Anhydrides Haworth synthesis

There are two main synthetic routes to naphthalene the Haworth synthesis and a Diels-Alder approach. In the Haworth synthesis (Scheme 12.1), benzene is reacted under Friedel-Crafts conditions with succinic anhydride (butanedioic anhydride) to produce 4-oxo-4-phenylbutanoic acid, which is reduced with either amalgamated zinc and HCl (the Clemmensen reduction) or hydrazine, ethane-1,2-diol and potassium hydroxide (the Wolff-Kischner reaction) to 4-phenylbutanoic acid. Ring closure is achieved by heating in polyphosphoric acid (PPA). The product is 1-tetraione and reduction of the carbonyl group then gives 1,2,3,4-tetrahydronaphthalene (tetralin). Aromatization is achieved by dehydrogenation over a palladium catalyst. 

There are two major routes to phenanthrene, both of which can be used to prepare substituted derivatives. In the Haworth synthesis (Scheme 12.11), reaction of naphthalene with succinic anhydride yields an oxobut-anoic acid which is reduced under Clemmensen conditions to the butanoic acid. Cyclization in sulfuric acid and reduction of the resulting ketone is followed by dehydrogenation over palladium-on-carbon to phenanthrene. Alkyl or aryl derivatives can be obtained by treatment of the intermediate ketone with a Grignard reagent prior to dehydration and oxidation. 

Benzanthracene, Benzlajanthracene 2,3-benzphenanthrene tetraphene benzanthrene naphthanthra-cene. C,HI2 mol wt 228.28. C 94.70%, H 5.30%. Occurs in coal tan Cook el at. J. Chcm. Soc. 1933, 395. Synthesis from naphthalene and phthalic anhydride Elbs, Her. 19, 2209 (1886). From o-to uy] naphthalene Fieser, Dietz, Ber. 62, 1827 (1929). From phenanthrene and succinic anhydride Haworth, Mavin, J. Chcm. Soc. 1933, 1012. Absorption spectrum Capper, Marsh, J. Chem. Soc. 1926, 726 Clar. Ber. 65, 507 (1932) Mayneord, Roe, Proc. Roy. Soc. London A152, 299 (1935). Review E. Clar. Polycyclic Hydrocarbons (Academic Press, New York, 1964) 2 vols. 

A further example is given below illustrating the use of a dibasic anhydride (succinic anhydride) the succinoylation reaction is a valuable one since it leads to aroyl carboxylic acids and ultimately to polynuclear hydrocarbons. This general scheme of synthesis of substituted hydrocarbons through the use of succinic anhydride is sometimes called the Haworth reaction. Thus a-tetralone (see below) may be reduced by the Clemmensen method to tetralin (tetrahydronaphthalene) and the latter converted into naphthalene either catal3d.ically or by means of sulphur or selenium (compare Section, VI,33). 

Reaction of succinic anhydride with benzene in the presence of anhydrous aluminium chloride (slightly over two equivalents see above) yields 3-benzoylpropanoic acid. This may be reduced by the Clemmensen method in the presence of a solvent (toluene) immiscible with the hydrochloric acid to 4-phenylbutanoic acid. Cyclisation to a-tetralone (Expt 6.123) is then effected smoothly by treatment with hot polyphosphoric acid. This reaction sequence represents the first stages in the Haworth procedure for the synthesis of polycyclic aromatic hydrocarbons (see Section 6.1.4, p. 839). 

Haworth phenanthrene synthesis. Acylation of aromatic compounds with aliphatic dibasic acid anhydrides to (i-aroylpropionic acids, reduction of the carbonyl group according to Clemmensen or Wolff-Kishner procedures, cyclization of the y-arylbutyric acid with 85% sulfuric acid, and conversion of the cyclic ketone to polycyclic hydroaromatic and subsequently to aromatic compounds. 

Anthracene. IsraeU chemists have modified the Haworth succinic anhydride synthesis of phenanthrenes to a synthesis of anthracene. Thus treatment of the ketone (1) with PPA at 140° for an extended period results in formation... 

Haller-Bauer reaction, 525 a-Halo acyl chlorides, 75 2-Haloethyl esters, 553 y-Halo ketones, 524 Halomcthyl aryl ketones, 103 Halomethyl aryl sulfones, 41 Halomethylation, 105 tj-Halo-l-phenyl-l-alkynes, 165 Halopropyl isocyanates, 570 2-Halopyridines, 479 Halo-a,p-unsaturated ketones, 647-648 p-Halovinyl ketones, 644 Haworth succinic anhydride synthesis, 474 Hemithioacetal interchange, 381-382... 

The Haworth reaction is a classical method for the synthesis of tetralone, beginning with benzene and succinic anhydride. The three-step protocol involves a Friedel-Crafts acylation, followed by reduction of the arylketone, and an intramolecular Friedel-Crafts acylation. The tetralone analog may be further reduced and dehydrogenated to form new aromatic species, in what is known as the Haworth phenanthrene synthesis. 

Although the modem Haworth reaction is more commonly used to form tetralone analogs, the reaction sequence first targeted the synthesis of phenanthrene and its derivatives. The original protocol used by Robert Downs Haworth in 1932 involved the reaction of naphthalene (1) with succinic anhydride (2) and aluminum chloride to form nearly equal quantities of naphthoylpropionic acids 3 and 4. 

The Haworth phenanthrene synthesis has been extensively used in the synthesis of derivatives of chrysene,an environmental pollutant which exhibits tumorigenic and mutagenic properties. For example Harvey and coworkers treated 61 with succinic anhydride under Friedel-Crafts conditions to produce 62. Reduction of the ketoacid under Wolff-Kishner conditions is followed by esterification to yield 63. Dehydrogenation of 63 is followed by saponification to yield carboxylic acid 64. Intramolecular Friedel-Crafts acylation produces tetralone derivative 65, which undergoes carbonyl reduction and dehydrogenation to produce 66. 

As one outcome of an investigation into methods for the synthesis of the berberine type of alkaloid by Perkin and his collaborators, in the course of which an extensive series of bases related to, or associated with berberine, including the interesting linear berberine paraberine), were prepared, Haworth, Perkin and Pink devised a general method for such syntheses, of which examples are given under protopine (p. 299) and cryptopine (p. 295), and which was applied by Haworth, Koepfli and Perkin to oxyberberine and palmatine (p. 342). For these two alkaloids it involved the preparation of 3 4-dimethoxyfeonjophthalic anhydride, which was condensed with )S-piperonylethylamine and the resulting phlhalamic acid (XXIII), as the methjd ester, boiled with phosphorus oxychloride, which converted it into oxyberberine (XXH). 

The conversion of tetrahydroberberine into tetrahydropalmatine, first achieved by Spath and Lang, is described elsewhere (p. 292). By demethylenating berberine sulphate Sp th and Quietensky obtained the dihydric phenolic base (XXV R = R = H), which on complete 0-methylation yielded palmatine (XXV R = R = Me), and on partial methylation gave jatrorrhizine (XXV R = H R = Me), the latter being isolated and identified as di-tetrahydrojatrorrhizine (p. 291). Columbamine is represented by (XXV R = Me R = H). A complete synthesis of palmatine was effected by Haworth, Koepfli and Perkin, who condensed 3 4-dimethoxyAomophthalic anhydride with 8-veratryl-ethylamine to -j8-veratrylethyl-3 4-dimethoxy omophthalamic acid, the methyl ester (XXVI) of which was converted by treatment with phosphorus oxychloride into oxypalinatine (XXVII), CjiHjiO N, buff-coloured prisms, m.p. 183°. This behaves like oxyberberine (XXII, p. 335), and on electrolytic reduction yields dZ-tetrahydropalmatine, m.p. 147°, which on oxidation with iodine in alcohol furnished palmatine (XXV R = R = Me) in the form of the iodide, m.p. 241° (dec.). 

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