Dicyclohexylcarbodiimide, activation carboxylic acids

Another in situ procedure for activating carboxylic acids utilizes earbodiimides, such as dicyclohexylcarbodiimide (DCC). DCC (19) plays an important role in peptide synthesis. Addition of a carboxylic acid to the C-N double bond leads to the activated species, an acyl isourea 20, which upon attack by a nucleophile (and alcohol or an amine) releases the corresponding ester or amide along with 21 (for the mechanism, see Chapter 5). However, in the conversion of 5 to 7 the DCC procedure gives poor results. 

Barton Esterification Reductive Decarboxylation. O-Acyl thiohydroxamates or Barton esters are useful precursors of carbon-centered radicals via thermolysis or photolysis. Several different methods are available for converting carboxylic acids into Barton esters (eq 1). These reactions generally proceed via the attack of a 2-mercaptopyridine-N-oxide salt on an activated carboxylic acid that has either been preformed (acid chloride, mixed anhydride) or generated in situ (with 1,3-dicyclohexylcarbodiimide or tri-n-butylphosphine + 2,2 -dithiodipyridine-l,r-dioxide). However, HOTT has the distinct advantages of (1) being easy to prepare and handle without the need for any special precautions, (2) facilitates efficient Barton esterification of carboxylic acids, and (3) simplifies subsequent work-up and purifications by avoiding the need to remove by-products like 1,3-dicyclohexylurea. 

Schemes are available, however, that start from the free carboxylic acid, plus an activator . Dicyclohexylcarbodiimide, DCC, has been extensively employed as a promoter in esterification reactions, and in protein chemistry for peptide bond formation [187]. Although the reagent is toxic, and a stoichiometric concentration or more is necessary, this procedure is very useful, especially when a new derivative is targeted. The reaction usually proceeds at room temperature, is not subject to steric hindrance, and the conditions are mild, so that several types of functional groups can be employed, including acid-sensitive unsaturated acyl groups. In combination with 4-pyrrolidinonepyridine, this reagent has been employed for the preparation of long-chain fatty esters of cellulose from carboxylic acids, as depicted in Fig. 5 [166,185,188] ...

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 is fundamental for synthesis of polypeptides (see also Section 13.3.1). Dicyclohexylcarbodiimide... 

Use of the relatively small cyclopropane ring drastically reduces the potential for deleterious steric bulk effects and adds only a relatively small lipophilic increment to the partition coefficient of the drug. One of the clever elements of the rolicyprine synthesis itself is the reaction of d,l tranylcypromine (67) with L-5-pyrrolidone-2-carboxylic acid (derived from glutamic acid) to form a highly crystalline diastereomeric salt, thereby effecting resolution. Addition of dicyclohexylcarbodiimide activates the carboxyl group to nucleophilic attack by the primary amine thus forming the amide rolicyprine (68). 

The addition of carboxylic acids to dicyclohexylcarbodiimide was mentioned in the context of Figures 6.15 and 6.26, but there we looked at it only from the point of view of activating a carboxylic acid. This addition follows the proton-catalyzed mechanism of Figure 8.12. 

Dicyclohexylcarbodiimide (DCC) is a reagent commonly used to form amide bonds (see Section 22.1 OD). DCC makes the OH group of the carboxylic acid a better ieaving group, thus activating the carboxy group toward nucleophilic attack. 

Figure 4.41. Amino Acid Activation. Dicyclohexylcarbodiimide is used to activate carboxyl groups for tbe formation of peptide bonds.

Carbodiimides, in particular dicyclohexylcarbodiimide, have been applied in many syntheses where dehydration had to be performed under mild conditions. It is therefore no surprise that this reagent was also introduced for the synthesis of acid anhydrides from carboxylic acids." " In order to avoid N-acylation the reactions are carried out at low temperature. First 0-acylisoureas are formed, which then react further with free acid to the acid anhydride (equation 34). The reaction has been exploited in particular for the preparation of peptides." )V-alkoxycarbonyl-protected amino acids can be transformed in high yield to the corresponding anhydrides, which themselves are activated acid derivatives and may be converted to peptides. As in many other examples polymer-bound carbodiimides may prove superior sometimes, as the isolation of the products is facilitated. Easy preparation of acid anhydrides is possible in this way." ... 

The synthesis of the protein conjugates is shown in Figure 3. Commercially available carboxylic acids were converted to activated esters by direct DCC (N,N-dicyclohexylcarbodiimide) coupling with N-hydroxysuccinimide or by conversion to the corresponding acid chloride derivative followed by reaction with N-hydroxysuccinimide. Reactiion of the resulting N-hydroxysuccinimide esters with either BSA or OVA led to the desired lysine bonded nitroaromatic hapten-protein conjugates. 

Surface carboxylic acids can also be activated by using diimides, such as 1, 3-dicyclohexylcarbodiimide (DCC) or l-ethyl-3-(dimethylaminopropyl)carbo-diimide (EDC). Activation with diimides is a mild procedure which takes advantage of reagents developed for peptide synthesis (see figure 6.7). This approach can be used to couple simple molecules to surfaces or for the immobilization of larger entities such as enzymes. This is illustrated by a... 

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