1,3-Dicyclohexylcarbodiimide-4-Dimethylaminopyridine1

(DCC)

[538-75-0]  · C13H22N2  · 1,3-Dicyclohexylcarbodiimide-4-Dimethylaminopyridine  · (MW 206.33) (DMAP)

[1122-58-3]  · C7H10N2  · 1,3-Dicyclohexylcarbodiimide-4-Dimethylaminopyridine  · (MW 122.17)

(powerful dehydrating mixture used for the preparation of esters,2 lactones,3,4 and amides from carboxylic acids and alcohols or amines)

Alternate Name: DCC/DMAP.

Physical Data: DCC: mp 34-35 °C; bp 122-124 °C. DMAP: mp 108-110 °C.

Solubility: DCC: highly sol dichloromethane, THF, acetonitrile, DMF. DMAP: sol dichloromethane, THF, acetonitrile, DMF, ethyl acetate.

Form Supplied in: DCC: opalescent solid; widely available. DMAP: yellow to tan crystals; widely available.

Handling, Storage, and Precautions: DCC is an acute skin irritant in susceptible individuals. Because of its low melting point, it is conveniently handled as a liquid by gentle warming of the reagent container. It should be handled with gloves in a fume hood, and stored under anhydrous conditions. DMAP causes skin and eye burns, and is readily absorbed through the skin. It should be handled with gloves in a fume hood and stored under dry conditions.

Ester Synthesis.

The combination of the powerful dehydrating agent 1,3-Dicyclohexylcarbodiimide (DCC) and the nucleophilic acylation catalyst 4-Dimethylaminopyridine (DMAP)1 is widely used in the preparation of esters from carboxylic acids and alcohols. The coupling of carboxylic acids with phenols, thiophenols, and thiols can generally be carried out in the absence of any acylation catalyst,5 but reactions with alcohols do require a catalyst. DMAP is most commonly used, although other related derivatives such as 4-pyrrolidinopyridine (PPY) have in some cases been more effective.6 These reactions are quite general, although yields typically decrease as steric bulk increases. t-Butyl esters can frequently be synthesized in yields greater than 80%.6-8 To facilitate purification of the product, water-soluble carbodiimides such as 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride (EDCI)9 can be used in place of DCC.

Under typical conditions, DCC (1.1 equiv) is added to a concentrated solution (0.1-1.0 M) of the carboxylic acid (1.0 equiv), alcohol (1.0-3.0 equiv), and DMAP (0.01-0.10 equiv) in dichloromethane or dichloromethane/DMF at 0 °C. After 1 h the solution is allowed to warm to rt and stirring is continued for an additional 1-5 h. After removal of the precipitated dicyclohexylurea (DCU) by filtration, the product can be recovered by extraction.

Because DMAP and its related derivatives (in conjunction with a coupling agent) are such powerful acylating agents, racemization has frequently been observed in reactions with chiral carboxylic acids, particularly with amino acids. For example, in the synthesis of the t-butyl ester of Boc-Asp(OBz)-CO2H, greater than 60% racemization was observed2 using EDCI with DMAP (0.5 equiv). The degree of racemization is highly dependent upon the components, and generally increases with steric bulk. Racemization can be suppressed by using low temperatures, short reaction times, and a minimum of DMAP.

The role of DMAP in these reactions is two-fold. First, the pyridine nitrogen can undergo nucleophilic attack upon the O-acyl active ester, forming the N-acylpyridinium. This charge-separated adduct facilitates electrophilic attack of the nucleophile and increases the leaving group ability. The second role of DMAP is its function as a base (pKa9.70). As such, it can assist in the deprotonation of the nucleophile. If DMAP is used in stoichiometric amounts, it can be used to neutralize acids formed if the activating agent is an anhydride rather than a carbodiimide.

Lactones.

DCC/DMAP has been frequently used in the synthesis of lactones of various ring sizes. The reaction conditions and considerations are essentially the same as for ester formation. In several cases, however, the catalyst was effective only when used as the hydrochloride or trifluoroacetate salt.4,10,11

Amides.

Although amide bond formation reactions can often be carried out without any acyl-transfer catalyst, the use of DMAP can dramatically increase the reaction rate. For example, the rate of reaction between m-chloroaniline and benzoyl chloride was increased by a factor of nearly 6 × 103 when pyridine was replaced by DMAP as the catalyst.12 However, DMAP is not frequently used for this purpose13 because of the potential for racemization with chiral carboxylic acids. In these cases, less powerful acyl-transfer catalysts are used.


1. Höfle, G.; Steglich, W.; Vorbrüggen, H. AG(E) 1978, 17, 569.
2. Dhaon, M. K.; Olsen, R. K.; Ramasamy, K. JOC 1982, 47, 1962.
3. Johnson, W. S.; Bauer, V. J.; Margrave, J. L.; Frisch, M. A.; Dreger, L. H.; Hubbard, W. N. JACS 1961, 83, 606.
4. Stork, G.; Rychnovsky, S. D. JACS 1987, 109, 1565.
5. Grunwell, J. R.; Foerst, D. L. SC 1976, 6, 453.
6. Hassner, A.; Alexanian, V. TL 1978, 4475.
7. Neises, B.; Steglich, W. OS 1985, 63, 183.
8. Neises, B.; Steglich, W. AG(E) 1978, 17, 522.
9. Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. L. JOC 1961, 26, 2525.
10. Keck, G. E.; Boden, E. P.; Wiley, M. R. JOC 1989, 54, 896.
11. Bowden, E. P.; Keck, G. E. JOC 1985, 50, 2394.
12. Litvinenko, L. M.; Kirichenko, A. I. Dokl. Akad. Nauk SSSR 1967, 176, 97 (CA 1968, 68, 68 325u).
13. Wang, S. S.; Tam, J. P.; Wang, B. S. H.; Merrifield, R. B. Int. J. Pept. Protein Res. 1981, 19, 459.

Jeffrey S. Albert & Andrew D. Hamilton

University of Pittsburgh, PA, USA



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