Carboxylic acid derivatives substitution reactions

These substitution products A and B need not be the final product of the reaction of nucleophiles with carboxyl species. Sometimes they may be formed only as intermediates and continue to react with the nucleophile. Being carbonyl compounds (substitution products A) or carboxylic acid derivatives (substitution products B), they can in principle undergo, another addition or substitution reaction (see above). Thus, carboxylic acid derivatives can react with as many as two equivalents of nucleophiles, and carbonic acid derivatives can react with as many as three. 

How the C=0 group in derivatives of carboxylic acids promotes substitution reactions chl2... 

Even though the most widely used preparation is still the reaction of alkali isothiocyanates or alkyl and aryl isothiocyanates with a-amino carboxylic acid derivatives, the reaction of dithiocarbamic acid esters (CCX) with a-amino carboxylic acids (CCXI) has certain advantages especially in the synthesis of heterocyclically substituted imidazolidin-4-one-2-thiones (221). 

The first-order kinetics of this unusual substitution reaction is here to illustrate a point, but it should not distract you from the fact that most nucleophilic substitutions of carboxylic acid derivatives (the reactions you met in Chapter 10) are bimolecular reactions with ratedetermining formation of the tetrahedral intermediate. 

Both stages involve more than one step and these steps differ in detail among the various carboxylic acid derivatives and for different reaction conditions This chapter is organized to place the various nucleophilic acyl substitutions into a common mechanis tic framework and to point out the ways m which individual classes differ from the rest... 

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. 

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

The second fundamental reaction of carbonyl compounds, nucleophilic acyl substitution, is related to the nucleophilic addition reaction just discussed but occurs only with carboxylic acid derivatives rather than with aldehydes and ketones. When the carbonyl group of a carboxylic acid derivative reacts with a nucleophile, addition occurs in the usual way, but the initially formed tetra-... 

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... 

Closely related to the carboxylic acids and nitriles discussed in the previous chapter are the carboxylic acid derivatives, compounds in which an acyl group is bonded to an electronegative atom or substituent that can net as a leaving group in a substitution reaction. Many kinds of acid derivatives are known, but we ll be concerned primarily with four of the more common ones acid halides, acid anhydrides, esters, and amides. Esters and amides are common in both laboratory and biological chemistry, while acid halides and acid anhydrides are used only in the laboratory. Thioesters and acyl phosphates are encountered primarily in biological chemistry. Note the structural similarity between acid anhydrides and acy) phosphates. 

Carboxylic acid derivatives are among the most widespread of all molecules, both in laboratory chemistry and in biological pathways. Thus, a study of them and their primary reaction—nucleophilic acyl substitution—is fundamental to understanding organic chemistry. We ll begin this chapter by first learning about carboxylic acid derivatives, and then we ll explore the chemistry of acyl substitution reactions. 

The addition of a nucleophile to a polar C=0 bond is the key step in thre< of the four major carbonyl-group reactions. We saw in Chapter 19 that when. nucleophile adds to an aldehyde or ketone, the initially formed tetrahedra intermediate either can be protonated to yield an alcohol or can eliminate th< carbonyl oxygen, leading to a new C=Nu bond. When a nucleophile adds to carboxylic acid derivative, however, a different reaction course is followed. Tin initially formed tetrahedral intermediate eliminates one of the two substituent originally bonded to the carbonyl carbon, leading to a net nucleophilic acy substitution reaction (Figure 21.1. ... 

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 common reactions of carboxylic acid derivatives are substitution by water (hydrolysis) to yield an acid, by an alcohol (alcoholysis) to yield an ester, by an amine (aminolysis) to yield an amide, by hydride ion to yield an alcohol (reduction), and by an organometallic reagent to yield an alcohol (Grignard reaction). 

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