N,N'-Dicyclohexylcarbodiimide

Dicyclohexylcarbodiimide (DCC) is an organic compound with chemical formula C₁₃H₂₂N₂ whose primary use is to couple amino acids during artificial peptide synthesis. Under standard conditions, DCC exists in the form of white crystals with a heavy, sweet odor. The low melting point of this material allows it to be melted for easy handling. DCC is highly soluble in dichloromethane, tetrahydrofuran, acetonitrile and dimethylformamide, but insoluble in water.

It should be handled with caution because it is a potent allergen and a sensitizer, often causing allergic reactions, particularly skin rashes.

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Structure

The structure of DCC is not a planar structure as shown in the simplified picture above. Two resonance structures are available to DCC and elucidate the structure of this molecule:

These structures show that the central N=C=N moiety does remain linear, however, the cyclohexyl groups are not confined to a particular geometry. Also, a lack of pi bonding between the two nitrogens and the cyclohexyl groups allows them to rotate on the N-C bond axis.

Synthesis of DCC

Of the several syntheses of DCC, Pri-Bara et al. use palladium acetate, iodine, and oxygen to couple cyclohexyl amine and cyclohexyl isocyanide.^[1] Yields of up to 67% have been achieved using this reaction scheme. The reaction is as follows:

Tang et al. condense two isocyanates using the catalyst OP(MeNCH₂CH₂)₃N in yields of 92%.^[2] The reaction is as follows:

Lastly, a method for the synthesis of DCC involving a phase transfer catalyst has been published by Jaszay et al. The disubstituted, arenesulfonyl chloride, and potassium carbonate react in the presence of benzyl trimethylammonium chloride.

The N=C=N moiety gives characteristic IR spectroscopic signature at 2117 cm^-1.^[2]15N NMR shows a characteristic shift of 275.0 ppm upfield of nitric acid.¹³C NMR of this compound contains a peak at about 139 ppm downfield from TMS depending on solvent choice (DMSO or chloroform).

Reactivity of DCC

DCC is a strong dehydrating agent for the preparation of amides, ketones, nitriles, and can invert secondary alcohols. During reaction, it hydrates to form dicyclohexylurea (DCU), a compound which is insoluble in water.

Moffatt Oxidation

A solution of DCC and dimethyl sulfoxide (DMSO) is used in a reaction termed the Pfitzner-Moffatt oxidation. This procedure is used for the gentle oxidation of alcohols to aldehydes and ketones. Unlike metal-mediated oxidations, the reaction conditions are sufficiently mild to halt over-oxidation of aldehydes to carboxylic acids. Generally, 1 equivalent of the alcohol to be oxidized is mixed with 3 equiv DCC and a proton source (0.5 equiv) in DMSO and left to react overnight at room temperature. The reaction is quenched by the addition of acid.

Primary alcohols:

Secondary alcohols:

Dehydroxylation

Alcohols can also be dehydroxylated using DCC. This reaction proceeds by first forming an O-acylurea intermediate which is then hydrogenolyzed to produce the corresponding alkane.

Inversion of secondary alcohols

Secondary alcohols can be stereochemically inverted by formation of a formyl ester followed by saponification. The secondary alcohol is mixed directly with DCC, formaldehyde, and a strong base such as sodium methoxide.

Esterification

A range of alcohols, including even some tertiary alcohols, can be esterified using a carboxylic acid in the presence of DCC and a catalytic amount of DMAP.^[3]

Mechanism of DCC-promoted peptide coupling

During artificial protein synthesis (such as Fmoc solid-state synthesizers), the C-terminus is often used as the attachement site on which the amino acid monomers are added. To enhance the electrophilicity of carboxylate group, the negatively charged oxygen must first be "activated" into a better leaving group. DCC is used for this purpose. The negatively charged oxygen will act as a nucleophile, attacking the central carbon in DCC. DCC is temporarily attached to the former carboxylate group (which is now an ester group), making nucleophilic attack by an amino group (on the attaching amino acid) on the former C-terminus more efficient.

See also

• Carbodiimide

References

1. ^ Ilan Pri-Bara and Jeffrey Schwartz (1997). "N,N-Dialkylcarbodiimide synthesis by palladium-catalysed coupling of amines with isonitriles". Chem Commun 4. doi:10.1039/a606012i.
2. ^ ^{a b} Jiansheng Tang, Thyagarajan Mohan, John G. Verkade (1994). "Selective and Efficient Syntheses of Perhydro-1 ,3,5-triazine-2,4,6-trioneasn d Carbodiimides from Isocyanates Using ZP(MeNCH2CH2)sN Catalysts". J. Org. Chem. 59: 4931-4938. doi:10.1021/jo00096a041.
3. ^ B. Neises, W. Steiglich (1990). "Esterification of Carboxylic Acids with Dicyclohexylcarbodiimide/4-Dimethylaminopyridine: Tert-Butyl Ethyl Fumarate". Org. Synth.; Coll. Vol. 7: 93. 

1. Issa Yavari, John D. Roberts (1978). "Nitrogen-15 Nuclear Magnetic Resonance Spectroscopy. Carbodiimides". J. Org. Chem. 43: 4689-4690. doi:10.1021/jo00419a001.
2. Zsuzsa Jaszay, Imre Petnehazy, Laszlo Toke, Bela Szajani (1987). "Preparation of Carbodiimides Using Phase-Transfer Catalysis". Synthesis 5: 520-523. doi:10.1055/s-1987-27992.