1,1'-Carbonyldiimidazole (CDI) is an

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...

with the molecular formula (C₃H₃N₂)₂CO. It is a white crystalline

solid Solid is one of the State of matter#Four fundamental states, four fundamental states of matter (the others being liquid, gas, and Plasma (physics), plasma). The molecules in a solid are closely packed together and contain the least amount o ...

. It is often used for the coupling of

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s for

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

synthesis and as a reagent in

organic synthesis Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than inorganic compounds, and their synthesis has developed into one o ...

Preparation

CDI can be prepared straightforwardly by the reaction of

phosgene Phosgene is the organic chemical compound with the formula COCl2. It is a toxic, colorless gas; in low concentrations, its musty odor resembles that of freshly cut hay or grass. Phosgene is a valued and important industrial building block, espe ...

with four equivalents of

imidazole Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole Diazole refers ...

under anhydrous conditions. Removal of the side product, imidazolium chloride, and solvent results in the crystalline product in ~90% yield. :4 C₃H₄N₂ + C(O)Cl₂ → (C₃H₃N₂)₂CO + 2 ₃H₃N₂H₂l In this conversion, the imidazole serves both as the nucleophile and the base. An alternative precursor 1-(trimethylsilyl)imidazole requires more preparative effort with the advantage that the coproduct trimethylsilyl chloride is volatile. CDI hydrolyzes readily to give back imidazole: :(C₃H₃N₂)₂CO + H₂O → 2 C₃H₄N₂ + CO₂ The purity of CDI can be determined by the amount of CO₂ that is formed upon hydrolysis.

Use in synthesis

CDI is mainly employed to convert amines into

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

carbamate In organic chemistry, a carbamate is a category of organic compounds with the general formula and structure , which are formally derived from carbamic acid (). The term includes organic compounds (e.g., the ester ethyl carbamate), formally o ...

ureas 220 px, B vitamin, is a urea. In chemistry, ureas are a class of organic compounds with the formula (R2N)2CO where R = H, alkyl, aryl, etc. Thus, in addition to describing the specific chemical compound urea ((H2N)2CO), urea is the name of a funct ...

. It can also be used to convert alcohols into

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

Acid derivatives

The formation of amide is promoted by CDI. Although the reactivity of CDI is less than

acid chloride In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group . Their formula is usually written , where R is a side chain. They are reactive derivatives of carboxylic acids (). A specific example o ...

s, it is more easily handled and avoids the use of

thionyl chloride Thionyl chloride is an inorganic compound with the chemical formula . It is a moderately volatile, colourless liquid with an unpleasant acrid odour. Thionyl chloride is primarily used as a chlorinating reagent, with approximately per year bein ...

in acid chloride formation, which can cause side reactions. An early application of this type of reaction was noted in the formation of peptide bonds (with CO₂ formation as a driving force). The proposed mechanism for the reaction between a carboxylic acid and CDI is presented below. : Mechanism for CDI acid activation

In the realm of peptide synthesis, this product may be treated with an amine such as that found on an amino acid to release the imidazole group and couple the peptides. The side products, carbon dioxide and imidazole, are relatively innocuous. Racemization of the

s also tends to be minimal, reflecting the mild reaction conditions. CDI can also be used for

esterification In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

, although

alcoholysis In chemistry, solvolysis is a type of nucleophilic substitution (S1/S2) or elimination reaction, elimination where the nucleophile is a solvent molecule. Characteristic of S1 reactions, solvolysis of a chirality (chemistry), chiral reactant affor ...

requires heat or the presence of a potent nucleophiles as sodium ethoxide, or other strong bases like NaH. This reaction has generally good yield and wide scope, although forming the ester from tertiary alcohols when the acid reagent has a relatively acidic α-proton is troublesome, since C-C condensations can occur, though this itself may be a desirable reaction. A similar reaction involving

thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...

s and

selenol Selenols are organic compounds that contain the functional group with the connectivity C– Se–H. Selenols are sometimes also called selenomercaptans and selenothiols. Selenols are one of the principal classes of organoselenium compounds. The be ...

s can yield the corresponding esters. The alcohol reaction can also be used to form glycosidic bonds. Similarly, an acid can be used in the place of an alcohol to form the

anhydride An organic acid anhydride is an acid anhydride that is an organic compound. An acid anhydride is a compound that has two acyl groups bonded to the same oxygen atom. A common type of organic acid anhydride is a carboxylic anhydride, where the pa ...

, although

dicyclohexylcarbodiimide ''N'',''N''′-Dicyclohexylcarbodiimide (DCC or DCCD) is an organic compound with the chemical formula (C6H11N)2C. It is a waxy white solid with a sweet odor. Its primary use is to couple amino acids during artificial peptide synthesis. The low ...

is a more typical reagent. The equilibrium can be shifted in the favor of the anhydride by utilizing an acid in a 2:1 ratio that forms an insoluble salt with the imidazole. Typical acids are trifluoro- and

trichloroacetic acid Trichloroacetic acid (TCA; TCAA; also known as trichloroethanoic acid) is an analogue of acetic acid in which the three hydrogen atoms of the methyl group have all been replaced by chlorine atoms. Salts and esters of trichloroacetic acid are calle ...

s. Symmetric anhydrides can thus be formed by replacing this trifluoro- or trichloroacetyl group with the acid that was used to form the original reagent. Another related reaction is the reaction of

formic acid Formic acid (), systematically named methanoic acid, is the simplest carboxylic acid, and has the chemical formula HCOOH and structure . It is an important intermediate in chemical synthesis and occurs naturally, most notably in some ants. Es ...

with CDI to form the formylized imidazole. This reagent is a good formylating agent and can regenerate the unsubstituted imidazole (with formation of carbon monoxide) upon heating. Yet another reaction involves the acylation of triphenylalkelynephosphoranes. ::(C₆H₅)₃P=CHR + R'-CO-Im → (C₆H₅)₃P⁺-CHR-COR' + Im⁻
(C₆H₅)₃P⁺-CHR-COR' + (C₆H₅)₃P=CHR → (C₆H₅)₃P=CR-COR' + (C₆H₅)₃P⁺-CH₂R These can undergo the

Wittig reaction The Wittig reaction or Wittig olefination is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide called a Wittig reagent. Wittig reactions are most commonly used to convert aldehydes and ketones to alkenes. Most o ...

to form α,β unsaturated ketones or aldehydes. The reagent can even undergo reaction with

peroxide In chemistry, peroxides are a group of compounds with the structure , where R = any element. The group in a peroxide is called the peroxide group or peroxo group. The nomenclature is somewhat variable. The most common peroxide is hydrogen p ...

to form the

peroxycarboxylic acid A peroxy acid (often spelled as one word, peroxyacid, and sometimes called peracid) is an acid which contains an acidic –OOH group. The two main classes are those derived from conventional mineral acids, especially sulfuric acid, and the peroxy ...

, which can react further to form diacyl peroxides. The imidazole group is also reduced by LiAlH₄ to form aldehydes from the carboxylic acid (rather than amines or alcohols). The reagent can also be reacted with

Grignard reagent A Grignard reagent or Grignard compound is a chemical compound with the general formula , where X is a halogen and R is an organic group, normally an alkyl or aryl. Two typical examples are methylmagnesium chloride and phenylmagnesium bromide ...

s to form ketones. A C-C acylation reaction can occur with a malonic ester-type compound, in the following scheme useful for syntheses of macrolide antibiotics. :

Other reactions

The N-phenylimino derivative of CDI can be formed in a Wittig-like reaction with

triphenylphosphine phenylimide Triphenylphosphine phenylimide is the organophosphorus compound with the formula Ph3P=NPh ( Ph = C6H5). It is a white solid that is soluble in organic solvents. The compound is a prototype of a large class of Staudinger reagents, resulting from ...

. :OCIm₂ + Ph₃P=NPh → PhN=CIm₂ + Ph₃PO CDI can act as a carbonyl equivalent in the formation of tetronic acids or pulvinones from hydroxyketones and diketones in basic conditions. : An alcohol treated with at least 3 equivalents of an activated halide (such as allyl bromide or iodomethane) and CDI yields the corresponding halide with good yield. Bromination and iodination work best, though this reaction does not preserve the

stereochemistry Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...

of the alcohol. In a similar context, CDI is often used in dehydration reactions. As CDI is an equivalent of

, it can be used in similar reaction, however, with increased selectivity: it allows the synthesis of asymmetric bis alkyl carbonates{{cite journal , author=Steve P. Rannard, Nicola J. Davis , title=Controlled Synthesis of Asymmetric Dialkyl and Cyclic Carbonates Using the Highly Selective Reactions of Imidazole Carboxylic Esters , journal=Organic Letters , volume=1 , year=1999 , pages=933–936 , doi=10.1021/ol9908528 , issue=6

References

Reagents for organic chemistry Imidazoles

Preparation

Use in synthesis

Acid derivatives

Other reactions

See also

References