Anhydrides, mixed disproportionation

Most peptide chemists refer to unsymmetrical anhydrides as mixed anhydrides. This title is best reserved for those cases in which unsymmetrical anhydrides undergo disproportionation to give a mixture of anhydrides ... 

An additional minor source of urethane can be the reaction of unconsumed reagent with V-nucleophile (path C). Aminolysis of chloroformate occurs if there is an excess of reagent or if the anhydride-forming reaction is incomplete. The latter is more likely when the residues activated are hindered. This side reaction can be avoided by limiting the amount of reagent and extending the time of activation. A third side reaction that is of little consequence is disproportionation of the mixed anhydride to the symmetrical anhydride and dialkyl pyrocarbonate (see Section 7.5). 

FIGURE 7.7 Disproportionation of a mixed anhydride.14 Two molecules of anhydride generate symmetrical anhydride 8 and pyrocarbonate 9 probably via a bimolecular reaction.18... 

NL Benoiton, Y Lee, FMF Chen. Studies on the disproportionation of mixed anhydrides of IV-alkoxycarbonylamino acids. Int J Pept Prot Res 41, 338, 1993. 

Triethylamine (7) is a strong, hindered base originally employed for mixed-anhydride reactions. However, it reduces the rate of anhydride formation if the solvent is dichloromethane or chloroform (see Section 7.3) and promotes disproportionation of the anhydride under conditions in which /V-mcthylmorpholinc does not (see Section 7.5). It causes enantiomerization of urethane-protected amino-acid /V-carboxyanhydrides and reaction between two molecules with release of carbon dioxide (see Section 7.14). It is also used in the synthesis of Atosiban (see Section 8.9). There is no reaction for which it is recommended as superior to other tertiary amines, except possibly for coupling employing BOP-C1 (see Section 8.14). 

Acylation of arenes. These mixed anhydrides have been used Tor acylation of arenes. However these reagents are sensitive to moisture and tend to disproportionate. One solution is to generate the reagents in situ. Thus acyl trifluoro-acetates can be generated in the presence of the arene from a carboxylic acid, TFAA, and 85% phosphoric acid (as catalyst) in CHjCN. Ketones of the type O II... 

Carboxylic mixed anhydrides are very important for the rapid synthesis of peptides by the stepwise procedure,however the use of carboxylic mixed anhydrides,e.g.those derived from pivalic acid and a protected amino acid (1),suffers from two disadvantages. Firstly,regiospecificity of attack at the desired carboxyl function is largely determined by steric effects and will not be 100% for all coupling reactions.Secondly,such mixed anhydrides have a propensity towards disproportionation to symmetric anhydrides which is highly undesirable in terms of reaction efficiency.This latter process can be depressed by operation of the reaction at -15 °C, but with the concurrent decrease in reaction rate and,on large scale manufacture,increased costs. 

Acetic acid is quantitatively converted to acetic anhydride by reaction with ketene. Mixed anhydrides are formed when homologs of acetic acid or aromatic acids are used in the reaction. Upon distillation at atmospheric pressure, the mixed anhydrides disproportionate into acetic anhydride and the symmetrical anhydride corresponding to the carboxylic acid. Yields of propionic, n-butyric, and w-caproic anhydrides prepared by this method are in the range of 80% to 87%. ... 

Hydrolysis of Benzoic Isobutyric Anhydride. Reactions of mixed anhydrides can be complicated by disproportionation reactions (equation 10). The process may be operative in any investigation of anhydride hydrolysis, but it would go undetected in studies with symmetrical anhydrides or in studies that just monitor reaction rates by consumption of base. To obtain a more complete understanding of the catalytic behavior of 3, 4, 5, and 6 in transacylation reactions, the hydrolysis of benzoic isobutyric anhydride was investigated. 

A conceptual alternative way to the activation of the carboxylic acid function is the reaction of carboxylic acids with amino groups activated as isocyanates - and isothiocyanates (equation 16). Preparation of these derivatives is racemization free. The reaction proceeds via mixed acid anhydrides in aromatic hydrocarbon solvents at elevated temperatures, and decarboxylation leads to the V-substituted amide. Pyridine as solvent enhances the conversion rate but increases also the amount of the urea side product via disproportionation. Application to peptide chemistry is limited, because peptide ester fragments tend to form hydantoins. ... 

Other carboxylic acids give mixed anhydrides in this reaction,180-182 but these readily disproportionate to the pair of symmetrical anhydrides. This provides a method of obtaining good yields of acid anhydrides that are difficultly accessible by other routes. In Org. Syn. Williams and Krynitzky183 describe the preparation of hexanoic anhydride from the acid and ketene. 

Before concluding this section dealing with anhydrides of acylamino adds we have to return to symmetrical anhydrides. Their already mentioned formation through disproportionation of mixed anhydrides... 

Aromatic Sulfonation. Reaction of an arene (ArH) with SO3 leads to sulfonation with formation of arenesulfonic acids (ArSOsH). Mechanistically two different stages can be recognized, viz. primary and secondary sulfonation. In the primary stage, arenepyrosulfonic acids (ArS206H) are formed. A pyrosulfonic acid is a mixed anhydride, liable to disproportionate... 

Acid Activation. Chlorodiphenylphosphine oxide has been utilized for the activation of acids via in situ formation of the diphenylphosphinic (DPP) mixed anhydrides. These anhydrides are superior to carbon-based mixed anhydrides because they do not suffer from disproportionation to symmetrical anhydrides. Also,... 

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