Carboxylic acid nucleophilic acyl substitution reactions

There is one last reaction to consider. Remember the reaction of a carboxylic acid such as butanoic acid with a base such as NaOH or NaOCHg described in Chapter 6 (Section 6.2). Sodium methoxide is a good base (Chapter 12, Section 12.1), but as seen in Chapter 11 (Section 11.3.2), methoxide is also a good nucleophile. What happens when butanoic acid reacts with sodium methoxide in ether The answer is that the acid-base reaction dominates indeed, the acid-base reaction is much faster than the acyl substitution reaction. Therefore, sodium methoxide reacts with butanoic acid to give the sodium salt of butanoic acid (76, the conjugate base) and methanol (the conjugate acid). If a potential nucleophile is a potent base, the acid-base reaction will dominate with carboxylic acids. Nucleophilic acyl substitution reactions dominate with acid derivatives, with some exceptions that are discussed in Chapter 22. 

Amides are the least reactive carboxylic acid derivative, and the only nucleophilic acyl substitution reaction they undergo is hydrolysis. Amides are fairly stable in water, but the amide bond is cleaved on heating in the presence of strong acids or bases. Nominally, this cleavage produces an amine and a car boxylic acid. 

Nucleophilic Acyl Substitution Reactions of Carboxylic Acid Derivatives (Chapter21)... 

As a general rule, nucleophilic addition reactions are characteristic only of aldehydes and ketones, not of carboxylic acid derivatives. The reason for the difference is structural. As discussed previously in A Preview of Carbonyl Compounds and shown in Figure 19.14, the tetrahedral intermediate produced by addition of a nucleophile to a carboxylic acid derivative can eliminate a leaving group, leading to a net nucleophilic acyl substitution reaction. The tetrahedral intermediate... 

Carboxylic Acid Derivatives Nucleophilic Acyl Substitution Reactions... 

A nucleophilic acyl substitution reaction involves the substitution of a nucleophile for a leaving group in a carboxylic acid derivative. Identify the leaving group (Cl- in the case of an acid chloride) and the nucleophile (an alcohol in this case), and replace one by the other. The product is isopropyl benzoate. 

Esters can also be synthesized by an acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol, a process called the Fischer esterification reaction. Unfortunately, the need to use an excess of a liquid alcohol as solvent effectively limits the method to the synthesis of methyl, ethyl, propyl, and butyl esters. 

We said in Section 17.4 that carboxylic acids are reduced by L1AIH4 to give primary alcohols, but we deferred a discussion of the reaction mechanism at that time. In fact, the reduction is a nucleophilic acyl substitution reaction in which —H replaces -OH to give an aldehyde, which is further reduced to a primary alcohol by nucleophilic addition. The aldehyde intermediate is much more reactive than the starting acid, so it reacts immediately and is not isolated. 

Conversion of Acid Halides into Anhydrides Nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion gives an acid anhydride. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way. 

The chemistry of carboxylic acid derivatives is dominated by the nucleophilic acyl substitution reaction. Mechanistically, these substitutions take place by... 

The Hell-Volhard-Zelinskii reaction is a bit more complex than it looks and actually involves substitution of an acid bromide enol rather than a carboxylic acid enol. The process begins with reaction of the carboxylic acid with PBr3 to form an acid bromide plus HBr (Section 21.4). The HBr then catalyzes enolization of the acid bromide, and the resultant enol reacts with Br2 in an cr-substitution reaction to give an cv-bromo acid bromide. Addition of water hydrolyzes the acid bromide in a nucleophilic acyl substitution reaction and yields the a-bromo carboxylic acid product. 

Fischer esterification reaction (Section 21.3) The acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol to yield an ester. 

Preparation of amides Ammonia, 1° and 2° amines react with carboxylic acids to produce, respectively, 1°, 2° and 3° amides, through a nucleophilic acyl substitution reaction. The reaction of ammonia and a carhoxylic acid initially forms a carhoxylate anion and an ammonium cation. Normally the... 

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