Chemistry of Acid Halides

Acid chlorides are prepared from carboxylic acids by reaction with thionyl chloride (SOCN), as we saw in the previous section. Similar reaction of a carbox Tic acid with phosphorus tribromide (PBr3) yields the acid bromide. 

Acid halides are among the mr)st reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. T he halogen can be replaced by -OH to yield an add, by -OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

In fatty-acid biosynthesis, a carboxylic acid is activated by reaction with ATP to give an acyl adenylate, which undergoes nucleophilic acyl substitution with the -SH group on coenzyme A. (ATP = adenosine triphosphate AMP = adenosine monophosphate.) 

which expels adenosine monophosphate (AMP) as leaving group and yields the fatty acyl CoA. 

Conversion of Acid Halides into Acids Hydrolysis Add chlorides react with water to yield carboxylic acids. This hydrolysis reaction is a typical nucleophilic acyl substitution process and is initiated ( y attack of water on the acia chloride carbonyl group. The tetrahedral intermediate undergoes elimination of Cl and loss of H to give the product carboxylic acid plus HCl. 

CHAPTER l6 CARBOXYLIC ACID DERIVATIVES NUCLEOPHILIC ACYL SUBSTITUTION REACTIONS 

Because HCl is generated during the hydrolysis, the reaction is often carried out in the presence of a base such as pyridine or NaOH to remove the HCl and prevent it from causing side reactions. 

The net effect of Fischer esterification is substitution of an -OH group by OR. Ail steps are reversible, and the reaction can be driven in either direction by choice of reaction conditions. Ester formation is favored when a large excess of alcohol is used as solvent, but carboxylic acid formation is favored when a large excess of water is present. 

Problem 21.8 Show how you might prepare the following esters  

Problem 21.9 If 5-hydroxypentanoic acid is treated with acid catalyst, an intramolecular esterification reaction occurs. What is the structure of the product Intramolecular means within the same molecule.) 

Conversion of Carboxylic Acids Into Amides (RCO2H — RCONH2) 

Amides are difficult to prepare by direct reaction of carboxylic acids with amines because amines are bases that convert acidic carboxyl groups into their carboxylate anions. Since the carboxylate anion has a negative charge, it is no longer likely to be attacked by a nucleophile. We ll see a better method for making amides from acids in Section 26.10 in connection with the synthesis of proteins from amino acids. 

Conversion of Carboxylic Adds into Amides (RC02H — RCONH2) 

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The preparation of the acid derivatives is organized according to their precursors. The synthetic method of choice in a particular case will depend on a number of factors of which the presence of other functional groups in the molecule under study is not the least important. The methods will be evaluated with respect to their scope of application. The chemistry of acid halides has been reviewed. Methods of preparation are treated in Houben-WeyP as well as in other reference books. This applies also to acid anhydrides and a-ketonitriles. ... 

J. Kivinen in S. Ratal, The Chemistry of Acid Halides, S. 177, Interscience Publ., New York 1972. 

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