Preparation of acid anhydrides

Introduction. The object of this experiment is to illustrate two general methods for the preparation of acid anhydrides. Two carboxyl groups may under certain conditions be dehydrated to give an anhydride. The two carboxyl groups may be derived from the same molecule, as in succinic and phthalic anhydrides, or from different molecules, as in acetic anhydride. The simple anhydrides are usually prepared in the laboratory by the action of an acyl chloride on the salt of the acid  

If the acyl chlorides are not available, use may be made of excess of acetic anhydride or acetyl chloride to dehydrate the acid. For example, succinic acid when refluxed with excess of acetic anhydride or acetyl chloride is converted completely to succinic anhydride  

In many cases, particularly for aryl acid anhydrides, the sodium, ammonium, or potassium salt of the acid is heated with sufficient phosphorus oxychloride or thionyl chloride to convert half of the salt into the acid chloride. The latter reacts with the other half of the salt to give the anhydride. This method is used for the preparation of the anhydride of o-sulfobenzoic acid (see page 339). Finally, a few dicarboxylic acids, such as phthalic acid, which contain two carboxyl groups attached to adjacent carbon atoms, when heated above their melting point lose water and form the anhydride. 

The most important use of anhydrides is for the acylation of hydroxy and amino compounds. Acetic anhydride is the most im- 

1 Anhydrous sodium acetate is dehydrated by heating in an iron dish, as directed on page 354 of the Appendix. 

---

Preparation of acid anhydrides Acid anhydrides are prepared from carboxylic acids by the loss of water. For example, acetic anhydride is prepared industrially by heating acetic acid to 800 °C. Other anhydrides are difficult to prepare directly from the corresponding carboxylic acids. Usually they are prepared from acid chloride and sodium carboxylate salt (see below). 

Preparation of acid anhydrides Acid chloride reacts with sodium carhoxylate to give acid anhydride through nucleophilic acyl substitution reaction. Both symmetrical and unsymmetrical acid anhydrides are prepared in this way. 

Acid Anhydrides Preparation of Acid Anhydrides Ketene Reaction... 

Potassium nitrate may be used for the preparation of acid anhydrides from acid chlorides, by distilling the latter after mixing with the alkaline nitrate.43... 

Carbodiimides, in particular dicyclohexylcarbodiimide, have been applied in many syntheses where dehydration had to be performed under mild conditions. It is therefore no surprise that this reagent was also introduced for the synthesis of acid anhydrides from carboxylic acids." " In order to avoid N-acylation the reactions are carried out at low temperature. First 0-acylisoureas are formed, which then react further with free acid to the acid anhydride (equation 34). The reaction has been exploited in particular for the preparation of peptides." )V-alkoxycarbonyl-protected amino acids can be transformed in high yield to the corresponding anhydrides, which themselves are activated acid derivatives and may be converted to peptides. As in many other examples polymer-bound carbodiimides may prove superior sometimes, as the isolation of the products is facilitated. Easy preparation of acid anhydrides is possible in this way." ... 

Chlorosulfonyl isocyanate was introduced by Olah for the preparation of acid anhydrides. Under very mild conditions it is even possible to obtain formic acid anhydride. This method has been applied successfully to other examples (equation 38). ... 

One of the classic procedures for the preparation of acid anhydrides is based on the reaction of metal salts of acids with acid halides. It offers the opportunity to obtain symmetrical and unsymmetrical acid anhydrides. A number of different metal salts have been applied over the years. 

For the reaction of sodium salts with acid halides a procedure was developed which allows preparation of acid anhydrides in aqueous solution in the presence of a tertiary base (Table 8). 

Mild dehydrating agents are available in yneamines and 1-alkoxyalkynes. They have been applied occasionally to the preparation of acid anhydrides.The great advantage of these reagents is that the reaction takes place under neutral conditions and, therefore, acid anhydrides of acid sensitive compounds can be obtained. An extension of this approach was described recently. Trimethylsilyl-ethoxyacetylene, which can be prepared from ethoxyacetylene, serves as a very mild dehydrating agent.By means of this compound various types of acid sensitive carboxylic acid anhydrides can be made quantitatively or almost quantitatively (equation 40). Some examples are collected in Table 11. 

Of commercial interest is the preparation of acid anhydrides from hydrocarbons by direct oxidation. This methodology has been developed in particular for the synthesis of cyclic anhydrides, which are then introduced for the production of polymers. " ... 

Thallium compounds, particularly thallous ethoxide, have been used successfully in several reactions, such as the alkylation and acylation of / -dicarbonyl compounds or the preparation of acid anhydrides and phenol esters . No side reactions occur and the yields are quantitative in many cases. Trialkyllead alkoxides catalyze a variety of addition reactions, such as the addition of malo-nates to aryl isocyanates . ... 

---