Carboxylates modification with

One aspect of carboxyl modification of particular interest is its replacement with other acidic functional groups. One of these, the replacement of the carboxyl with a 5-tetrazolyl group, is of particular interest because of the resultant improved antibacterial properties. This transformation is shown in Scheme 20 (78USP4115385). 

The Hunsdiecker reaction is the treatment of the dry silver salt of a carboxylic acid with bromine in carbon tetrachloride. Decarboxylation occurs, and the product isolated is the corresponding organic bromide 16). Since dry silver salts are tedious to prepare, a modification of the reaction discovered by Cristol and Firth (77) is now... 

The present procedure offers a convenient alternative to the Prevost reaction and the Woodward modification of the Prevost reaction in which silver carboxylates are used instead of thal-lium(I) carboxylates. Thallium(I) salts have the advantages of being generally stable crystalline solids that can be readily prepared in high yield by neutralization of the appropriate carboxylic acid with thallium(I) ethoxide. Silver salts, on the other hand, are frequently unstable and difficult to dry. Thallium and its compounds are, however, extremely toxic, and great care must therefore be taken in the use and disposal of thallium salts. ... 

Additional acceleration of acylation can be obtained by inclusion of cupric salts, which coordinate at the pyridine nitrogen. This modification is useful for the preparation of highly hindered esters.122 Pyridine-2-thiol esters can be prepared by reaction of the carboxylic acid with 2,2 -dipyridyl disulfide and triphenylphosphine123 or directly from the acid and 2-pyridyl thiochloroformate.124... 

Modification of carboxylate groups with diamines also may be done in organic solvent for those molecules insoluble in aqueous buffers. Some peptides are quite soluble in solvents such as DMF and DMSO, but relatively insoluble in water. Such molecules may be reacted in these... 

The same type of modification with carboxylate molecules can be done in aqueous solution using EDC. If the ligand to be coupled only has a single carboxylate with no amines or other nucleophiles present, then the dendrimer and ligand may be dissolved at a similar molar ratio in aqueous buffer and EDC added to facilitate the coupling reaction. 

Dextran derivatives containing carboxyl- or amine-terminal spacer arms may be prepared by a number of techniques. These derivatives are useful for coupling amine- or carboxylate-containing molecules through a carbodiimide-mediated reaction to form an amide bond (Chapter 3, Section 1). Amine-terminal spacers also can be used to create secondary reactive groups by modification with a heterobifunctional crosslinking agent (Chapter 5). 

The histidine residue in position 12 is crucial for activity. Its destruction by photooxidation or modification by iodination (No. 13, Table XIB) or carboxymethylation in the 3 position on the ring (No. 24, Table XIA) all destroy potential activity. The first two also substantially lower the association constant while the latter has no effect or may even increase it slightly. The CM group in the 3 position is, of course, easily accommodated and the interaction of the free carboxyl group with other positive charges nearby, e.g., His 119, may explain the increase in association constant. Conversion to a pyrazolyl residue destroys activity but not binding (No. 19). 

A method with an enormous potential for dextran modification is the homogeneous one-pot synthesis after in situ activation of the carboxylic acids with CDI, which is a rather well known technique in general organic chemistry and was published in 1962 [ 197]. It is especially suitable for the functionalisation of the biopolymers, because during conversion the reactive imidazolide of the acid is generated and only CO2 and imidazole are formed as by-products (Fig. 29). 

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