Phenylhydrazone of acetophenone

The Fischer Indolisation Reaction occurs when the phenylhydrazone of a suitable aldehyde or ketone undergoes cyclisation with loss of ammonia, under the influence of various reagents, such as zinc chloride, ethnnolic hydrogen chloride, or acetic acid. For example, the phenylhydrazone of acetophenone (p. 257) when heated with zinc chloride gives 2 phenylindole. ... 

Then add 3 drops of acetophenone (or about 0 3 g. of powdered benzo-phenone dissolved in 1 ml. of acetic acid) and shake the mixture. A precipitate of the phenylhydrazone is produced on scratching. 

Prepare acetophenonephenylhydrazone by warming a mixture of 20 g. of acetophenone (Section IV, 136) and 18 g. of phenylhydrazine on a water bath for 1 hour. Dissolve the hot mixture in 40 ml. of rectihed spirit, and shake or stir to induce crystallisation. Cool the mixture in ice, filter and wash with 12 ml. of rectified spirit. Dry in a vacuum desiccator over anhydrous calcium chloride for at least half an hour. The yield of phenylhydrazone, m.p. 105-106 , is 28 g. 

The present procedure was developed from those of Wallach and Freylon, based upon the general method discovered by Leuckart. a-Phenylethylamine also can be prepared satisfactorily by the reduction of acetophenone oxime with sodium and absolute alcohol or sodium amalgam, but the reagents are more expensive and the processes less convenient. The amine has been obtained by reducing acetophenone oxime electro-lytically, by reducing acetophenone phenylhydrazone with sodium amalgam and acetic acid, from a-phenylethyl bromide and hexamethylenetetramine, and by the action of methyl-magnesium iodide upon hydrobenzamide, as well as by other methods of no preparative value. 

The coupling of enamines with aromatic diazonium salts has been used for the syntheses of monoarylhydrazones of a-diketones (370,488-492) and a-ketoaldehydes (488,493). Cleavage of the initial enamine double bond and formation of the phenylhydrazone of acetone and acetophenone has been reported with the enamines of isobutyraldehyde and 2-phenylpropionalde-hyde. Rearrangement of the initial coupling product to the hydrazone tautomer is not possible in these examples. 

An important general method of preparing indoles, known as the Fischer Indole synthesis, consists in heating the phenylhydrazone of an aldehyde, ketone or keto-acfd in the presence of a catalyst such as zinc chloride, hydrochloric acid or glacial acetic acid. Thus acetophenone phenylhydrazone (I) gives 2-phenylindole (IV). The synthesis involves an intramolecular condensation with the elimination of ammonia. The following is a plausible mechanism of the reaction ... 

Hydrazones are also useful substrates in the preparation of pyrazoles. Reaction of N-monosubstituted hydrazones with nitroolefins led to a regioselective synthesis of substituted pyrazoles <060L3505>. lf/-3-Ferrocenyl-l-phenylpyrazole-4-carboxaldehyde was achieved by condensation of acetylferrocene with phenylhydrazine followed by intramolecular cyclization of the hydrazone obtained under Vilsmeier-Haack conditions <06SL2581>. A one-pot synthesis of oxime derivatives of l-phenyl-3-arylpyrazole-4-carboxaldehydes has been accomplished by the Vilsmeier-Haack reaction of acetophenone phenylhydrazones <06SC3479>. 

Prepare acetophenone phenylhydrazone by warming a mixture of 20 g (0.167 mol) of acetophenone and 18 g (0.167 mol) of phenylhydrazine (CAUTION, in handling) with 60 ml of ethanol and a few drops of glacial acetic acid. Filter the cold reaction mixture, wash the solid with dilute hydrochloric acid followed by about 12 ml of cold rectified spirit. Recrystallise a small portion from ethanol and thus obtain a sample of pure acetophenone phenylhydrazone as a white solid, m.p. 106 °C. 

Treatment of a mixture of acetophenone phenylhydrazone and dimethyl acetylenedi-carboxylate with aluminium chloride gives the ene hydrazone 98, which undergoes a spontaneous Fischer indole reaction to yield the pyrrole 99 with elimination of aniline (equation 41)62. 

Acetophenone phenylhydrazone 908 Equimolar amounts of acetophenone (40 g) and phenylhydrazine (36 g) are heated for 1 h on the water-bath, and the product is dissolved in hot ethanol (80 ml). On rubbing and cooling in ice, the phenylhydrazone crystallizes, amounting to 54-57 g after washing with 25 ml of ethanol a further 4-10 g are provided by concentration of the mother liquor and washings. When dried over calcium chloride in a vacuum-desiccator, the phenylhydrazone (total yield 61-64 g, 87-91 %) has m.p. 105-106°. 

Phenylindole is prepared from the reaction of acetophenone and phenylhydrazine, a method known as the Fischer indole synthesis. Propose a mechanism for this reaction. Hint The reactive species is the enamine tautomer of the phenylhydrazone.)... 

AlClg added under argon to a mixture of acetophenone phenylhydrazone and dimethyl acetylenedicarboxylate in benzene, and stirred 1 hr. at room temp. 2,3-bis(methoxycarbonyl)-5-phenylpyrrole. Y 74%. F. e. s. J. Barluenga, F. Palacios, and V. Gotor, Synthesis 1975, 642. 

Acetophenone similarly gives an oxime, CHjCCgHjlCtNOH, of m.p. 59° owing to its lower m.p. and its greater solubility in most liquids, it is not as suitable as the phenylhydrazone for characterising the ketone. Its chief use is for the preparation of 1-phenyl-ethylamine, CHjCCgHslCHNHj, which can be readily obtained by the reduction of the oxime or by the Leuckart reaction (p. 223), and which can then be resolved by d-tartaric acid and /-malic acid into optically active forms. The optically active amine is frequently used in turn for the resolution of racemic acids. 

Aldehydes and ketones may frequently be identified by their semicarbazones, obtained by direct condensation with semicarbazide (or amino-urea), NH,NHCONH a compound which is a monacidic base and usually available as its monohydrochloride, NHjCONHNH, HCl. Semicarbazones are particularly useful for identification of con jounds (such as acetophenone) of which the oxime is too soluble to be readily isolated and the phenylhydrazone is unstable moreover, the high nitrogen content of semicarbazones enables very small quantities to be accurately analysed and so identified. The general conditions for the formation of semicarbazones are very similar to those for oximes and phenylhydrazones (pp. 93, 229) the free base must of course be liberated from its salts by the addition of sodium acetate. 

Alkyl- and aryl-hydrazones of aldehydes and ketones readily peroxidise in solution and rearrange to azo hydroperoxides [1], some of which are explosively unstable [2], Dry samples of the p-bromo- and p-fluoro-hydroperoxybenzylazobenzenes, prepared by oxygenation of benzene solutions of the phenylhydrazones, exploded while on filter paper in the dark, initiated by vibration of the table or tapping the paper. Samples were later stored moist with benzene at —60°C to prevent explosion [3], A series of a-phenylazo hydroperoxides derived from the phenyl-or p-bromophcnyl-hydrazones of acetone, acetophenone or cyclohexanone, and useful for epoxidation of alkenes, are all explosive [4], The stability of several substituted phenylazo hydroperoxides was found to be strongly controlled by novel substituent effects [5],... 

Acetonitrile, 407 Acetophenone, 725,729,730 phenylhydrazone, 852 p-Acetotoluidide, 593, 605 Acetoxime, 343 Acetylacetone, 861, 862, 863 Acetylation, reductive, 749 Thiele, 749 Acetyl chloride, 367 2-Acetylcyciohexanone, 862, 864 Acetylene, 245, 897 reactions of, 245, 246 Acetylenic compounds, synthesis of, 467-469, 895-902 Acetylglycine, 909 Acetylmethylurea, 968, 969 Acetylsalicylio acid, 996 Acetyl-o-toluidide, 578 2-Acetylthiophene, 837 Acid anhydrides of aliphatic carboxylic acids, 371... 

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