Carboxylic acids with acyl chlorides

The customary method for the laboratory synthesis of acid anhydrides is the reac tion of acyl chlorides with carboxylic acids (Table 20 1)... 

Acylatmg agents such as acyl chlorides and carboxylic acid anhydrides can react with phenols either at the aromatic ring (C acylation) or at the hydroxyl oxygen (O acylation)... 

The alcohol groups of carbohydrates undergo chemical reactions typical of hydroxyl functions They are converted to esters by reaction with acyl chlorides and carboxylic acid anhydrides... 

Whereas acyl chlorides and carboxylic acid anhydrides can be reduced to aldehydes using Na2[Fe(CO>4] e.g. Scheme 10) most esters cannot, because of their low reactivity as acylating agents. However, Na2[Fe(CO)4] does give low yields of aldehydes (<40%) with esters of aromatic alcohols. ... 

Thionyl chloride (39) in the presence of a few drops of DMF (catalyst) is a valuable reagent for the conversion of sulfonic acids (31) into the sulfonyl chlorides (32) (Scheme 32). This resembles the well-known reaction of thionyl chloride with carboxylic acids for the preparation of acyl chlorides, and has the advantage that both the by-products are gaseous. 

Because acylation of amines with acyl chlorides and anhydrides yields an acid as one of the products (HCl from acyl chlorides, a carboxylic acid from an anhydride), the efficient synthesis of amides requires some attention to stoichiometry. 

The mechanism is similar to that for the formation of chlorides from alcohols and thionyl chloride. The hydroxyl group is converted to a good leaving group by thionyl chloride, followed by a nucleophilic acyl substitution in which chloride is the nucleophile (compare with Sec. 7.10). Phosphorus pentachloride and other reagents can also be used to prepare acyl chlorides from carboxylic acids. 

This reaction presumably proceeds via the acyl chloride, because it is known that triphenylphosphine and carbon tetrachloride convert acids to the corresponding acyl chloride. Similarly, carboxylic acids react with the triphenylphosphine-bromine adduct to give acyl bromides. Triphenylphosphine/A/ -bromosuccinimide also generates acyl bromides in situ Alcohols can be esterified by heating in excess ethyl formate or ethyl acetate and triphenylphosphine in carbon tetrabromide. All these reactions are mechanistically analogous to the alcohol-to-halide conversions that were discussed in Section 3.1.2. 

The main applications of oxalyl chloride, as described in Chapter 4, are the formation of aryl isocyanates and chloroformates (by reactions with amines and hydroxylic substrates, respectively), and the formation of acyl chlorides from carboxylic acids under very mild conditions. Oxalyl chloride reacts with amides to give acyl isocyanates, and it is used with dimethyl sulfoxide as a mild reagent for the oxidation of alcohols (Swern-type oxidation). It is also used with N,N-dimethylformamide as a mild reagent for chlorination and formylation. Oxalyl chloride is widely used in commercial formulations of speciality polymers, antioxidants, photographic chemicals, X-ray contrasting agents, and chemiluminescent materials. Other physical properties are presented in Chapter 3. 

We recall that the size of the nucleophile strongly affects the rate of an Sj 2 reaction. Thus, r rr-butoxide is a poorer nucleophile than ethoxide ion (Section 9.1). For the same steric reasons, the order of reactivity of an alcohol with an acyl chloride (or carboxylic acid) decreases in the order primary > secondary > tertiary. 

The reaction of acyl halides with carboxylic acids affords good yields of simple and mixed anhydrides. The use of pyridine or triethylamine helps to remove the hydrogen chloride by-product. However, the preparation of benzoic anhydride from benzoic acid and benzoyl chloride has also been carried out in the absence of trialkylamines by heating under reduced pressure, in the presence of zinc chloride or by refluxing in chlorohydrocarbons such as methylene chloride. 

Thionyl chloride reacts with carboxylic acids to yield acyl chlorides... 

Acyl chlorides react with carboxylic acids to yield acid anhydrides When this reaction is used for preparative purposes a weak organic base such as pyridine is normally added Pyridine is a catalyst for the reaction and also acts as a base to neutralize the hydrogen chloride that is formed... 

Esterification with carboxylic acid anhydrides (Section 15.8) Carboxylic acid anhydrides react with alcohols to form esters in the same way that acyl chlorides do. 

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