Of carboxylic acids and acyl derivatives

Tetrakis(triphenylphosphine)palla-dium(0), 289 Tributyl tin chloride, 315 of amines and other N-alkylations Potassium /-butoxide, 252 of carboxylic acids and acyl derivatives at the a carbon... 

Trichloroisocyanuric acid, 322 of carboxylic acids and acyl derivatives N-Chlorosuccinimide, 62... 

Carboxylic acids and acid anhydrides also serve as acylating agents in Friedel-Crafts reactions. We consider these acylating agents in Chapters 20 and 21 when we study the reactions of carboxylic acids and their 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. 

This chapter is concerned with the cathodic reduction of carboxylic acids and their derivatives, that is, esters, amides, anhydrides, acyl halides, hydrazides, nitriles, and corresponding thio derivatives. Cyclic derivatives of substituted carboxylic and polycarboxylic acids, such as lactones, lactams, imides, and anhydrides, are also included. Only those transformations in which the functional group itself is involved are discussed. Reductive coupling of carboxylic acids and derivatives is covered in Chapter 22, and there is some overlap with reduction of heterocycles in Chapter 18. 

The reactions of carboxylic acids and their derivatives are characterized by nucleophilic addition—elimination at their acyl (carbonyl) carbon atoms. The result is a substitution at the acyl carbon. Key to this mechanism is formation of a tettahedtal intermediate that returns to a carbonyl group after the elimination of a leaving group. We shall encounter many reactions of this general type, as shown in the following box. 

The reactions of carboxylic acids and their derivatives are summarized here. Many (but not all) of the reactions in this summary are acyl substitution reactions (they are principally the reactions referenced to Sections 17.5 and beyond). As you use this summary, you will find it helpful to also review Section 17.4, which presents the general nucleophilic addition-elimination mechanism for acyl substitution. It is instructive to relate aspects of the specific acyl substitution reactions below to this general mechanism. In some cases proton transfer steps are also involved, such as to make a leaving group more suitable by prior protonation or to transfer a proton to a stronger base at some point in a reaction, but in all acyl substitution the essential nucleophilic addition-elimination steps are identifiable. 

The Chemical Synthesis of Peptides Carboxylic acids and acyl derivatives of the carboxyl functional group are very important in biochemistry. For example, the carboxylic acid functional group is present in the femily of lipids called fatty acids. Lipids called glycerides contain the ester functional group, a derivative of carboxylic acids. Furthermore, the entire class of biopolymers called proteins contain repeating amide functional group linkages. Amides are also derivatives of carboxylic acids. Both laboratory and biochemical syntheses of proteins require reactions that involve substitution at activated acyl carbons. 

Chapter 16 (Section 16.6) introduced dicarboxylic acids along with their common and lUPAC names. The common names and the lUPAC names are shown again in Table 20.1 for dicarboxylic acids of C2-C10. This chapter deals with the chemistry of carboxylic acids and their derivatives, and dicarboxylic acids have their acyl halide, ester, anhydride, and amide derivatives. The two carboxylic acid units lead to some interesting structural variations, however. 

The reductions of ketones, aldehydes, carboxylic acids and acyl derivatives are fundamental reactions in organic synthesis and the use of aqueous media has allowed high regio- and stereoselective processes to be performed under mild conditions. 

REACTIONS OF CARBOXYLIC ACIDS AND THEIR DERIVATIVES A PREVIEW Nucleophilic Acyl Substitution... 

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]... 

The smooth conversion of the enol acetate (151) into an A -acyl derivative (152) under extremely mild conditions points to the high acylating capacity of these esters. This cleavage of isoxazolium salts is also caused by other anions of carboxylic acids, and thus they can be readily converted to reactive enol esters. A very convenient and specific synthesis of peptides due to Woodward et is based on... 

A number of other methods exist for the a halogenation of carboxylic acids or their derivatives. Acyl halides can be a brominated or chlorinated by use of NBS or NCS and HBr or HCl. The latter is an ionic, not a free-radical halogenation (see 14-2). Direct iodination of carboxylic acids has been achieved with I2—Cu acetate in HOAc. " ° Acyl chlorides can be a iodinated with I2 and a trace of HI. Carboxylic esters can be a halogenated by conversion to their enolate ions with lithium A-isopropylcyclohexylamide in THF and treatment of this solution at -78°C with... 

Monothiodiacylhydrazines 127, derived from the acylation of thiosemicarbazides or as intermediates in the reactions of (1) thiohydrazides with carboxylic acids and their derivatives (see Section 5.10.9.2.2(i)) or (2) hydrazides with thiocarbonyl compounds (see Section 5.10.9.2.3(i)), cyclize in the presence of an acid catalyst to give 1,3,4-thiadiazoles 128 (Equation 39, Table 4). 

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). 

Friedel-Crafts Acylation, The Friedel-Crafts acylation procedure is the most important method for preparing aromatic ketones and their derivatives. Acetyl chloride (acetic anhydride) reacts with benzene in the presence of aluminum chloride or acid catalysts to produce acetophenone [98-86-2], CgHgO (1-phenylethanone). Benzene can also be condensed with dicarboxylic acid anhydrides to yield benzoyl derivatives of carboxylic acids. These benzoyl derivatives are often used for constructing polycyclic molecules (Haworth reaction). For example, benzene reacts with succinic anhydride in the presence of aluminum chloride to produce p-benzoylpropionic acid [2051-95-8] which is converted into a-tetralone [529-34-0] (30). 

Hi) Carboxylic acids and derivatives. The haloform reaction on thienyl methyl ketones leads to thiophenecarboxylic acids, which can be treated with Raney nickel to produce the open-chain acids. This method has been used for the five-carbon homologation of carboxylic acids and to produce dicarboxylic acids (Scheme 51). Long-chain carboxylic acids may also be prepared by using dicarboxylic acid derivatives for the acylation of thiophenes (Scheme 52). In the synthesis of Queen substance, the precursor (213) has been generated by Raney nickel desulfurization of the appropriate thiophene-2-acetic acid derivative (79T329). 

As reported in the literature, the acylation of aromatic hydrocarbons can be carried out by using zeolites as catalysts and carboxylic acids or acyl chlorides as acylating agents. Thus toluene can be acylated by carboxylic acids in the liquid phase in the presence of cation exchanged Y-zeolites (ref. 1). The acylation of phenol or phenol derivatives is also reported. The acylation of anisole by carboxylic acids and acyl chlorides was obtained in the presence of various zeolites in the liquid phase (ref. 2). The acylation of phenol by acetic acid was also carried out with silicalite (ref. 3) or HZSM5 (ref. 4). The para isomer has been generally favoured except in the latter case in which ortho-hydroxyacetophenone was obtained preferentially. One possible explanation for the high ortho-selectivity in the case of the acylation of phenol by acetic acid is that phenylacetate could be an intermediate from which ortho-hydroxyacetophenone would be formed intramolecularly. 

Structures 24 are conveniently thought of as derivatives of carboxylic acids, and include acids, esters, anhydrides, acyl halides, and amides. These structures (and others less commonly encountered) can be readily interconverted, either directly or indirectly the number of different reactions is therefore large.109 Because these processes occupy an important place in organic chemistry and because carboxylic acid derivatives are of central importance in biochemical systems and therefore of considerable interest in the study of enzyme action, they have been the subject of intensive investigation.110 We shall outline briefly the main features, and in order to give an idea of the kinds of mechanistic questions involved, we consider ester hydrolysis in somewhat greater detail. 

The following discussion deals not only with this reaction, but related reactions in which a transition metal complex achieves the addition of carbon monoxide to an alkene or alkyne to yield carboxylic acids and their derivatives. These reactions take place either by the insertion of an alkene (or alkyne) into a metal-hydride bond (equation 1) or into a metal-carboxylate bond (equation 2) as the initial key step. Subsequent steps include carbonyl insertion reactions, metal-acyl hydrogenolysis or solvolysis and metal-carbon bond protonolysis. 

Ketones, aldehydes, and carboxylic acids all contain the carbonyl group, yet the reactions of acids are quite different from those of ketones and aldehydes. Ketones and aldehydes commonly react by nucleophilic addition to the carbonyl group but carboxylic acids (and their derivatives) more commonly react by nucleophilic acyl substitution, where one nucleophile replaces another on the acyl (C=0) carbon atom. 

Acyl derivatives other than carboxylic acids and their derivatives may be considered in two categories. One of these, IV-acylation, has been discussed earlier (Section 4.12.3.2.2). If in view of the frequently occurring ambiguity of such procedures, an unambiguous synthesis is required, one may proceed as in Scheme 140. 

The electrophile shown in step 2 is the proton. In almost aU the reactions considered in this chapter, the electrophihc atom is either hydrogen or carbon. Note that step 1 is exactly the same as step 1 of the tetrahedral mechanism of nucleophilic substim-tion at a carbonyl carbon (p. 1255), but carbon groups (A, B = H, alkyl aryl, etc.) are poor leaving groups so that substitution does not compete with addition. For carboxylic acids and their derivatives (B = OH, OR, NH2, etc.) much better leaving groups are available and acyl substitution predominates (p. 1254). It is thus the nature of A and B that determines whether a nucleophilic attack at a carbon-heteroatom multiple bond will lead to substitution or addition. 

Acyl compounds—carboxylic acids and their derivatives—typically undergo nucleophilic substitution in which —OH, —Cl, —OOCR, —NH2, or —OR is replaced by some other basic group. Substitution takes place much more readily than at a saturated carbon atom indeed, many of these substitutions do not usually take place at all in the absence of the carbonyl group, as, for example, replacement of-NHjby-OH. 

---