Haworth reaction

Friedel-Crafts reaction of an arene with succinic anhydride is followed by reduction and an additional intramolecular Friedel-Crafts reaction to give tetralone. The entire process is called the Haworth reaction. 

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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). 

Haworth reaction Hell-Volhard-Zelinsky reaction Hoesch reaction Hofmaim reaction. ... 

Friedel-Crafts Acylation. The Friedel-Crafts acylation procedure is the most important method for preparing aromatic ketones and thein derivatives. Acetyl chloride (acetic anhydride) reacts with benzene ia the presence of aluminum chloride or acid catalysts to produce acetophenone [98-86-2], CgHgO (1-phenylethanone). Benzene can also be condensed with dicarboxyHc acid anhydrides to yield benzoyl derivatives of carboxyHc acids. These benzoyl derivatives are often used for constmcting polycycHc molecules (Haworth reaction). For example, benzene reacts with succinic anhydride ia the presence of aluminum chloride to produce P-benzoylpropionic acid [2051-95-8] which is converted iato a-tetralone [529-34-0] (30). 

Friedel-Crafts acylation can be carried out with cyclic anhydrides,272 in which case the product contains a carboxyl group in the side chain. When succinic anhydride is used, the product is ArCOCH2CH2COOH. This can be reduced (9-37) to A1CH2CH2CFLCOOH, which can then be cyclized by an internal Friedel-Crafts acylation. The total process is called the Haworth reaction 173... 

Haworth reaction, for synthesis of polynuclear hydrocarbons, 726, 728J, 737, 738... 

Acylation by acid anhydrides also prevents somerization, but Ihis is wastelut ot reagent, since half of If IS converted into the cartao> ylic acid, and is therefore economicafly unacceptable. Nevertheless, cyclic anhydrides are viable reagents, as m the Haworth reaction (see Chapter 12). 

Haworth reaction A reaction in which an aryl compound is treated with a cyclic anhydride, such as succinic anhydride, and the intermediate Friedel-Crafts product is reduced and then cyclised via an internal Friedel-Crafts reaction to give a 1,2-disubstituted aromatic compound with a carbonyl group in the new ring. The whole sequence is called the Haworth reaction. 

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 tetralone derivatives produced by the Haworth reaction are important synthetic intermediates. However, in Haworth s original work, his efforts were directed toward the synthesis of phenanthrene fi-om naphthalene. Thus the synthesis of tetralone derivative 12 by the standard Haworth conditions is followed by a Clemmensen " or Wolff-Kishner reduction of the ketone... 

The Haworth synthesis of tetralone derivatives has found substantial utility in natural product and small molecule synthesis. Zubaidha and co-workers performed the Haworth reaction on 2-methylanisole (15) to yield 18 as an intermediate in the synthesis of ( )-heritol (19), a potent itchthyotoxin. Beginning with 15, acylation to yield 16 is followed by the Clemmensen reduction to produce 17. Subsequent intramolecular Friedel-Crafts acylation results in the formation of tetralone 18. Ferraz and coworkers have also synthesized 18 in the same manner as an intermediate for the synthesis of ( )-mutisianthol (20), a potential antitumor agent. In addition, this substrate 18 has been used for the synthesis of various a-tetralols as substrates for enzymatic resolution studies. ... 

In addition to tolerating substitution on the aromatic ring, the Haworth reaction proceeds with derivatives of succinic anhydride, allowing for broad substrate scope. Norlander and coworkers used an amide-... 

In efforts toward the synthesis of aromatic ring-fused cyclic 1,2-diketones, Ranu and Jana also made use of the Haworth reaction when anisole (30) and 31 were treated under Friedel-Crafts conditions to produce 32. Subsequent reduction and cyclization produced 33 in good yield. ... 

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