N,N
'-Dicyclohexylcarbodiimide is an
organic compoundAn organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
with chemical formula C
13H
22N
2 whose primary use is to couple amino acids during artificial
peptide synthesisIn organic chemistry, peptide synthesis is the production of peptides, which are organic compounds in which multiple amino acids are linked via amide bonds which are also known as peptide bonds...
. Under standard conditions, it 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. It is highly soluble in
dichloromethaneDichloromethane is an organic compound with the formula CH2Cl2. This colorless, volatile liquid with a moderately sweet aroma is widely used as a solvent. Although it is not miscible with water, it is miscible with many organic solvents...
,
tetrahydrofuranTetrahydrofuran is a colorless, water-miscible organic liquid with low viscosity at standard temperature and pressure. This heterocyclic compound has the chemical formula 4O. As one of the most polar ethers with a wide liquid range, it is a useful solvent. Its main use, however, is as a precursor...
,
acetonitrileAcetonitrile is the chemical compound with formula . This colourless liquid is the simplest organic nitrile. It is produced mainly as a byproduct of acrylonitrile manufacture...
and
dimethylformamideDimethylformamide is an organic compound with the formula 2NCH. Commonly abbreviated as DMF , this colourless liquid is miscible with water and the majority of organic liquids. DMF is a common solvent for chemical reactions...
, but insoluble in water. The compound is often abbreviated
DCC.
Structure and spectroscopy
The C-N=C=N-C core of carbodiimides (N=C=N) is linear, being related to the structure of
alleneAn allene is a compound in which one carbon atom has double bonds with each of its two adjacent carbon centres. Allenes are classified as polyenes with cumulated dienes. The parent compound of allene is propadiene. Compounds with an allene-type structure but with more than three carbon atoms are...
. Three principal resonance structures describe carbodiimides:
- RN=C=NR ↔ RN+≡C-N-R ↔ RN--C≡N+R
The N=C=N moiety gives characteristic IR spectroscopic signature at 2117 cm
-1. The
15N
NMRNMR may refer to:Applications of Nuclear Magnetic Resonance:* Nuclear magnetic resonance* NMR spectroscopy* Solid-state nuclear magnetic resonance* Protein nuclear magnetic resonance spectroscopy* Proton NMR* Carbon-13 NMR...
spectrum shows a characteristic shift of 275.0 ppm upfield of nitric acid and the
13C NMR spectrum features a peak at about 139 ppm downfield from TMS.
Preparation
Of the several syntheses of DCC, Pri-Bara
et al. use palladium acetate, iodine, and oxygen to couple cyclohexyl amine and cyclohexyl
isocyanideAn isocyanide is an organic compound with the functional group -N≡C. It is the isomer of the related cyanide , hence the prefix iso....
. Yields of up to 67% have been achieved using this route:
- C6H11NC + C6H11NH2 + O2 → (C6H11N)2C + H2O
Tang
et al. condense two
isocyanateIsocyanate is the functional group of elements –N=C=O , not to be confused with the cyanate functional group which is arranged as –O–C≡N or with isocyanide, R-N≡C. Any organic compound which contains an isocyanate group may also be referred to in brief as an isocyanate. An isocyanate may have more...
s using the catalyst OP(MeNCH
2CH
2)
3N in yields of 92%:
DCC has also been prepared from
dicyclohexylureaDicyclohexylurea is an organic compound, specifically, a urea. It is the byproduct of the reaction of dicyclohexylcarbodiimide with amines or alcohols. It may be prepared by the reaction of cyclohexylamine and S,S-dimethyl dithiocarbonate....
using a
phase transfer catalystIn chemistry, a phase transfer catalyst or PTC is a catalyst that facilitates the migration of a reactant from one phase into another phase where reaction occurs. Phase transfer catalysis is a special form of heterogeneous catalysis. Ionic reactants are often soluble in an aqueous phase but...
by Jaszay
et al. The disubstituted urea, arenesulfonyl chloride, and
potassium carbonatePotassium carbonate is a white salt, soluble in water , which forms a strongly alkaline solution. It can be made as the product of potassium hydroxide's absorbent reaction with carbon dioxide. It is deliquescent, often appearing a damp or wet solid...
react in toluene in the presence of benzyl triethylammonium chloride to give DCC in 50% yield.
Reactions
DCC is a dehydrating agent for the preparation of
amideIn chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
s,
ketoneIn organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
s,
nitrileA nitrile is any organic compound that has a -C≡N functional group. The prefix cyano- is used interchangeably with the term nitrile in industrial literature. Nitriles are found in many useful compounds, one example being super glue .Inorganic compounds containing the -C≡N group are not called...
s. In these reactions, DCC hydrates to form
dicyclohexylureaDicyclohexylurea is an organic compound, specifically, a urea. It is the byproduct of the reaction of dicyclohexylcarbodiimide with amines or alcohols. It may be prepared by the reaction of cyclohexylamine and S,S-dimethyl dithiocarbonate....
(DCU), a compound that is insoluble in water. DCC can also be used to
invertWalden inversion is the inversion of a chiral center in a molecule in a chemical reaction. Since a molecule can form two enantiomers around a chiral center, the Walden inversion converts the configuration of the molecule from one enantiomeric form to the other. For example, in a SN2 reaction,...
secondary alcohols.
Moffatt oxidation
A solution of DCC and
dimethyl sulfoxideDimethyl sulfoxide is an organosulfur compound with the formula 2SO. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water...
(DMSO) effects the so-called
Pfitzner-Moffatt oxidationThe Pfitzner–Moffatt oxidation, sometimes referred to as simply the Moffatt oxidation, is a chemical reaction which describes the oxidation of primary and secondary alcohols by dimethyl sulfoxide activated with a carbodiimide, such as dicyclohexylcarbodiimide...
. This procedure is used for the oxidation of
alcoholIn chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
s to
aldehydeAn aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
s and ketones. Unlike metal-mediated
oxidationsRedox reactions describe all chemical reactions in which atoms have their oxidation state changed....
, the reaction conditions are sufficiently mild to avoid over-oxidation of aldehydes to
carboxylic acidCarboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
s. Generally, three equivalents of DCC and 0.5 equivalent of proton source in DMSO and allowed to react overnight at room temperature. The reaction is quenched with acid:
Dehydration
Alcohols can also be dehydrated using DCC. This reaction proceeds by first giving the O-acylurea intermediate which is then hydrogenolyzed to produce the corresponding alkene:
- RCHOHCH2R' + (C6H11N)2C → RCH=CHR' + (C6H11NH)2CO
Inversion of secondary alcohols
Secondary alcohols can be stereochemically inverted by formation of a formyl ester followed by
saponificationSaponification is a process that produces soap, usually from fats and lye. In technical terms, saponification involves base hydrolysis of triglycerides, which are esters of fatty acids, to form the sodium salt of a carboxylate. In addition to soap, such traditional saponification processes...
. The secondary alcohol is mixed directly with DCC,
formic acidFormic acid is the simplest carboxylic acid. Its chemical formula is HCOOH or HCO2H. It is an important intermediate in chemical synthesis and occurs naturally, most notably in the venom of bee and ant stings. In fact, its name comes from the Latin word for ant, formica, referring to its early...
, and a strong base such as
sodium methoxideSodium methoxide is a chemical compound, with formula CH3ONa. This colourless solid, which is formed by the deprotonation of methanol, is a widely used reagent in industry and the laboratory...
.
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
DMAP4-Dimethylaminopyridine is a derivative of pyridine with the chemical formula 2NC5H4N. This colourless solid is a useful nucleophilic catalyst for a variety of reactions such as esterifications with anhydrides, the Baylis-Hillman reaction, hydrosilylations, tritylation, the Steglich...
.
DCC-promoted peptide coupling
During protein synthesis (such as Fmoc
solid-state synthesizersIn organic chemistry, peptide synthesis is the production of peptides, which are organic compounds in which multiple amino acids are linked via amide bonds which are also known as peptide bonds...
), the N-terminus is often used as the attachement site on which the amino acid
monomerA monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
s are added. To enhance the
electrophilicityIn general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...
of carboxylate group, the negatively charged oxygen must first be "activated" into a better
leaving groupIn chemistry, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl−, Br−, and I−, and sulfonate esters, such as para-toluenesulfonate...
. DCC is used for this purpose. The negatively charged oxygen will act as a
nucleophileA nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
, attacking the central carbon in DCC. DCC is temporarily attached to the former carboxylate group forming a highly electrophilic intermediate, making
nucleophilic attackIn organic and inorganic chemistry, nucleophilic substitution is a fundamental class of reactions in which an electron nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms called the leaving group; the positive or partially positive...
by the terminal amino group on the growing peptide more efficient.
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