Carboxylic acids, conversion dehydrating agents

Another way to esterify a carboxylic acid is to treat it with an alcohol in the presence of a dehydrating agent. One of these is DCC, which is converted in the process to dicyclohexylurea (DHU). The mechanism has much in common with the nucleophilic catalysis mechanism the acid is converted to a compound with a better leaving group. However, the conversion is not by a tetrahedral mechanism (as it is in nucleophilic catalysis), since the C—O bond remains intact during this step ... 

Carboxylic acids can also be activated by converting them to their anhydrides. For this purpose they are dehydrated with concentrated sulfuric acid, phosphorus pentoxide, or 0.5 equivalents of SOCl2 (1 equivalent of SOCl2 reacts with carboxylic acids to form acid chlorides rather than anhydrides). However, carboxylic anhydrides cannot transfer more than 50% of the original carboxylic acid to a nucleophile. The other 50% is released—depending on the pH value—either as the carboxylic acid or as a carboxylate ion and is therefore lost. Consequently, in laboratory chemistry, the conversion of carboxylic acids into anhydrides is not as relevant as carboxylic acid activation. Nonetheless, acetic anhydride is an important acetylat-ing agent because it is commercially available and inexpensive. 

Conversion of this salt to an amide requires temperatures too high for the survival of the peptide, therefore we must convert the carboxyl group to a more reactive acyl derivative, that is, we must "activate" the carboxyl function. However, we do not have to activate the carboxyl group prior to amidation instead we treat the N-protected amino acid with the ester of the second amino acid (remember we must use the ester form in order to block the carboxyl function) in the presence of dicyclohexylcarbodiimide (DCC), a potent non-acidic dehydrating agent ... 

Oxazolines are formed directly from the reaction of carboxylic acids with 2-ami-no-2-methyl-l-propanol in refluxing toluene but a two-step procedure involving reaction of 2-amino-2-methyl-l-propanol with an acid chloride followed by treatment of the resultant amide with excess thionyl chloride as a dehydrating agent is generally preferred (Scheme 2.128].2 o 26i Alternatives include reaction of dimethylaziridine with a carboxylic acid in the presence of dicyclohexylcarbo-diimide to form the N-acylaziridine followed by acid-catalysed rearrange-ment or reaction of an orthoester, or an imidate ester, with an amino alcohol as illustrated by the conversion of 129.1 to 1293 [Scheme 2.129). ... 

Conversion of the carboxylic gronp into the diphosphonic acid group takes place by a complex reaction mechanism. The phosphorus-halogen compound acts primarily as a dehydrating agent, although the hydrolysis products of the phosphorus-halogen component that accumulates may also participate in the substitution reaction. 

Various PEKs were prepared via electrophilic substitution processes such as that exemplarily outlined in equation (54) [79]. The problems of this approach are in principle the same as in the case of PESs. An inert expensive solvent is needed, it is difficult to reach high conversions without side reactions and the number of useful monomers is lower than in the case of syntheses based on nucleophilic substitution reactions. The electrophilic polycondensations may be subdivided into two different methods. Firstly, acid chlorides are used as electrophilic monomers in combination with a Lewis acid. Secondly, free carboxylic acid served as monomers in combination with an acidic dehydrating agent. None of the polycondensation methods described in this section is new, and origin and early exploration of these methods has been reviewed in the 1st edition of this handbook (Chapter 9). 

Here chlorosulfonic acid functions as an acidic dehydrating agent and, as was mentioned in the introduction (Chapter 1, p 6), it can be employed as a catalyst in the esterification of carboxylic acids. The reagent was thus effective in the conversion of acetonedicarboxylic acid into the diethyl ester (72% yield) (see Chapter 5, p 174). 

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