Carbodiimides reacting with carboxylic acids

N-substituted carbodiimides can react with carboxylic acids to form highly reactive, o-acylisourea derivatives that are extremely short-lived (Reaction 11). This active species then can react with a nucleophile such as a primary amine to form an amide bond (Reaction 12)... 

Triaminophosphonium salts, unlike carbodiimides, only react with carboxylic acids under basic conditions, thereby yielding acyloxyphosphonium salts (Figure 13.5). Depending on the counterion X and on the precise reaction conditions, the acyloxyphosphonium salt can either acylate the amine directly or be transformed into the symmetric anhydride or an active ester [2,82], which then acylates the amine. At low... 

Reaction of the carbodiimide with the acid then provides a means for the synthesis of a biologically high-energy acid anhydride. This suggests a potential route for the synthesis of a peptide bond. For example, it has already been pointed out that amines will react with acid anhydrides to form peptide bonds. Further, under the mild conditions (i.e., room temperature) that carbodiimide will react with carboxylic acids, competing reactions will not occur. For example, carbodiimides will only undergo nucleophilic attack by alcohols under refluxing conditions. 

Carboxylic acids may be covalently modified with adipic acid dihydrazide or carbohydrazide to yield stable imide bonds with extending terminal hydrazide groups. Hydrazide functionalities don t spontaneously react with carboxylate groups the way they do with aldehyde groups (Section 4.5, this chapter). In this case, the carboxylic acid first must be activated with another compound that makes it reactive toward nucleophiles. In organic solutions, this may be accomplished by using a water-insoluble carbodiimide (Chapter 3, Section 1.4) or by creating an intermediate active ester, such as an NHS ester (Chapter 2, Section 1.4). 

Biotin-hydrazide also may be used to couple with carboxylate-containing molecules. Hydrazidcs can be coupled with carboxylic acid groups by using the carbodiimide reaction (Chapter 3, Section 1.1). The carbodiimide activates a carboxylate to an o-acylisourea intermediate. Biotin-hydrazide can react with this intermediate via nucleophilic addition to form a stable covalent bond. 

FIGURE 7.1 A carbodiimide reacts with a carboxylic acid (A) to give the O-acylisourea, which may rearrange (B) to the A-acylurea. It also reacts with amino groups (C) to produce guanidines if no carboxyl group is available. 

Under the above conditions the carbodiimides react with the carboxylic acid viaN-acylation. 

In view of the rapid reaction of carbodiimides with water they are often used in dehydration reactions. Major examples are the intra- and intermolecular esterification reactions of carboxylic acids, and the formation of peptides from carboxylic acids and protected amino acids. Especially, dicyclohexylcarbodiimide (DCC) or diisopropylcar-bodiimide (DIPCD) are often used in carbodiimide mediated reactions because the corresponding urea byproducts are insoluble in most organic solvents and water, and therefore are readily removed by filtration. Also, water soluble carbodiimides, such as N-ethyl-N -(3-dimethylamino)propylcarbodiimide (EDC) or its hydrochloride (EDCCl, sometimes referred to as EDAC) are often used in these reactions. EDC reacts with carboxyl groups at pH of 4.0-6.0, but loses its reactivity at lower pH. Sometimes solid phase reactions are conducted using carbodiimide terminated linear or crosslinked polymers. 

In conclusion, I have shown that the mechanism of stabilization has been investigated by allowing to react the carbodilmide with various model substances, e.g., water, acetic acid, etiianol. The structure of the products of solvolysis has also been elucidated. It has also been demonstrated that the carbodiimide reacts with residual or newly formed moisture and lactic acid, or the carboxyl and hydroxyl end groups in the PLA. These groups are hampering the thermal degradation and hydrolysis of PLA. 

In contrast to carbodiimides, trichloroacetonitrile reacts neither with phosphoric acid diesters nor with carboxylic acids. F. esterification s. F. D. Gramer and G. Weimann, Ghem. Ind. 1960, 46. 

A novel poiyesterification procedure avoiding the need for pre-activated carboxylic acid was recently reported by Moore and Stupp [429]. This method reacts phenolic groups directly with carboxylic acids in solution and under mild conditions. It requires the use of carbodiimide dehydrating agent [431,432] and a novel catalyst which is a 1 1 molecular complex formed by 4-(dimethylamino) pyridine and p-toluenesulfonic acid [429], Under these conditions, linear polyesters with molecular weights in excess of IS 000 were obtained [429], but the molecular weights of exclusively aromatic polyesters prepared by this method may be lower. 

The reaction between acyl halides and diazomethane is of wide scope and is the best way to prepare diazo ketones. Diazomethane must be present in excess or the HX produced will react with the diazo ketone (10-74). This reaction is the first step of the Amdt-Eistert synthesis (18-8). Diazo ketones can also be prepared directly from a carboxylic acid and diazomethane or diazoethane in the presence of dicyclohexyl-carbodiimide. ... 

Some procedures recommend the use of water as the solvent in an EDC reaction, while the pH is maintained constant by the addition of HC1. Buffered solutions are more convenient, because the pH does not have to be monitored during the course of the reaction. For acidic pH conjugations, MES [2-(N-morpholino)ethane sulfonic acid] buffer at 0.1 M works well. When doing neutral pH reactions, a phosphate buffer at 0.1 M is appropriate. Any buffers may be used that do not interfere with the reaction, but avoid amine- or carboxylate-containing buffer salts or other components in the medium that may react with the carbodiimide. 

Hydrazide groups can react with carbonyl groups to form stable hydrazone linkages. Derivatives of proteins formed from the reaction of their carboxylate side chains with adipic acid dihydrazide (Chapter 4, Section 8.1) and the water-soluble carbodiimide EDC (Chapter 3, Section 1.1) create activated proteins that can covalently bind to formyl residues. Hydrazide-modified enzymes prepared in this manner can bind specifically to aldehyde groups formed by mild periodate oxidation of carbohydrates (Chapter 1, Section 4.4). These reagents can be used in assay systems to detect or measure glycoproteins in cells, tissue sections, or blots (Gershoni et al., 1985). 

More recently, the fixation efficiency on cotton of Cl Reactive Red 177 (7-43) and its 4-carboxyphenylazo analogue in the presence of various carbodiimides (including 7-44 and 7.45) was investigated, as well as homogeneous reactions of selected carboxylic acids with alcohols (including acetylcellulose in acetone). The carboxylated dye reacted more effectively with cotton cellulose in the presence of cyanamide rather than dicyandiamide,... 

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