Carboxylate salts, reaction with acyl chloride

Hydrolysis (Section 20 4) Acyl chlorides react with water to yield carboxylic acids In base the acid is converted to its carbox ylate salt The reaction has little prepara tive value because the acyl chloride is nearly always prepared from the carboxyl ic acid rather than vice versa... 

As noted in the preceding section, one of the most general methods of synthesis of esters is by reaction of alcohols with an acyl chloride or other activated carboxylic acid derivative. Section 3.2.5 dealt with two other important methods, namely, reactions with diazoalkanes and reactions of carboxylate salts with alkyl halides or sulfonate esters. There is also the acid-catalyzed reaction of carboxylic acids with alcohols, which is called the Fischer esterification. 

The acylation of amines with carboxylic acid chlorides leads to the production of one equivalent acid, which will form a salt with unreacted amine and diminish the yield. The addition of an additional equivalent of base to neutralise this acid is a way to optimise the conditions. Normally, aqueous base is slowly added to the reaction mixture. 

Due to the attractivity of this method several groups have developed onium salt supported versions of classical reactions. For example, starting from hydroxyl derived imidazolium salts, formation of supported acrylates with acryloyl chloride followed by reaction with diene in refluxing toluene afforded Diels Alder adduct in good yields (>65%). After saponification, products are isolated without further purification [127], Alternatively, starting from carboxylic acid derived imidazolium salts, acyl chloride formation with thionyl chloride in acetonitrile, followed by reaction with 4-aminophenol led to supported N-arylamide. Williamson alkylation using NaOH as a base and subsequent cleavage from the onium salt support under acidic condition (HCI/I I2()/ AcOH) allowed for isolation of various alkoxy substituted anilines with >98% purity... 

Functionalized terpyridines can be created to contain a variety of binding and catalytic functional groups (15). Bromomethyl derivatives can be reacted with the sodium salts of alcohols to form ethers, or reacted with the sodium salts of amines to form substituted amines. Each sodium salt was formed by reaction with sodium hydride. Gabriel synthesis leads to the creation of an aminomethyl derivative, which can be converted into amide with acyl chlorides, ureas with isocyanates, or thioureas with isothiocyanates. Terpyridine-5-carboxylic acid is converted to the acyl chloride with thionyl chloride and can be coupled with a variety of amines to form amide derivatives. 

Imides can be prepared by the attack of amides or their salts on acyl halides, anhydrides, and carboxylic acids or esters. The best synthetic method for the preparation of acyclic imides is the reaction between an amide and an anhydride at 100°C catalyzed by H2S04. When acyl chlorides are treated with amides in a2 l molar ratio at low temperatures in the presence of pyridine, the products are N,N-diacylamides, (RCO)3N. ... 

The traditional method for transforming carboxylic acids into reactive acylating agents capable of converting alcohols to esters or amines to amides is by formation of the acyl chloride. Molecules devoid of acid-sensitive functional groups can be converted to acyl chlorides with thionyl chloride or phosphorus pentachloride. When milder conditions are necessary, the reaction of the acid or its sodium salt with oxalyl chloride provides the acyl chloride. When a salt is used, the reaction solution remains essentially neutral. 

Additional work was carried out by the GE group on optimization of the reaction yield and to eliminate unwanted linear oligomers [14], Three side reactions which interfere with synthesis of cyclics were identified reaction of the amine with acid chloride to form an acyl ammonium salt, followed by decomposition to an amide (Equation (3.2)) reaction with CH2CI2 to form a salt (Equation (3.3)) hydrolysis of the acid chloride, forming carboxylate via catalysis... 

Acyl chlorides. Acyl chlorides are formed rapidly by reaction of carboxylic acids with SOCl2 and pyridine in CH2C12 at 25°. The dicyclohexylammonium salts of carboxylic acids react particularly rapidly (ca. 1 minute). The acid chlorides prepared in situ in this way react with amines in the presence of DMAP or DBU to form amides in >85% yield. This SOCl2-Py method is also useful for peptide synthesis with slight racemization. 

This same polyamide can be prepared by reaction of the diacyl chloride of adipic acid with hexamethylenediamine. In Section 19.6 we saw that the conversion of the salt of a carboxylic acid and an amine to an amide could be accomplished by heating but that this method was not often used in the laboratory because of the rather vigorous conditions that must be employed. However, in an industrial setting, cost is a more important factor. Because the reaction starting only with the diacid and the diamine is much less expensive than first converting the diacid to its acyl chloride, the former method is the one used to prepare nylon 6,6. 

A second, more versatile, method involves the O-acyl thiohydroxamates. These compounds are generally prepared by reaction of acyl chlorides with the commercial sodium salt (1) of 2-mercapto-pyridine A(-oxide (equation 6 X = Cl). Use of mixed anhydrides formed by reaction of the carboxylic acid with isobutyl chloroformate (equation 6 X = OCC>2CH2CHMe2) renders the procedure compatible with unprotected indoles, phenols, secondary and, presumably, tertiary alcohols. An alternative mode of preparation of the 0-acyl thlohydroxamates involves the s t (2) in reaction with the carboxylic acid (equation 7). 

The classical Hunsdiecker reaction (equation 18), involving the reaction of silver carboxylates with halogens, and the various associated side reactions, has been reviewed several times. Optimum yields are obtained with bromine, followed by chlorine. Iodine gives acceptable yields provid that the correct stoichiometry of 1 1 is used. The reaction is most frequently carried out in tetrachloromethane at reflux. From a practical point of view, one drawback is the difficulty encountered in the preparation of dry silver carboxylates the reaction of silver oxide on the acyl chloride in tetrachloromeAane at reflux has been employed to circumvent this problem. Evidently the use of molecular bromine limits the range of functional groups compatible with the reaction the different reaction pathways followed by the silver salts of electron poor (equation 19) and electron rich (equation 20) aryl carboxylates illustrate this point well. 

Anhydrides can t be used to make acid chlorides, because RCOO is a stronger base and therefore a poorer leaving group than d . Anhydrides can be used to make all other acyl derivatives, however. Reaction with water and alcohols yields carboxylic adds and esters, respectively. Reaction with two equivalents of NH3 or amines forms 1°, 2°, and 3° amides. A molecule of carboxylic acid (or a carboxylate salt) is always formed as a by-product. 

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