Perkin synthesis

Synthesis of a,/3- and /3,y-unsaturated carboxylic acids a. Perkin synthesis 

In 1868 W. H. Perkin, Sen., discovered that heating the sodium derivative of salicylaldehyde with acetic anhydride led to coumarin,882 and this reaction has gained great importance as a method of synthesizing %,/ -unsaturated acids. The method consists of heating an aromatic aldehyde with the anhydride of an aliphatic acid and the sodium or potassium salt of the same acid. This reaction, the Perkin synthesis, can also be carried out with cinnamaldehyde but not with purely aliphatic aldehydes. 

Cainelli, F. Bertini, P. Grasselli, and G. Zubiani, Tetrahedron Lett., 1967, 5153. 

Cinnamic acid 883 Freshly distilled benzaldehyde (20 g), acetic anhydride (30 g), and freshly molten sodium acetate (10 g) are heated under reflux for 16 h. When cold, the product is stirred into water, the unchanged benzaldehyde and some of the acetic acid are removed in steam, the residue is neutralized with dilute alkali, and the solution is filtered hot. Acidification with hydrochloric acid then precipitates cinnamic acid (15-17 g, 57 %). Longer heating (24 h) raises the yield to 70-75 %.879 

Under the usual conditions of the Perkin reaction, cinnamaldehyde gives an excellent yield of 5-phenyl-2,4-pentadienoic acid 890 but decarboxylation occurs when it is heated with phenylacetic acid and acetic anhydride in the presence of lead(n) oxide, 1,4-diphenyl-1,3-butadiene being formed in 30% yield,891 and under these conditions two equivalents of cinnamaldehyde and one of succinic acid give l,8-diphenyl-l,3,5,7-octatetraene.892 

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Fig. 2 Representative traditional methods for coumarins synthesis, (a) Perkin synthesis (b) Pechmann-type condensation (c) Knoevenagel-type condensation...

The two most important natural pentoses, 1 -arabinose and 1 -xylose, occur in nature as polymeric anhydrides, the so-called pentosans, viz. araban, the chief constituent of many vegetable gums (cherry gum, gum arabic, bran gum), and xylan, in wood. From these pentapolyoses there are produced by hydrolysis first the simple pentoses which are then converted by sufficiently strong acids into furfural. This aldehyde is thus also produced as a by-product in the saccharification of wood (cellulose) by dilute acids. Furfural, being a tertiary aldehyde, is very similar to benzaldehyde, and like the latter undergoes the acyloin reaction (furoin) and takes part in the Perkin synthesis. It also resembles benzaldehyde in its reaction with ammonia (p. 215). 

Production. Coumarin is currently produced by Perkin synthesis from salicyl-aldehyde. In the presence of sodium acetate, salicylaldehyde reacts with acetic anhydride to produce coumarin and acetic acid. The reaction is carried out in the liquid phase at elevated temperature. 

Use of the Knoevenagel reaction (67OR(l5)204), in which a benzaldehyde reacts with an activated methylene compound in the presence of an amine, goes some way to overcoming the inherent difficulties of the Perkin synthesis of coumarins (see later). In order to obtain the coumarin rather than the usual cinnamic acid, a 2-hydroxy substituent must be present... 

The vigorous conditions which are necessary serve to detract from the value of the Perkin synthesis, leading to the production of tarry material which adversely affects the yield of coumarin. Difficulties encountered in the synthesis of substituted o-hydroxybenzaldehydes also limit the application of this route. The obvious advantages of the method are that there are no doubts about the orientation of the product and that, unlike the Pechmann reaction, formation of the isomeric chromones is not possible. 

In addition to the examples of coumarin syntheses given in the reviews mentioned above and in the treatise on heterocyclic compounds (B-51MI22400), more recent studies have made use of the Perkin synthesis. These include the use of substituted phenoxyacetic acids to prepare 3-phenoxycoumarins (78CI(L)628> and the synthesis of chlorocoumarins from chlorosalicylaldehydes (81T2613). The use of DBU in place of sodium acetate was necessary to effect the ring closure of a number of o-hydroxyketones (78BCJ1907). 

The Perkin synthesis of cinnamic acids is considered to involve reaction of the enolate anion derived from the acid anhydride with the aldehyde, giving rise to the alkoxide (391). Intramolecular acylation follows and the resulting /3-acyloxy derivative undergoes elimination to the unsaturated acid (Scheme 125). 

Malonic acid itself can react with aldehydes in the presence of piperidine by way of a Knoevenagel condensation. A decarboxylation occurs after the condensation, and this decarboxylation cannot be avoided. Figure 13.55 shows how the overall reaction can be employed for the synthesis of cinnamic or sorbic acid. This reaction sequence occurs under much milder conditions than the Perkin synthesis of cinnamic acids. (The Perkin synthesis consists of the condensation of aromatic aldehydes with acetic acid anhydride in the presence of sodium acetate.)... 

This is the simplest case of the reaction but it has been mostly used in the synthesis of higher members of the unsaturated acid series, e.g., the nine carbon acid, nonylenic acid, which is prepared from the seven carbon aldehyde known as oenanthylic aldehyde, or oenanthol, obtained from castor oil. Even more important than its application in the synthesis of higher acids of the ethylene series is the use of the reaction in the synthesis of aromatic unsaturated cLcids derived from benzene and containing an unsaturated side chain (see cinnamic acid. Part II). The reaction is known as the Perkin Synthesis or as the Perkin-Fittig Synthesis from the men who suggested and explained it. 

Perkin Synthesis of Coumarin.—Coumaric acid and coumarin may be synthesized by the Perkin reaction for synthesizing unsaturated aromatic acids (p. 698). These syntheses are of historical interest as the two compounds obtained were the first onesprepared by this reaction. Instead of taking a simple aromatic aldehyde it is only necessary to take a phenol aldehyde viz., salicylic aldehyde,... 

Kalnin, P. The mechanism of the Perkin synthesis. Helv. Chim. Acta 1928,11, 977-1003. 

The reaction involved in the Perkin synthesis takes place in accordance with this equation ... 

Recently, it has been reported that significantly higher yields are obtained and shorter reaction times required in the Perkin synthesis of cinnamic acids when sodium acetate is replaced by cesium acetate. ... 

Cinnamic acid is manufactured by the so-called Perkin synthesis, which has been applied to the preparation of a large number of unsaturated acids. When benzoic aldehyde is heated with anhydrous sodium acetate in the presence of acetic anhydride, condensation takes place as the result of the loss of water CeHs.CHO + CHg.COONa = CeHB.CHrCH.COONa + H2O A similar condensation takes place between benzoic aldehyde and homologues of acetic acid. The hydrogen atoms which are eliminated from the salt of the fatty acid are those in the a-posi-tion —... 

CeHs-CHO + CHs.CHj.COONa = CeHsCH C.COONa + H2O It has been shown that the formation of unsaturated acids by the Perkin synthesis takes place as the result of two reactions. The aldehyde and the salt first form an addition-product, which resembles in structure other addition-products of aldehydes — H H... 

Benzaldehyde condenses with aliphatic compounds in an analogous manner the Perkin synthesis (553) is an example —... 

This reaction was first reported by Perkin in 1883. It is the nucleophilic alkylation between malonic ester and Q, o)-alkyl dihalide to form cyclic aliphatic 1,1-diester or acid and is known as the Perkin reaction or Perkin synthesis. Although it was once referred to as the Perkin condensation, this name should not be used for this type of reaction. Using this protocol, Perkin successfully prepared cyclopropane-, cyclobutane-, cyclopentane-, cyclohexane-, and cycloheptane-1,1-dicarboxylie acids. However, this reaction is often complicated by the side reaction that forms Q, o, a ,a -tetracarboxylic ester from the Sn2 reaction between malonic ester and o, a -alkyl dihalide, this side reaction can be depressed if alcoholic sodium malonic ester is added slowly to the o, a -alkyl dihalide with vigorous stirring. It is interesting that the K2CO3 promoted a reaction between dimethyl 1,3-acetonedicarboxylate and tran5 -l,4-dibromobutene yields vinyldihydrofuran. ... 

Other references related to the Perkin synthesis are cited in the literature. ... 

Perkin, Sir William Henry (1838-1907) English chemist who worked as assistant to August Hofmann and, in 1856, discovered a brilliant purple dye. Later named mauveine, his invention became immensely popular, earned him a fortune, and led to the foundation of the modern synthetic dye industry. Some of his work on the synthesis of organic compounds, known as the Perkin synthesis, led to the development of the synthetic perfume industry. 

Hrnciar, P., and D. Joniak Phthalides and 1,3-Indandiones. XXL Perkin Synthesis of 7-Nitro-3-benzalphthalide and 4-Nitro-3-benzalphthalide their Reduction and Conversion into 4-Acetamino-2-phenylindan-l,3-dione. Chem Zvesti 20, 336 (1966). Chem. Abstr. 65, 8832h (1966). 

Perkin Synthesis. This synthesis is a well-known organic reaction yielding cinnamic acid from an aromatic aldehyde and an anhydride. Commonly, sodium acetate has been used in the reaction as a base catalyst. However, significant increase in yield was found when cesium acetate was used instead of sodium acetate (eq 6). In fact, yields were shown to increase up to 10 times with certain aryl substrates when cesium acetate was substituted for sodium acetate. ... 

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