Carboxylic acid derivatives acylation reactions

As one of the most reactive groups of carboxylic acid derivatives, acyl halides are very useful substrates for the preparation of the other classes of derivatives. For example, anhydrides may be synthesized by the reaction of carboxylic acid salts with an acyl halide. In this reaction, the carboxylate anion acts as the nucleophile, eventually displacing the halide leaving group. 

In the early days, greatest interest was focused on the acid-catalyzed hydrolysis (by hydrochloric acid in the presence of 2,4-dinitrophenylhydrazine) of Reissert compounds to aldehydes and the corresponding heterocyclic carboxylic acid derivatives. This reaction is fairly general for compounds of quinoline (178) and isoquinoline (179) (Table 18), but it is not applicable to pyridines as they rarely form Reissert compounds. The 3-hydroxyquino-line Reissert compound does not yield benzaldehyde, probably because acylation of the 3-hydroxy group prevents formation of the required cyclic intermediate (180). Some nitroquinolines and isoquinolines give low yields of benzaldehyde. Rather curiously, disub-stituted quinoline Reissert compounds yield less of the aldehyde than of the corresponding... 

Carboxylic acids and their derivatives like esters, amides, anhydrides, and acyl halides are formally synthesized from olefins, carbon monoxide, and compounds represented by Nu-H such as H2O, ROH, RNH2, RCOOH (Equations (4) and (5)). Alkynes also react under similar conditions to afford the corresponding unsaturated carboxylic acid derivatives. These reactions have been named hydrocarboxylation, hydroalkoxycarbonylation, and hydroaminocarbonylation. 

Among the various carboxylic acid derivatives, acyl chlorides are especially useful because they are readily converted to acid anhydrides, esters, and amides by nucleophilic acyl substitution (Table 19.1). Yields are high and the reaction rates are much... 

Acyl halides are among the most reactive of carboxylic acid derivatives. Acyl chlorides are more common and less expensive than bromides or iodides. They can be prepared from acids by reaction with thionyl chloride. 

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... 

This chapter concerns the preparation and reactions of acyl chlorides acid anhydrides thioesters esters amides and nitriles These com pounds are generally classified as carboxylic acid derivatives and their nomenclature is based on that of carboxylic acids... 

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... 

The reaction of lithio derivatives with appropriate electrophiles has been utilized in the preparation of alkyl, aryl, acyl and carboxylic acid derivatives. Representative examples of these conversions are given in Scheme 79. Noteworthy is the two-step method of alkylation involving reaction with trialkylborane followed by treatment with iodine (78JOC4684). 

The discussion of acylation reactions in this chapter is focused on fluonnated carboxylic acid derivatives and their use to build up new fluorine-containing molecules of a general preparative interest Fifteen years ago, fluonnated carboxylic acids and their derivatives were used mainly for technical applications [/] Since then, an ever growing interest for selectively fluonnated molecules for biological applications [2, 3, 4, 5] has challenged many chemists to use bulk chemicals such as tnfluoroacetic acid and chlorodifluoroacetic acid as starting materials for the solution of the inherent synthetic problems [d, 7,, 9]... 

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. 

Correlations with o in carboxylic acid derivative reactions have been most successful for variations in the acyl portion, R in RCOX. Variation in the alkyl portion of esters, R in RCOOR, has not led to many good correlations, although use of relative rates of alkaline and acidic reactions, as in the defining relation, can generate linear correlations. The failure to achieve satisfactory correlations with cr for such substrates may be a consequence of the different steric effects of substituents in the acyl and alkyl locations. It has been shown that solvolysis rates of some acetates are related to the pA", of the leaving group, that is, of the parent alcohol. The pK of alcohols has been correlated with but this relationship... 

When a Br nsted base functions catalytically by sharing an electron pair with a proton, it is acting as a general base catalyst, but when it shares the electron with an atom other than the proton it is (by definition) acting as a nucleophile. This other atom (electrophilic site) is usually carbon, but in organic chemistry it might also be, for example, phosphorus or silicon, whereas in inorganic chemistry it could be the central metal ion in a coordination complex. Here we consider nucleophilic reactions at unsaturated carbon, primarily at carbonyl carbon. Nucleophilic reactions of carboxylic acid derivatives have been well studied. These acyl transfer reactions can be represented by... 

The formulated mechanism is supported by the finding that no halogen from the phosphorus trihalide is transferred to the a-carbon of the carboxylic acid. For instance, the reaction of a carboxylic acid with phosphorus tribromide and chlorine yields exclusively an a-chlorinated carboxylic acid. In addition, carboxylic acid derivatives that enolize easily—e.g. acyl halides and anhydrides—do react without a catalyst present. 

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. 

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 aldehyde intermediate can be isolated if 1 equivalent of diisobutvl-aluminum hydride (D1BAH) is used as the reducing agent instead of LiAlH4. The reaction has to be carried out at -78 °C to avoid further reduction to the alcohol. Such partial reductions of carboxylic acid derivatives to aldehydes also occur in numerous biological pathways, although the substrate is either a thioester or acyl phosphate rather than an ester. 

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