preparation and properties of which have already been described (Section 111,70). 

Suggestions as to the methods for identifying the above classes of compounds will be found under Class Reactiona in Section XI,7. Some fimther remarks upon enolic compounds (see Table IV,1I4A) may be made here. Enols may be divided into (a) p-keto esters and (b) 1 3-diketones. With 5 per cent, sodium hydroxide solution, a p-keto ester yields the salt of the corresponding acid, which when heated with dilute hydrochloric acid is decarboxylated to a ketone ... 

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