Nucleophilic acyl substitution reactions of carboxylic acid derivatives

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

This chapter will discuss methods for the preparation of esters, acid chlorides, anhydrides, and amides from carboxylic acids, based on acyl substitution reactions. Acyl substitution reactions of carboxylic acid derivatives will include hydrolysis, interconversion of one acid derivative into another, and reactions with strong nucleophiles such as organometallic reagents. In addition, the chemistry of dicarboxylic acid derivatives will be discussed, as well as cyclic esters, amides, and anhydrides. Sulfonic acid derivatives will be introduced as well as sulfate esters and phosphate esters. Finally, nitriles will be shown to be acid derivatives by virtue of their reactivity. 

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. 

An acid-base reaction (Reaction [1]) occurs with OH, NH3, and amines, aU common nucleophiles used in nucleophilic acyl substitution reactions. Nonetheless, carboxylic acids can be converted to a variety of other acyl derivatives using special reagents, with acid catalysis, or sometimes, by using rather forcing reaction conditions. These reactions are summarized in Figure 22.3 and detailed in Sections 22.10A-22.10D. 

The characteristic reaction of carboxylic acid derivatives is nucleophilic acyl substitution. This is a general reaction that occurs with hoth negatively charged nucleophiles (Nu ) and neutral nucleophiles (HNu ). 

A characteristic reaction of carboxylic acid derivatives is nucleophilic acyl substitution. In this reaction a negative or neutral nucleophile replaces a leaving group to form a substitution product. The leaving groups and nucleophiles are the groups that define the various acid derivatives as a result, the reaction usually involves the conversion of one acid derivative into another. The order of reactivity of acid derivatives is acid chloride > anhydride > acid or ester > amide. In general, reaction of any of these derivatives with water produces acids with alcohols, esters result and with amines, amides are formed. 

We can make the following general statement about the reactions of carboxylic acid derivatives A carboxylic acid derivative will undergo a nucleophilic acyl substitution reaction, provided that the newly added group in the tetrahedral intermediate is not a much weaker base than the group that was attached to the acyl group in the reactant. 

The major difference between these two types of carbonyl addition reactions is that aldehydes and ketones do not have a group, Y, that can leave as a stable anion. They undergo only nucleophilic acyl addition. The four carboxylic acid derivatives we study in this chapter do have a group, Y, that can leave as a stable anion accordingly, they undergo nucleophilic acyl substitution. 

The characteristic reaction of carboxylic acid derivatives is nucleophilic acyl Problem 18.19 substitution. 

Acylium ion (Section 12 7) The cation R—C=0 Acyl transfer (Section 20 3) A nucleophilic acyl substitution A reaction in which one type of carboxylic acid derivative IS converted to another... 

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. 

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... 

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. 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, 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. 

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

The most important reactions of carboxylic acids are the conversions to various carboxylic acid derivatives, e.g. acid chlorides, acid anhydrides and esters. Esters are prepared by the reaction of carboxylic acids and alcohols. The reaction is acid catalysed and is known as Fischer esterification (see Section 5.5.5). Acid chlorides are obtained from carboxylic acids by the treatment of thionyl chloride (SOCI2) or oxalyl chloride [(COCl)2], and acid anhydrides are produced from two carboxylic acids. A summary of the conversion of carboxylic acid is presented here. All these conversions involve nucleophilic acyl substitutions (see Section 5.5.5). 

Reactions of Carboxylic Acids and Derivatives Nucleophilic Acyl Substitution... 

Step 1 Reaction of the diphosphate oxygen of GDP with the phosphorus of the acyl phosphate to produce an intermediate similar to the intermediates formed in nucleophilic acyl substitutions of carboxylic acid derivatives. 

Chapter 22 continues the study of carbonyl compounds with a detailed look at nucleophilic acyl substitution, a key reaction of carboxylic acids and their derivatives. Substitution at sp hybridized carbon atoms was introduced in Chapter 20 with reactions involving carbon and hydrogen nucleophiles. In Chapter 22, we learn that nucleophilic acyl substitution is a general reaction that occurs with a variety of heteroatomic nucleophiles. This reaction allows the conversion of one carboxylic acid derivative into another. Every reaction in Chapter 22 that begins with a carbonyl compound involves nucleophilic substitution. Chapter 22 also discusses the properties and chemical reactions of nitriles, compounds that contain a carbon-nitrogen triple bond. Nitriles are in the same carbon oxidation state as carboxylic acids, and they undergo reactions that form related products. 

Sections 22.8-22.14 are devoted to specific examples of nucleophilic acyl substitution using heteroatoms as nucleophiles. There are a great many reactions, and it is easy to confuse them unless you learn the general order of reactivity of carboxylic acid derivatives. Keep in mind that every reaction that begins with an acyl starting material involves nucleophilic substitution. 

Carboxylic acid derivatives such as esters and amides undergo nucleophilic acyl substitution reactions with the ketone dianion derived fiom benzophenone, providing modest yields of the corresponding carbonyl products (equations 102 and 103). Benzhydrol is a significant by-product in these reactions. 

Among the most important reactions of carboxylic acids are those that convert the carboxyl group into an acid derivative by a nucleophilic acyl substitution. Acid chlorides, anhydrides, esters, and amides can all be prepared from carboxylic acids (Figure 21.4). 

The chemistry of carboxylic acid derivatives is dominated by the nucleophilic acyl substitution reaction. Mechanistically, these substitutions] take place by addition of a nucleophile to the polar carbonyl group of the acid derivative, followed by expulsion of a leaving group from the tetrahedral intermediate. 

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