Carboxylic acids activation toward acylation

Mechanism of esterification of carboxylic acids The esterification of carboxylic acids with alcohols is a kind of nncleophilic acyl snbstitntion. Protonation of the carbonyl ojq gen activates the carbonyl gronp towards nncleophilic addition of the alcohol. Proton transfer in the tetrahedral intermediate converts the hydrojq l group into - 0H2 group, which, being a better leaving group, is eliminated as neutml water molecule. The protonated ester so formed finally loses a proton to give the ester. 

The Fischer esterification mechanism (Key Mechanism 20-2) is an acid-catalyzed nucleophilic acyl substitution. The carbonyl group of a carboxylic acid is not sufficiently electrophilic to be attacked by an alcohol. The acid catalyst protonates the carbonyl group and activates it toward nucleophilic attack. Attack by the alcohol, followed by loss of a proton, gives the hydrate of an ester. 

Imidazolides are powerful acylating agents. Therefore moisture has to be excluded and the acids have to be preactivated before addition of the amine. The tendency toward racemization is low, especially in DMF. The by-products of the reaction, imidazole and carbon dioxide, are easily removable. Other activating reagents (Table 6) can be applied. The advantage of COMODD and A, /V -carbonyldi-2-thione-1,3-thiazolidine is that the actival carboxylic acids are stable and isolable. 

To overcome tbe problem of tbe bigb amount of graphite utilized and mainly to avoid tbe use of tbe expensive and pollutant acyl balides and benzene, graphite can be coupled with para-toluenesulfonic acid and utilized to activate the more ecocompatible carboxylic acids toward electrophilic acylation. i With this catalyst, not only a solvent-free process can be developed but also high yields with not activated aromatic substrates and with unactivated carboxylic acids (i.e., para-nitrobenzoic acid) can be obtained (Table 4.25). 

The first methods for aza-annulation with a-amido-derived acrylate reagents, such as 344, involved activation of the carboxylic acid toward acylation through the use of DPPA (eq. 69).42 Efficient aza-annulation of 104 and 109 generated the corresponding amino acid derivatives 345 and 346. 

Thioesters are the most common forms of activated carboxylic acids in a cell. Although thioesters hydrolyze at about the same rate as oxygen esters, they are much more reactive than oxygen esters toward attack by nitrogen and carbon nucleophiles. This allows a thioester to survive in the aqueous environment of the cell—without being hydrolyzed—waiting to be a substrate in a nucleophilic acyl substitution reaction. 

The vitamin precursor of CoASH is pantothenate. We have seen that CoASH is used in biological systems to activate carboxylic acids by converting them into thioesters, which are much more reactive toward nucleophilic acyl substitution reac-... 

For a complete description of the synthetic utility of the Houben-Hoesch reaction as it applies to other aromatic systems, as well as some mechanistic discussions, the reader is directed to two reviews on the subject. Due to the diminished electrophilic reactivity of nitriles compared to other carboxylic acid derivatives as well as the broad number of Friedel-Crafts substrates, most Houben-Hoesch pyrrole acylation reactions are conducted intramolecularly. However, an impressive intermolecular example was delineated by Chang and co-workers in efforts directed toward the synthesis of novel 2-[5-aroylpyrrolo]alkanoic acids, for evaluation of their potential analgesic and anti-inflammatory activities. Treatment of substituted pyrrole 4 and 3-cyanopyridine (5) with acid in dry chloroform resulted in the preparation of 6 in good yield. 

A great deal of work has been done on the in situ activation of carboxylic acids toward nucleophilic substitution by amines. This type of reaction forms the backbone of the methods for synthesis of peptides and proteins. (See also Section 13.6). DCC is very widely used for coupling carboxylic acids and amines to give amides. Because amines are better nucleophiles than alcohols, the leaving group in the acylation reagent need not be as reactive as is necessary for alcohols. The -nitrophenyl and 2,4,5-trichlorophenyl " ... 

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