Preparation of acid chlorides

Carboxylic acids can be converted into acid chlorides using thionyl chloride (SOCl2) or phosphorus trichloride (PC13). 

Attack of the lone pair via the C=0 bond SN2-type reaction 

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Sulphur oxide dichloride is used as a chlorinating agent in organic chemistry, for example in the preparation of acid chlorides ... 

One of the general methods for the preparation of acid chlorides is the action of phosphorus pentachloride on the corresponding carboxylic acid ... 

For the preparation of acid chlorides from the corresponding imidazolides it is not necessary that the imidazolide be isolated. Instead it can be formed in situ by conversion of the appropriate carboxylic acid with CDI. 

This modification of the continuous reactor (cf. benzoylacetanilide, p. 2) with countercurrent distillation is preferred for reactions in which a large amount of solvent or excess of one reactant is essential, but increase of total volume is undesirable. It is especially useful if the substances involved are heat-sensitive with this apparatus the reactants are heated for only a few minutes at most. It is particularly applicable to the preparation of acid chlorides from carboxylic acids and thionyl chloride (cf. Notes 3 and 4). An indefinite amount of product can be prepared by replenishing the reactants as they are consumed. 

Unlike acetoacetyl chloride, which decomposes at temperatures above —20°, 2,2,4-trimethyl-3-oxovaleryl chloride is stable at elevated temperatures. It may find use as an intermediate for example, it can be used in the preparation of acid chlorides by an exchange reaction which is forced to completion by decarboxylation of the by-product, /3-keto acid ... 

Nowadays, the most economical way of preparing hydroxamic acid derivatives is the reaction of hydroxylamine with acid chlorides or esters . Unfortunately, the preparation of acid chlorides is often tedious. In addition, it is very difficult to avoid further acylation during the reaction with hydroxylamine. 

Preparation of acid chlorides The best way to make acid chlorides is the reaction of a carboxylic acid with either thionyl chloride (SOCI2) or oxalyl chloride (COCl)2 in the presence of a base (pyridine). The mechanism of formation of acid chloride is similar to the reaction of alcohol with SOCI2. 

Preparation of acid chlorides is one of the easiest methods to activate an acid. Thionyl chloride (SOCh) [12, 13] is used widely to generate acid chlorides. The reaction of SOCb with water or other nucleophiles is extremely exothermic, and generates large quantities of sulfur dioxide and HCI. Nevertheless, acid chlorides (via SOCI2) and mixed anhydrides (via acid chlorides or chloroformates), are the most common reagents used for amide formation in the pharmaceutical industry, with N,N -carbonyldiiniidazole (CDl) growing in popularity[8]. 

Traditional textbook preparations of acid chlorides from carboxylic acids include... 

Another superior reagent for the preparation of acid chlorides is oxallyl chloride in methylene chloride. Addition of a carboxylic acid leads to the smooth evolution of gas (CO2, CO, HC1) which can be used as a crude monitor of the reaction progress. The acid chloride is very easily purified since oxallyl chloride boils at 62°C and is easily evaporated from the product. In many instances, the crude product is sufficiently pure to be used directly. 

The technical product frequently contains traces of acids, sulphur chlorides and sulphuryl chloride it is essential to remove these before using the reagent for the preparation of acid chlorides, etc. Commercial purified thionyl chloride is satisfactory for most purposes. A colourless product of high purity may be obtained by either of the following methods. 

With Thionyl Chloride. Although thionyl chloride has been more widely used in the preparation of acid chlorides for cyclization with both stannic and aluminum chloride, it is perhaps less generally advantageous than phosphorus pentachloride. If it is desired to obtain the acid chloride essentially free of by-products, thionyl chloride presents some advantage in that these by-products of the reaction are gaseous and therefore may be eliminated readily. Since, moreover, the reagent has a... 

Jang DO, Park DJ, Kim J. A mild and efficient procedure for the preparation of acid chlorides from carboxylic acids. Tetrahedron Lett. 1999 40 5323-5326. 

DBU was found to be an excellent catalyst in the preparation of acid chlorides from carboxylic acids or anhydrides at 70-105°C (70GEP1931074 74JOC1134). Thus, lauroyl chloride was obtained in 96.0% yield from lauric acid (74JOC1134). 

One general synthetic difficulty in the preparation of acid chlorides of amino acids, particularly those in which the (X-NH2 is protected by acylation, is the formation of azlactones. Tosyl derivatives partially avoid this difficulty. 

This reversibility is a disadvantage in the preparation of an ester directly from an acid the preference for the acid chloride route is due to the fact that both steps—preparation of acid chloride from acid, and preparation of ester from acid chloride—are essentially irreversible and go to completion. 

Scheme 84 Preparation of acid chlorides or anhydrides through reaction of 1,2,2,2-tetrachloroethyl chloroformate with carboxylic acids.

Scheme 179 Preparation of acid chlorides using tetrachloroethylene carbonate.

Preparation of acid chlorides. The thionyl chloride method of preparing acid chlorides fails with some carboxylic acids (e.g., p-NOjCsHaCOzH) and with all sulfonic acids. Bosshard and co-workers" found that dimethylformamide catalyzes both reactions, either when used as solvent or when employed in catalytic amount in an inert solvent. The reactive, hygroscopic intermediate dimethylformirainium chloride was isolated from one equivalent each of dimethylformamide and thionyl chloride, and also obtained by reaction of dimethylformamide with phosgene, oxalyl chloride, or phosphorus pentachloride. It reacts with an acid with regeneration of dimethylformamide, the catalyst. In one example, 0.3 mole of p-nitrobenzoic acid was heated briefly at 90-95° with 0.315 mole of thionyl chloride and 0.03 mole... 

Application of this method to heterocyclic acids permits easy preparation of acid chlorides previously requiring special procedures. Thus 5-methyl-3-isoxazole-carbonyl chloride was initially obtained only by the reaction of the sodium salt of the acid with phosphorus pentachloride" or with thionyl chloride the free acid does not react with thionyl chloride alone. An improved procedure is as follows."... 

Preparation of acid chlorides. Phthaloyl chloride is an excellent reagent for the conversion of acids and anhydrides into the acid chlorides, provided the boiling points are suitable for separation of products by distillation. In the case of maleic and succinic anhydride a catalytic amount of zinc chloride is required. Maleic anhydride is isomerized in the process. Thus a mixture of 1 mole of maleic anhydride, 230 g. of commercial phthaloyl chloride, and 2 g. of anhydrous zinc chloride is... 

An advantage of phosphorous oxychloride in the preparation of acid chlorides is that no gas is evolved. As is demonstrated in the following example, basic nitrogens do not interfere with the reaction. 

Acid chlorides, alkyl chlorides.1 The combination of dimethylformamide and thionyl chloride has been known for some time to be excellent for preparation of acid chlorides and of alkyl chlorides from acids and alcohols, respectively (1, 286-288). The actual chlorinating agent is considered to be [CICH=N (CH3)2]C1-. The combination of HMPT and thionyl chloride should be capable of forming a similar reagent ... 

Indeed this combination is an excellent reagent for preparation of acid chlorides and of alkyl chlorides. HMPT as solvent is useful also because it combines with the hydrochloric acid formed in many cases it is superior to pyridine. Reactions occur in good yield and at temperatures of about —20 to —10°. HMPT is also an excellent solvent for esterification of acyl chlorides with tertiary alcohols. 

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