Aldehydes Perkin reactions, acetic anhydride

In the Perkin reaction, acetic anhydride condenses with an aromatic aldehyde to yield a cinnamic acid. The reaction takes place by a mixed carbonyl condensation of the anhydride with the aldehyde to yield an a,/l-unsaturated intermediate that undergoes hydrolysis to yield the cinnamic acid. What is the structure of the unsaturated intermediate ... 

Condensation with Other Carbonyl Compounds. Carboxy Anhydrides (Perkin reaction). Carboxy anhydrides, such as acetic acid anhydride, are usually condensed with aldehydes which do not contain active a-H atoms. Although other aldehydes could be used, in this type of reaction, the formation of undesirable byproducts restricts the choice of aldehydes. With an aldehyde containing no a-H atoms, the basic catalyst will react with the a-H atoms of the carboxy anhydride and produce a basic anion, as shown in equation 11. 

A variant of the Perkin reaction is the Erlenmeyer-Plochl-azlactone synthesis By condensation of an aromatic aldehyde 1 with an N-acyl glycine 5 in the presence of sodium acetate and acetic anhydride, an azlactone 6 is obtained via the following mechanism ... 

Formylfuran behaves in a very similar manner to benzaldehyde and undergoes the usual reactions of an aromatic aldehyde, e.g. (i) the Cannizzaro reaction with cone, sodium hydroxide to give furan-2-ylmethanol and the sodium salt of furoic acid, (ii) the Perkin reaction with acetic anhydride and sodium acetate to yield an aldol product that dehydrates to 3-(furan-2-yl)propenoic acid, and (iii) a condensation with potassium cyanide in alcoholic solution to form furoin (under these conditions, benzaldehyde undergoes the benzoin condensation) (Scheme 6.32). 

Hydrogenation of benzaldehyde yields benzyl alcohol, condensation with aliphatic aldehydes leads to additional fragrance substances or their unsaturated intermediates. Unsaturated araliphatic acids are obtained through the Perkin reaction, for example, the reaction with acetic anhydride to give cinnamic acid. 

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. 

Enols or enolates from anhydrides are not used very often in aldol reactions other than in one important application, usually known as the Perkin reaction. An acid anhydride, such as acetic anhydride, is combined with a non-enolizable aldehyde and a weak base, usually the salt of the acid. This base is used so that nucleophilic attack on the anhydride does no hami, simply regenerating the anhydride. q... 

Classically, this separation of roles was accomplished by utilizing substrates that differed drastically in their ability to form enolate anions. In fact, the various name reactions mentioned above are distinguished not by basic differences in mechanism, but by the nature of the components preferentially utilized as substrates. For example, in the Perkin reaction, the condensation of an aromatic aldehyde with an aliphatic acid anhydride is based on the fact that the electrophilic component, e.g. benzaldehyde, lacks a-hydrogens and therefore is incapable of forming an enolate. At the same time the utilized electrophile, acetic anhydride, contains a carbonyl group with reduced propensity to interact with nucleophiles. Hence, it is incapable of undergoing self-condensa-... 

The reaction of benzaldehyde with phenylacetic acid to produce a mixture of the a-carboxylic acid derivatives of Z- and -stilbene a form of aldol condensation known as the Perkin reaction, is effected by heating a mixture of the components with acetic anhydride and triethylamine. In the course of the reaction the phenylacetic acid is probably present both as anion and as the mixed anhydride resulting from equilibration with acetic anhydride. A reflux period of 5 h specified in an early procedure has been shortened by a factor of 10 by restriction of the amount of the volatile acetic anhydride, use of an excess of the less expensive, high-boiling aldehyde component, and use of a condenser that permits some evaporation and consequent elevation of the reflux temperature. 

The Perkin reaction involves the condensation of a carboxylic acid anhydride and an aldehyde in the presence of a weak base, often the sodium or potassium salt of the acid or triethylamine, to give unsaturated carboxylic acids (equation 1). The first example of this reaction was described by Perkin in 1868 and involves a synthesis of coumarin by heating the sodium salt of salicylaldehyde with acetic anhydride (equation 2). The reaction is generally applicable only to aromatic aldehydes and is particularly useful for the preparation of substituted cinnamic acids, as illustrated by equation (3). ... 

Simple aliphatic or aromatic ketones are not suitable substrates in the Pericin transformation. Similarly, aliphatic aldehydes are not generally acceptable components in this reaction. This long-known limitation was studied by Crawford and Little. They demonstrated that many aliphatic aldehydes give diacetates and enol acetates when heated with acetic anhydride, with or without sodium acetate, suggesting this side reaction causes the typical Perkin process to fail. Semmeler had previously obtained similar results. They did show, however, that several short chain aldehydes, as well as frowj-citral (16), undergo the Perkin condensation with p-nitrophenylacetic anhydride the p-nitrophenyl substituent activates the anhy-... 

An important variation of the Perkin reaction is the Erlenmeyer azalactone synthesis exemplified by equation (4), involving condensation of an aldehyde and an N-acylglycine derivative in the presence of acetic anhydride and sodium acetate. Although this reaction, analogous to the classical Perkin condensation, was initially limited to the use of aromatic aldehydes, Baltazzi and Robinson reported that the use of lead acetate and THF allowed the preparation of several azalactones derived from aliphatic aldehydes (equation 15). The results for the condensation of several aldehydes and ketones with hippuric acid (28) under these conditions are shown in Table 2. The reaction proceeds through the intermediate (26) (intramolecular condensation of 25), which reacts with the aldehyde in Perkin fashion to provide the so-called azalactone product (Scheme 8). It is the formation of such oxazolones from acylamino acids which is be-... 

Phthalic anhydride, when used as the carbonyl component in the Perkin reaction, affords, on treatment with acetic anhydride and potassium acetate, phthalylacetic acid (15 equation 12).24 a-Arylacetic acids also react with aromatic aldehydes to afford a-arylcinnamic acids (Ogliaro modification of the Perkin condensation, equation 7) 1 this type of reaction presumably involves die formation of the mixed anhydride of phenylacetic acid and acetic acid and/or phenylacetic anhydride. This modification is also illustrative of the equilibrium that is established between acid, acid salt and acid anhydrides under the conditions of the reaction. 

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. 

The methylene group of malonic or cyanoacetic acid is sufficiently reactive to condense under mild conditions with aliphatic or aromatic aldehydes or with ketones. Initially such reactions were carried out in the same way as the Perkin reaction, in acetic acid solution or in the presence of acetic anhydride however, use of acetic anhydride is unnecessary. 

A variation of this condensation involves reaction with aldehydes, and it is called the Perkin reaction. Condensation of an aldehyde (having no enolizable protons) with the enolate of an acid anhydride leads to an acetoxy ester such as 182.10 Internal acyl substitution by the alkoxide forms the 0-acetyl ester and liberates the carboxylate anion (183). Subsequent reaction with more acetic anhydride generates a new mixed... 

The most important modification of the Perkin reaction was developed by Oglialoro using the sodium salt of acetic acid (e.g., phenylacetic acid, phenoxyacetic acid ) in condensation with acetic anhydride and an aldehyde (e.g., benzaldehyde, paraldehyde ). This type of reaction is referred to as the Perkin-Oglialoro reaction,Perkin-Oglialoro condensation, or Oglialoro modification. Other modifications include the use of different bases as the catalysts, (e.g., NaB(OMe)4-LiCl, CaH2, CsOAc, and CsF ), the use of microwave irradiation and cesium acetate or fluoride in combination with a small amount of pyridine as catalyst and the continuous distillation of acetic acid to enhance the conversion rate. ... 

Cinnamic acid was prepared from benzaldehyde and acetyl chloride by Bertagnini. Cinnamic aldehyde was synthesised by Chiozza from benzaldehyde, acetaldehyde, and hydrochloric acid, and on oxidation forms cinnamic acid. Perkin synthesised cinnamic acid by the action of acetic anhydride and sodium acetate on benzaldehyde. He thought an explanation of the reaction on the lines of Fittig s hypothesis ... 

Perkin obtained only cinnamic acid from benzaldehyde, acetic anhydride, and either sodium butyrate or sodium valerate instead of sodium acetate but with sodium propionate and propionic anhydride, or sodium butyrate and butyric anhydride, in all cases at i8o°, homologues of cinnamic acid were obtained. He concluded that the salt from which the anhydride is derived must be present, but the reaction is between the aldehyde and the acid anhydride ... 

Aliphatic aldehydes give low or no yields of acid. Coumarin can be prepared by a Perkin reaction of salicylaldehyde and acetic anhydride in the presence of triethylamine (eq 33). 

Aliphatic aldehydes are easily converted to the enol acetate using acetic anhydride and potassium acetate (eq 52). This reaction only works for aldehydes and is the principal reason for the failure of aldehydes to succeed in the Perkin reaction. Triethy-lamine and DMAP may also catalyze the reaction. 

Cinnamic acid was prepared by heating dichloride of benzylene with dry acetate of sodium. This was a practical modification of the Perkin reaction of benzoic aldehyde, acetic anhydride and acetate of sodium. English patent no. 3330, 1880 (Johnson for H. Caro). See ... 

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