Carbonyldiimidazole

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Carbonyldiimidazole
IUPAC name	1,1'-carbonyldiimidazole
Other names	N,N'-carbonyldiimidazole CDI
Identifiers
CAS number	[530-62-1]
SMILES	O=C(n1cncc1)n2ccnc2
Properties
Molecular formula	C7H6N4O
Molar mass	162.15 g/mol
Appearance	White fine powder
Density	? g/cm3, ?
Melting point	119 °C (392 K)
Solubility in water	Reacts with water
Hazards
MSDS	External MSDS
Main hazards	Corrosive
Related compounds
Related compounds	phosgene, imidazole
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references

1,1'-Carbonyldiimidazole, or CDI, (formula (C₃H₃N₂)₂CO), an organic compound, is a white crystalline solid. It is often used for the coupling of amino acids for peptide synthesis and as a reagent in organic synthesis.

Contents 1 Preparation 2 Use in synthesis 2.1 Acid Derivatives 2.2 Other Reactions 3 References

[edit] Preparation

CDI can be prepared straightforwardly by the reaction of phosgene with four equivalents of imidazole under anhydrous conditions.^[1] Removal of the side product, imidazolium chloride, and solvent results in the crystalline product in ~90% yield.^[2]

4 C₃H₄N₂ + C(O)Cl₂ → (C₃H₃N₂)₂CO + 2 [C₃H₃N₂H₂]Cl

In this conversion, the imidazole serves both as the nucleophile and the base. An alternative precursor 1-(trimethylsilyl)imidazole requires more preparative effort with no corresponding advantages.

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 (since the gas is formed essentially on a 1:1 molar ratio).^[3]

[edit] Use in synthesis

CDI is mainly employed to convert alcohols and amines into carbamates, esters, and ureas.^[1]

[edit] Acid Derivatives

One common extension of this scheme lies in the transacylation reaction of acids that is promoted by CDI. The reactivity of CDI is similar to that of acid chlorides, but it is more easily handled and its reactions have a wider scope in synthesis.^[3] An early application of this type of reaction was noted in the formation of imidazole peptide (and in general carboxylic acid) derivatives (with CO₂ formation as a driving force).

In the realm of peptide synthesis, this product may be treated with an amino acid or peptide ester (or amino acid hydrochloride in water) to release the imidazole group and couple the peptides. The side products, carbon dioxide and imidazole, are relatively innocuous.^[4] Racemization of the amino acids also tends to be minimal, due to mild reaction conditions.

CDI can also be used for esterification, although alcoholysis requires heat or the presence of a potent nucleophiles as sodium ethoxide,^[1][3]) and other strong bases like NaH. This reaction has generally good yield and wide scope (though 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).^[1] A similar reaction involving thiols and selenols can yield the corresponding esters.^[5] The alcohol reaction can be used to form glycosidic bonds, as well.^[6]

Similarly, an acid can be used in the place of an alcohol to form the anhydride. The equilibrium is best shifted in the favor of the anhydride by utilizing an acid in a 2:1 ratio that forms an insoluble salt with the imidazole, such as trifluoro- or trichloroacetic acid (and thus removes the free imidazole from the reaction). 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 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 to form α,β unsaturated ketones or aldehydes.

The reagent can even undergo reaction with peroxide to form the peroxycarboxylic acid, 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 reagents to form ketones.^[1]

A C-C acylation reaction can occur with a malonic ester-type compound, in the following scheme useful for syntheses of macrolide antibiotics.^[7]

[edit] Other Reactions

The N-phenylimino derivative of CDI can be formed in a Wittig-like reaction.^[1]

CDI can act as a carbonyl equivalent in the formation of tetronic acids or pulvinones from hydroxyketones and diketones in basic conditions.^[8]

An alcohol treated with at least 3 equivalents of an activated halide (such as allyl bromide or iodomethane) and CDI yields the corresponding bromide with good yield. Bromination and iodination work best, though this reaction does not preserve the stereochemistry of the alcohol. In a similar context, CDI is often used in dehydration reactions.^[3]

[edit] References

1. ^ ^{a b c d e f} H.A. Staab (1962). "Syntheses Using Heterocyclic Amides (Azolides)". Angewandte Chemie International Edition in English 1: 351–367. doi:10.1002/anie.196203511. 
2. ^ H.A. Staab and K. Wendel (1968). "1,1'-carbonyldiimidazole". Organic Syntheses 48: 44. 
3. ^ ^{a b c d} A. Armstrong (2001). "N,N'-Carbonyldiimidazole". Encyclopedia of Reagents for Organic Synthesis. doi:10.1002/047084289X.rc024. 
4. ^ R. Paul and G. W. Anderson (1960). "N,N'-Carbonyldiimidazole, a New Peptide Forming Reagent'". Journal of the American Chemical Society 82: 4596–4600. doi:10.1021/ja01502a038. 
5. ^ H.-J. Gais (1977). "Synthesis of Thiol and Selenol Esters from Carboxylic Acids and Thiols or Selenols, Respectively". Angewandte Chemie International Edition in English 16: 244–246. doi:10.1002/anie.197702441. 
6. ^ M.J. Ford and S.V. Ley (1990). "A Simple, One-Pot, Glycosidation Procedure via (1-Imidazolylcaronyl) Glycosides and Zinc Bromide". Synlett 1990: 255–256. doi:10.1055/s-1990-21053. 
7. ^ D.W. Brooks, et al. (1979). "C-Acylation under Virtually Neutral Conditions". Angewandte Chemie International Edition in English 18: 72–74. doi:10.1002/anie.197900722. 
8. ^ P.J. Jerris, et al. (1979). "A Facile Synthesis of Simple Tetronic Acids And Pulvinones". Tetrahedron Letters 47: 4517–4520. doi:10.1016/S0040-4039(01)86637-5.