Reactions of carboxylic acids and derivatives

Passage of F (15-20 %) in Nj (contaminated with 5-10 % Oj) into CF3C(0)NH2 at -6 C gave NFj, COFj, COj, and CF3COF. A similar treatment of CHF2C(0)NH2 at room temperature gave NF3, COFj, COj and CHFjC(0)F [594a]. 

The heating of an intimate powdered mixture of equimolar quantities of calcium ethane-1,2-dioate with calcium fluorosulfonate to about 130 C results in the evolution of CO and COFj, with no trace of ethane-1,2-dioyl fluoride [1055]  

A lower yield of COFj is obtained when Ca[S0 3F]j is reacted with the free ethane-1,2-dioic acid [1055]. 

Treatment of 00 00(0)C1 with an alkali metal fluoride in MeCN, at 50-80 C over 5 h, produced COFj in a high yield [969,971]. 

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

The photolysis of carboxylic acids and derivatives as lactones, esters and anhydrides can yield decarboxylated products 253>. This reaction has been utilized in the synthesis of a-lactones from cyclic diacyl peroxides 254) (2.34) and in the synthesis of [2,2]paracyclophane by bis-decarboxylation of a lactone precursor (2.35) 255). This latter product was also obtained by photoinduced desulfurization of the analogous cyclic sulfide in the presence of triethyl phosphite 256). 

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). 

Those reactions of carboxylic acid and phosphoric acid derivatives which are susceptible to metal ion catalysis in nonenzymatic systems are almost without exception catalyzed by enzymes containing metal ions. This circumstantial evidence indicates strongly that the metal ions in the enzymatic reactions are concerned with the catalytic action, and not simply binding. 

Carboxylic acid anhydrides generally react with sulfur tetrafluoride in the same manner as carboxylic acids to give acid fluorides, then trifluoromethyl derivatives. Various cyclic anhydrides, which are particularly stable under acidic conditions, react without cleavage to give, in a stepwise fashion, difluoro lactones and a,a,a, a -tetrafluoro ethers. Conversely, the corresponding diacids are readily dehydrated by sulfur tetrafluoride to give anhydrides in the first step of the reaction. Therefore, in this section reactions of carboxylic acids and carboxylic acid anhydrides are discussed together. 

Most SN reactions of carboxylic acids and their derivatives follow one of three mechanisms (Figures 6.2, 6.4, and 6.5). A key intermediate common to all of them is the species in which the nucleophile is linked with the former carboxyl carbon for the first time. In this intermediate, the reacting carbon atom is tetrasubstituted and thus tetrahedrally coordinated. This species is therefore referred to as the tetrahedral intermediate (abbreviated as Tet. Intermed. in the following equations). Depending on the nature of the reaction partners, the tetrahedral intermediate can be negatively charged, neutral, or even positively charged. 

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. 

II. Reactions of carboxylic acids and their derivatives (Section 21.3 - 21.9). 

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. 

The familiar substitution reactions of derivatives of carboxylic acids with basic reagents illustrate nucleophihc substitution at aliphatic sp carbons. (Substitution reactions of carboxylic acids, and their derivatives, with acidic reagents are covered in Chapter 4.) The mechanisms of these reactions involve two steps (1) addition of the nucleophile to the carbonyl group and (2) elimination of some other group attached to that carbon. Common examples include the basic hydrolysis and aminolysis of acid chlorides, anhydrides, esters, and amides. 

Degradation reactions of carboxylic acids and their derivatives to amines and their derivatives with one less carbon unit involve rearrangements of a carbon to an electron deficient nitrogen atom as key steps, namely the Hofmann Curtius (C), - Schmidt and Lessen rearrangements, as... 

In this section we give you a quick look at a few additional and potentially useful reactions of carboxylic acids and compounds derived from carboxylic acids (derivatives). 

The remaining sections of this chapter cover specific examples of these general principles. Keep in mind that all the reactions follow the same mechanism. Therefore, you can always determine the outcome of the reactions of carboxylic acids and carboxylic acid derivatives presented in this chapter by examining the tetrahedral intermediate and remembering that the weaker base is preferentially eliminated (Section 17.5). 

Reactions of Carboxylic Acids and their Derivatives.—A novel series of /8-lactones has been obtained from 17,20-dihydroxypregnan-21-oic acids (406) and (407). The reaction occurs, along with formation of the 17,20-diacetate, in acetic anhydride-pyridine. Lactonization is most efficient with the 20a-isomer (406) which affords the less-hindered rrans-20-acetoxy-lactone (408). The crystalline lactones (408) and (409) are stable at - 20 °C but suffer slow decarboxylation at room temperature or in refluxing benzene to give the trans- (410) and cis-enol acetate (411), respectively, of the 17-aldehyde (412). In a similar way the dihydroxy-acids (406) and (407) react with ethyl chlorocarbonate-pyridine to give 20-cathyl-21, 17a-lactones several novel transformations of these products are described. 

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. 

SUMMARY OF THE REACTIONS OF CARBOXYLIC ACIDS AND THEIR DERIVATIVES... 

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 study aids for this chapter include key terms and concepts (which are hyperlinked to the Glossary from the bold, blue terms in the WileyPLUS version of the book at wileyplus.com) and the Summary of Reactions of Carboxylic Acids and Their Derivatives found in Section 17.13. 

In this chapter, we will describe the structures, properties, preparation, and reactions of carboxylic acids and will also discuss some common carboxylic acid derivatives, in which the hydroxyl group of an acid is replaced by other functional groups. 

The experiments described in this chapter illustrate some of the representative reactions of carboxylic acids and their derivatives. For example, you will perform a Fischer esterification, one of the classic reactions in organic chemistry that was discovered by the Nobel laureate Emil Fischer (see the Historical Highlight at the end of Chapter 23 for an account of the life of this famous chemist), to prepare the anesthetic agent benzocaine from p-aminobenzoic acid (Sec. 20.2). In another experiment, you will synthesize the mosquito repellent N,N-diethyl-7n-toluamide (DEET) by a two-step process that involves the conversion of a carboxylic acid into an acid chloride and subsequent reaction with an amine to produce the desired amide (Sec. 20.3). 

Part I. The Reactions of Aldehydes and Ketones Oxidation, Reduction, Addition, Substitution, and Rearrangement Part II. The Reactions of Carboxylic Acids and Their Derivatives Oxidation, Reduction, Addition, Substitution, Elimination, and Rearrangement... 

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