Carbodiimides dicyclohexylcarbodiimide

As the last example of an SN reaction at the carboxyl carbon of a carbonic acid derivative, consider the synthesis of dicyclohexylurea in Figure 6.39. In this synthesis, two equivalents of cyclohexylamine replace the two methoxy groups of dimethyl carbonate. Dicyclohexylurea can be converted into the carbodiimide dicyclohexylcarbodiimide (DCC) by treatment with tosyl chloride and triethylamine. The urea is dehydrated. The mechanism of this reaction is identical to the mechanism that is presented in Figure 8.9 for the similar preparation of a different carbodiimide. 

Roughly 0.6-0.8 g. of the urea is usually obtained, m.p. 232-234°. The excess dicyclohexylcarbodiimide remains in the benzene. The oxidation is generally less satisfactory if less than 2.5 molar equivalents of carbodiimide is used. 

The reaction of Ccf -ATPase with dicyclohexylcarbodiimide Carbodiimides readily react in aqueous solutions with protein amino, carboxyl and sulfhydryl groups slower reactions with tyrosine and serine have also been reported [369,370]. The primary reaction product of carboxyl groups with dicyclohexylcarbodiimide is dicyclohexyl-O-acyl isourea [370]. Dicyclohexyl-O-acyl isourea is susceptible to nucleophilic attack either by water or by endogenous or exogenous nucleophiles, yielding a complex series of reaction products [369-371]. 

The first version of SPPS to be developed used the t-Boc group as the amino-protecting group. f-Boc can be cleaved with relatively mild acidic treatment and TFA is usually used. The original coupling reagents utilized for SPPS were carbodiimides. In addition to dicyclohexylcarbodiimide (DCCI), N, (V -diisopropylcarbodiimide (DIPCDI) is often used. The mechanism of peptide coupling by carbodiimides was... 

DCC= 1,3-dicyclohexylcarbodiimide, DIC = 1,3-diisopropyl-carbodiimide, EDC = 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide. 

A carbodiimide is added to the two reacting species. The urea generated from dicyclohexylcarbodiimide is insoluble and voluminous, so it is often replaced by diisopropylcarbodiimide, which generates a soluble urea. The soluble carbodiimide ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride (see Section 1.16) is suitable but expensive. Efficiency of coupling is greater in dichloromethane than in dimethylformamide. There is also the option of adding 1-hydroxybenzotriazole to minimize the side reactions of A-acylurca (see Section 2.12), cyano (see Section 6.15), and aspartimide (see Section 6.13) formation. 

The symmetrical anhydride is prepared using dicyclohexylcarbodiimide in dichloromethane, the urea and solvent are removed, and the anhydride is dissolved in dimethylformamide and added to the peptide-resin (see Section 2.5). The anhydride is a more selective acylating agent than the 0-acylisourea and, thus, gives cleaner reactions than do carbodiimides, but twice as much amino-acid derivative is required, so the method is wasteful. It avoids the acid-catalyzed cyclization of terminal glutaminyl to the pyroglutamate (see Section 6.16) and is particularly effective for acylating secondary amines (see Section 8.15). 

FIGURE 8.3 Synthesis of amides by aminolysis of unisolated activated esters obtained using carbodiimide by (A) ammonium hydroxide,12 (B) diaminomethane dihydrochloride neutralized with Et3N,15 and (C) the amine of crystalline salts of additives, R = H, Me, Et.13 DCC = dicyclohexylcarbodiimide HOBt = 1-hydroxybenzotriazole HONSu = A-hydroxysuccin-imide HONp = p-nitrophcnol HODhbt = 3-hydroxy-4-oxo-3,4-dihydrobenzotriazine. 

N-Hydroxythiopyridone 2(1H)-Pyridinethione, 1-hydroxy- (8,9) (1121-30-8) Dicyclohexylcarbodiimide highly toxic. Carbodiimide, dicyclohexyl- (8) Cyclohexanamine, N,N -methanetetraylbis- (9) (538-75-0)... 

At room temperature aliphatic and aromatic carbodiimides are liquid or solid. They usually can be purified by distillation under reduced pressure or by recrystallization to yield neutral products. On prolonged standing they polymerize to yield basic products. The liquid carbodiimides are less stable than the solid ones. The stability of carbodiimides increases with the degree of branching of the alkyl substituents attached to the nitrogen atom RCH2 < R2CH < R3C. For example, diethylcarbodiimide [14, 21] polymerizes in a few days, whereas diisopropyl- and dicyclohexylcarbodiimides [14] are stable for several months. Unsaturated substituents also cause a marked decrease in stability... 

A procedure widely used for coupling ligands to supports containing spacer groups is the carbodiimide method.52,53 Many different carbohydrate derivatives have been coupled to supports in this way. A variety of diimides has been employed in these couplings, and these include dicyclohexylcarbodiimide (DCC), 3-(3-dimethylaminopro-... 

Carbodiimides are diaza derivatives of C02. It is also possible to add heteroatom nucleophiles to them. This is especially relevant when the heteroatom nucleophile is a carboxylic acid and when the carbodiimide is dicyclohexylcarbodiimide ... 

Eledroosmotic flow (EOF) conditions were applied and yielded only 10% conversion with constant reactant movement [9]. The use of stopped-flow techniques, which periodically push and mix the flow, led to a 50% increase in yield. A change in the coupling agent from l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI) to dicyclohexylcarbodiimide (DCC) for reasons of limited solubility resulted in a 93% yield of the dipeptide. Batch P-dipeptide synthesis using EDCI gave a yield of 50% [6]. 

Esterification with alcohols in the presence of pyridine was used by Felder et al. [36]. Water produced in the reaction mixture is bound by the addition of N,N -dicyclohexyl-carbodiimide (Scheme 4.8). The acid (ca. 10 mequiv.) is dissolved in 25 ml of alcohol and 4 ml of pyridine and an excess of dicyclohexylcarbodiimide (12 mequiv.) are added (even more if the sample is not dry). The amount of pyridine can also be larger and it then acts as a solvent, e.g., if the alcohol used is solid (menthol). The mixture is then stirred at room temperature only with some higher alcohols or acids must the mixture be heated at 40—80°C for 30—120 min. If a precipitate of N,N -dicyclohexylurea is produced in the reaction, it is allowed to sediment and, after adding an internal standard,... 

Z + Z] Cycloaddition reactions are important in the construction of 1,3-thiazetidine rings . Isothiocyanates add carbodiimides across the carbonsulfur bond < 1975J(P2) 1475 >. For example, the reaction of the 2-thioxo-l,3-thiazepan-4-one derivative 208 with A,A-dicyclohexylcarbodiimide affords the 1,3-thiazetidine system 209 (Scheme 100) <1999JHC1167>. 

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