Reactions of Carboxylic Acids—General Features

The polar C—O and O-H bonds, nonbonded electron pairs on oxygen, and the n bond give a carboxylic acid many reactive sites, complicating its chemistry somewhat. By far, the most important reactive feature of a carboxylic acid is its polar O-H bond, which is readily cleaved with base. 

A Bransted-Lowry acid-base reac tion 

Much of the rest of Chapter 19 is devoted to the acidity of carboxylic acids, as well as some related acid—base reactions. Two other structural features are less important in the reactions of carboxylic acids, but they play a role in the reactions of Chapters 20 and 22. 

Finally, the polar C-O bonds make the carboxy carbon electrophilic, so carboxylic acids react with nucleophiles. Nucleophilic attack occurs at an sp hybridized carbon atom, so it results in the cleavage of the Jt bond, as well. This reaction is also discussed in Chapter 22. 

9 Carboxylic Acids—Strong Organic Bronsted-Lowry Acids 

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The establishment of the main features of the reactions of carboxylate ions with 3-unsubstituted isoxazolium salts is fully described in the classic paper by Woodward and Olofson.165 A generalized reaction scheme is shown as Scheme 10. Deprotonation at the 3-position is rapidly followed (or more probably accompanied) by ring opening to give the ketoketenimine (54). Ketoketenimines have been detected spectroscopically and are sufficiently stable for isolation in some cases.166,167 Reaction of carboxylic acid... 

Preparation of Carboxylic Acid Chlorides (and Anhydrides). Oxalyl chloride has found general application for the preparation of carboxylic acid chlorides since the reagent was introduced by Adams and Ulich. Acid chlorides produced by this means have subsequently featured in the synthesis of acyl azides, bromoalkenes, carboxamides, cinnolines, diazo ketones, (thio)esters, lactones, ketenes for cycloaddition reactions, intramolecular Friedel-Crafts acylation reactions, and the synthesis of pyridyl thioethers. ... 

The ruthenium carbene catalysts 1 developed by Grubbs are distinguished by an exceptional tolerance towards polar functional groups [3]. Although generalizations are difficult and further experimental data are necessary in order to obtain a fully comprehensive picture, some trends may be deduced from the literature reports. Thus, many examples indicate that ethers, silyl ethers, acetals, esters, amides, carbamates, sulfonamides, silanes and various heterocyclic entities do not disturb. Moreover, ketones and even aldehyde functions are compatible, in contrast to reactions catalyzed by the molybdenum alkylidene complex 24 which is known to react with these groups under certain conditions [26]. Even unprotected alcohols and free carboxylic acids seem to be tolerated by 1. It should also be emphasized that the sensitivity of 1 toward the substitution pattern of alkenes outlined above usually leaves pre-existing di-, tri- and tetrasubstituted double bonds in the substrates unaffected. A nice example that illustrates many of these features is the clean dimerization of FK-506 45 to compound 46 reported by Schreiber et al. (Scheme 12) [27]. 

The kinetics of reactions between aroylpyruvic acids, ArC0CH2C0C02H, and arylamines in toluene show evidence of several mechanistic features intramolecular carboxyl catalysis, and catalysis by a second molecule of nucleophile, either on its own, or in concert with an (external) carboxylic acid. An extended solvent study shows an increase in the efficiency of the aforementioned intramolecular carboxyl catalysis with decreasing polarity of the solvent.Hydrolysis of the related /3-keto esters, methyl 4-aryl-2-arylamino-4-oxobut-2-enoates [ArC0CH=C(NHAr)C02Me] in aqueous dioxane is subject to general acid catalysis. " ... 

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