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

(powerful dehydrating agent commonly used for the preparation of amides,2 esters,3 and anhydrides;4 used with DMSO for the mild oxidation of alcohols to ketones;5 used in the dehydrative conversion of primary amides to nitriles,6 b-hydroxy ketones to a,b-unsaturated ketones,7 and can effect the stereochemical inversion of secondary alcohols8)

Alternate Name: DCC.

Physical Data: mp 34-35 °C; bp 122-124 °C.

Solubility: highly sol dichloromethane, THF, acetonitrile, DMF.

Form Supplied in: opalescent solid; widely available.

Handling, Storage, and Precautions: 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.

Amide Formation.

Since the initial reports,9,10 DCC has become the most common reagent in peptide synthesis2,11,12 and in other amide bond-forming reactions of primary and secondary amines with carboxylic acids. The mechanism is considered to be well understood.2,5

Typically, DCC (1.1 equiv) is added to a concentrated solution (0.1-1.0 M) of the carboxylic acid (1.0 equiv), amine (1.0 equiv), and catalyst (when used) in methylene chloride or acetonitrile at 0 °C. The hydrated DCC adduct, dicyclohexylurea (DCU), quickly precipitates and the reaction is generally complete within 1 h at rt. The solvents THF and DMF can be used, but are reported to reduce reaction rates and encourage the formation of the N-acylurea side product, as well as increasing racemization in chiral carboxylic acids.13-16 If the amine is initially present as the salt (i.e. amine hydrochloride), it may be neutralized by adding 1 equiv of Diisopropylethylamine prior to adding DCC; however, the addition of tertiary amines (particularly Triethylamine) can facilitate N-acylurea formation and racemization.2 Racemization occurs via the formation of an oxazalone intermediate.2 The addition of coupling agents (acylation catalysts) such as 1-Hydroxybenzotriazole (HOBt),17 1-hydroxy-7-azabenzotriazole (HOAt),18 N-Hydroxysuccinimide (HOSu),19 and 3-hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one20 can generally ameliorate both problems. These additives are required for the coupling of sterically hindered components, or when the amine is weakly nucleophilic.

Another potential problem with DCC is that at the completion of the reaction some DCU remains in solution with the product, necessitating additional purification. Water-soluble carbodiimide derivatives such as 1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide Metho-p-toluenesulfonate21 and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride (EDCI)22 obviate this problem, as they are removed by a simple extraction. Many newer coupling agents have been developed for peptide synthesis and other acylation reactions. These include Benzotriazol-1-yloxytris(dimethylamino)phosphonium Hexafluorophosphate (BOP),23 O-Benzotriazol-1-yl-N,N,N,N-tetramethyluronium Hexafluorophosphate (HBTU),24 Bis(2-oxo-3-oxazolidinyl)phosphinic Chloride25 (BOP-Cl), and (1H-1,2,3-benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP).26 In addition to linear and polymeric amides, lactams of various ring sizes have been synthesized using these methods (eq 1).27

Ester and Thioester Formation.

These reactions occur through the same O-acylurea or anhydride active intermediate as in the amide coupling reactions, and the discussion of associated problems applies here as well. In general, alkyl and (particularly) aryl thiols can be efficiently coupled to carboxylic acids using DCC.28 Reactions of primary and secondary alcohols proceed reliably, but require the presence of an acylation catalyst. This is usually 4-Dimethylaminopyridine (DMAP),29,30 (see also 1,3-Dicyclohexylcarbodiimide-4-Dimethylaminopyridine), but others have been used including 4-pyrrolidinopyridine31 and pyridine (solvent) with catalytic p-Toluenesulfonic Acid.32 The acylation of more hindered alcohols often results in reduced yields; however, even t-butanol can be acylated, providing a useful route to t-butyl esters.3,31 Various other carbodiimide derivatives have also been used in the preparation of esters.33,34 As with amides, which are not limited to intermolecular reactions, a wide variety of lactones can also be synthesized.35,36

Anhydride Formation.

Among other anhydride-forming reagents, including Acetic Anhydride, Trifluoroacetic Anhydride, and Phosphorus(V) Oxide, DCC is one of the simplest, mildest, and most effective reagents for the preparation of symmetrical anhydrides,4,37 including formic anhydride,38 which is useful in the preparation of formamides (eq 2).

Anhydride formation is associated with each of the reaction types involving carboxylic acids. The anhydride is often the reactive species, to the extent that it competes with the O-acylurea or covalent catalyst adduct (see discussion of amide bond formation reactions).

Sulfinate and Phosphate Esters.

Anhydrides of sulfinic and sulfonic acids39,40 and phosphate monoesters can be prepared using DCC. Further reaction with alcohols or phenols gives the corresponding sulfinates41 and phosphate diesters.42,43 Pyrophosphates can be prepared from mono- and disubstituted phosphate esters.44 Reaction of activated sulfinates with amines gives the corresponding sulfinamides.45

Oxidation of Alcohols to Aldehydes and Ketones: Moffatt Oxidation.

The oxidation of primary and secondary alcohols46 to aldehydes and ketones, respectively, can be carried out by reaction with DMSO activated by DCC (see Dimethyl Sulfoxide-Dicyclohexylcarbodiimide).5,47,48 In comparison to the many metal-mediated oxidative reactions, the Moffatt oxidation is carried out under very mild conditions, and has found widespread use for reactions in the presence of sensitive functional groups (eq 3).49 In addition, over-oxidation of aldehydes to form carboxylic acids is not observed. Under typical reaction conditions, a solution of the alcohol (1 equiv), DCC (3 equiv), and a proton source (pyridinium trifluoroacetate) (0.5 equiv) is stirred in DMSO or DMSO/benzene overnight at rt. After quenching the reaction with aqueous acetic acid and removing DCU by filtration, the product can be isolated by extraction. In modifications of this reaction,46 DCC can be replaced by other DMSO-activating agents including acetic anhydride (see Dimethyl Sulfoxide-Acetic Anhydride),50 trifluoroacetic anhydride (see Dimethyl Sulfoxide-Trifluoroacetic Anhydride),51 and oxalyl chloride (see Dimethyl Sulfoxide-Oxalyl Chloride).52,53

Dehydrative-Type Couplings.

Because of the power of DCC as a dehydrating agent, it has found many uses in a variety of other dehydrative coupling reactions. These include the reaction of primary amines with DCC and Carbon Dioxide or Carbon Disulfide to form ureas (eq 4)54 or isothiocyanates (eq 5),55 respectively.

Symmetrical peroxides can be synthesized from benzoic acid derivatives and hydrogen peroxide (eq 6).56 Unsymmetrical peroxides can be synthesized from the corresponding carboxylic acid and peroxy acid.56

Aromatic and aliphatic alcohols and thiophenols can be coupled to form ethers (eq 7)57,58 and thioethers (eq 8),59,60 respectively, using DCC.

In cases where sensitivity of the compound precludes the formation of an acid chloride, a-diazo ketones can be synthesized by the DCC-mediated coupling of diazomethane to carboxylic acids (eq 9).61,62

Dehydration to Alkenes, Epoxides, Nitriles, and Ketenes.

b-Hydroxy ketones and b-hydroxy esters can be dehydrated, using DCC, to a,b-unsaturated ketones (eq 10)7,63 and esters (eq 11),64 respectively. Cyclopropanes can be synthesized by the dehydration of g-hydroxy ketones (eq 12).65

Other dehydration reactions include the conversion of primary amides to nitriles,6 aldehydes to nitriles (via the hydroxylamine) (eq 13),66,67 and carboxylic acids to ketenes (eq 14).68

Dehydroxylation of Alcohols.

Alcohols and phenols can be dehydroxylated to the corresponding alkane by hydrogenation of the O-acylurea adduct formed from the reaction of the alcohol with DCC (eq 15).69,70

Inversion of Secondary Alcohols.

Secondary alcohols can be stereochemically inverted by formylation (or esterification) with DCC, followed by saponification (eq 16).8

Heterocyclization Reactions.

DCC has frequently been used both as a reagent and as a reactant in the synthesis of heterocycles.1 For example, DCC-mediated cyclodesulfurative annulation reactions71 have been used to synthesize guanosine-type nucleotide analogs (eq 17).72

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Jeffrey S. Albert & Andrew D. Hamilton

University of Pittsburgh, PA, USA

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