1,1'-Carbonyldiimidazole CAS 530-62-1

1,1'-Carbonyldiimidazole, alias N.N'- carbonyl diimidazole, 1,1'- carbonyl diimidazole and carbonyl diimidazole, molecular formula C7H6N4O, CAS 530-62-1, molecular weight 162.15, white crystal, insoluble in water, soluble in alcohol and ether. Carbonyl diimidazole is a kind of compound with strong reactivity. It can react with ^-COOH, ^-NH2, ^-OH and other functional groups to synthesize many ketones, esters, ureas and other compounds that are difficult to obtain by common methods. For example, the reaction with amine can synthesize imidazole pesticides, while avoiding the use of highly toxic phosgene which is not easy to store and transport. Mainly used for organic synthesis, pesticide and pharmaceutical intermediates.

As a highly active carbonylation reagent, 1,1'-Carbonyldiimidazole (CDI) has shown wide application value in organic synthesis, biochemistry, materials science and medicine due to its unique chemical structure and reaction characteristics.

1. Core reaction mechanism and chemical properties

 

The CDI molecule consists of two imidazole rings bridged by a carbonyl group. Its carbonyl group is activated by the strong electron-withdrawing effect of the imidazole ring to form a highly reactive carbon positive center. This structure enables it to react selectively with functional groups containing active hydrogen (such as -COOH, -NH₂, -OH) to generate intermediates such as acyl imidazole, carbamoyl imidazole or ester imidazole. These intermediates can further react with nucleophiles (such as amines, alcohols, thiols) to form target products such as amides, esters, ureas, and carbamates. Its reaction characteristics include:

 

 

High selectivity: In the primary amine/secondary amine coexistence system, primary amines are preferentially activated at room temperature, and dual functional group activation can be achieved through condition regulation.

Mild reaction conditions: no strong acid, strong base or high temperature is required, and the reaction can be completed at room temperature to 60°C.
Intermediate stability: the generated acyl imidazole intermediate can be stably present in organic solvents for several hours, which is convenient for step-by-step operation.
Non-toxic alternative: it can replace highly toxic phosgene (COCl₂) for the synthesis of isocyanates and urea compounds.

2. Key role in peptide and protein synthesis

 

1. High-efficiency coupling agent for peptide bond formation
CDI is a core reagent in solid phase peptide synthesis (SPPS) and liquid phase peptide synthesis, and its mechanism of action includes:
Direct activation of carboxylic acid: reacts with the carboxyl group of amino acids to generate acyl imidazole, which then condenses with the amino group of another amino acid to form a peptide bond. For example, in the synthesis of antimicrobial peptide LL-37, the CDI coupling method can increase the yield by 15%-20% compared with the traditional DCC/HOBt method, while reducing the racemization side reaction.
Regional selective protection: by adjusting the reaction conditions, selective protection of the N-terminus or C-terminus can be achieved. For example, when synthesizing cyclic peptides, CDI can preferentially activate the side chain carboxyl groups to avoid the premature formation of main chain peptide bonds.

 

Peptide modification and branching: Using the carboxyl groups activated by CDI, fluorescent labels, polyethylene glycol (PEG) or dendrimer modification can be introduced. For example, fluorescein isothiocyanate (FITC) is coupled to the lysine side chain of insulin through CDI to achieve drug tracking visualization.

2. Protein cross-linking and immobilization
CDI-mediated cross-linking reactions can form zero-length amide bonds or single-carbon spaced carbamate bonds between protein molecules:
Enzyme immobilization: Glucose oxidase (GOx) is immobilized on the surface of amino-modified magnetic nanoparticles by activating the carboxyl groups through CDI. The activity recovery rate of the immobilized enzyme reaches 92%, and it can be reused more than 10 times.
Preparation of antibody-antigen complexes: In the synthesis of immunoadsorbent materials, CDI can couple protein A to hydroxylated carriers (such as agarose gel) to form a high-affinity adsorption layer for the specific purification of IgG in plasma.

3. Multifunctional Applications in Organic Synthesis

 

1. Synthesis of Ketones, Ester and Urea Compounds
Synthesis of Ketones: CDI reacts with organometallic reagents (such as Grignard reagents) to efficiently construct ketone skeletons. For example, in the synthesis of acetophenone, the CDI method increases the yield by 12% compared with the traditional acyl chloride route and avoids the generation of hydrogen chloride.
Synthesis of Ester: CDI activates carboxylic acids and condenses them with alcohols to form esters. This method has significant advantages in the synthesis of chiral esters. For example, in the preparation of key intermediates of the antiviral drug oseltamivir, the CDI method can control the enantiomeric excess (ee) to more than 99%.
Urea Compounds: CDI reacts with amines to form carbamoyl imidazole intermediates, which are further condensed with another amine to form urea. This route shortens the reaction steps by 2 steps compared with the phosgene method when synthesizing the herbicide fluroxypyr, and increases the atomic utilization by 30%.

 

2. Non-phosgene Synthesis of Isocyanates
CDI reacts with amines to form isocyanates, avoiding the use of highly toxic phosgene. For example, when synthesizing polyurethane raw material toluene diisocyanate (TDI), the CDI method can shorten the reaction time from 8 hours to 2 hours, and the product purity reaches 99.5%.

3. Construction of heterocyclic compounds
CDI can be used as a carbonyl donor to participate in heterocyclic synthesis:

Imidazolopyridines: Through the cyclization reaction of CDI and 2-aminopyridine, the imidazo[1,2-a]pyridine skeleton with antitumor activity can be efficiently constructed.
β-lactam antibiotic intermediates: CDI reacts with penicillin V potassium salt to synthesize 7-aminocephalosporanic acid (7-ACA), a key intermediate of cephalosporin antibiotics, with a yield increased by 18% compared with traditional chemical methods.

4. Surface modification technology in materials science

 

1. Polymer functionalization
1,1'-Carbonyldiimidazole can introduce functional molecules into polymer surfaces through covalent bonds:

Biocompatibility modification: On the surface of polylactic acid-co-glycolic acid (PLGA), CDI can couple polyethylene glycol (PEG) or RGD peptide, significantly reducing the immunogenicity of the material and promoting cell adhesion.

Conductive polymer modification: On the surface of polypyrrole (PPy), CDI can immobilize glucose oxidase to construct a highly sensitive glucose sensor with a detection limit as low as 0.1μM.

 

2. Nanomaterial surface engineering
CDI can achieve precise functionalization of nanoparticles:

Quantum dot modification: CDI is used to couple carboxylated CdSe quantum dots with amino antibodies to construct fluorescent immunoprobes for the detection of tumor marker CA125 with a sensitivity of 0.1ng/mL.

Functionalization of magnetic nanoparticles: On the surface of Fe₃O₄, CDI can couple folic acid molecules to achieve specific recognition of tumor cells by targeted drug delivery systems.

5. Pharmaceutical intermediates and drug synthesis

 

1. Synthesis of antibiotic intermediates
CDI is irreplaceable in the synthesis of β-lactam antibiotics:

Cephalosporin C side chain modification: CDI activates the carboxyl group of cephalosporin C, and can introduce aminothiazole side chains to construct the core structure of the third-generation cephalosporin.
Penicillin V potassium salt conversion: CDI can convert penicillin V potassium salt into 6-aminopenicillanic acid (6-APA) with a yield of 95%, and avoids the use of highly toxic chloroformate.

 

2. Key intermediates of antiviral drugs
When synthesizing the anti-HIV drug efavirenz, CDI can efficiently construct the urea group in its core structure, shortening the synthesis steps by 3 steps compared with the traditional route, and the total yield is increased from 45% to 68%.

3. Anti-tumor drug modification
CDI can be used for PEGylation modification of paclitaxel drugs, such as coupling mPEG-2000 to the 2'-hydroxyl group of paclitaxel through CDI, significantly extending the half-life of the drug (from 2.8 hours to 24 hours) and reducing immunogenicity.

Synthesis of 1,1'-Carbonyldiimidazole:

The imidazole is reacted with phosgene dissolved in benzene, the imidazole hydrochloride in the reactant is filtered, and the filtrate is concentrated to obtain 1,1'- carbonyldiimidazole with a yield of 91%.

Pour 200 ml of anhydrous benzene into a 500 ml conical funnel and weigh it with a stopper. Remove the glass plug and install a gas inlet pipe with a sand core filter on the funnel. Under the protection of room temperature and drying tube, about 20g phosgene is introduced in about 1h (the volume of benzene solution increases by about 12-16ml). Plug the funnel and weigh it immediately. The actual weight of phosgene is 16.55 g (0.167 mole). Therefore, the required amount of imidazole is calculated according to the molar ratio of phosgene to imidazole of 1:4. Then, install the funnel on a three necked flask containing 45.60g (0.669mol) imidazole and 500ml anhydrous tetrahydrofuran. Under cooling and electromagnetic stirring, drop the benzene solution of phosgene within 15-30 minutes. Continue mixing for 15 minutes, and let stand at room temperature for 1 hour. In a dry atmosphere, remove imidazole hydrochloride with a sand core funnel. The filtrate was concentrated to dryness under 40~50 ℃ and reduced pressure to obtain 24.5g (91%) of colorless crystal.

Be careful! Phosgene is toxic, and this operation should be carried out in the fume hood.

1. Question: As a coupling reagent, what are the main advantages of CDI compared with the traditional DCC or EDC? 
The greatest advantage of CDI lies in the fact that its reaction by-products are only imidazole and carbon dioxide, both of which are volatile or easily removable low-toxicity substances, thus avoiding the problem that reagents like DCC may generate difficult-to-remove by-products (such as DCU). This makes subsequent purification simpler and the product purity higher, especially suitable for the synthesis of peptides or drugs that are sensitive to impurities.

2. Q: Besides being used in the synthesis of amides, what other important special applications does CDI have? 
Answer: A key application is the efficient and gentle preparation of active esters. CDI first reacts with carboxylic acids to form highly active acylimidazole intermediates, which can react with N-hydroxysuccinimide (NHS) and others to generate stable NHS active esters. These active esters are widely used in biological conjugation and protein modification because of their good stability in the aqueous phase.

3. Q: What key safety precautions should be taken when using and storing CDI? 
Answer: CDI is extremely sensitive to moisture. When it comes into contact with water, it will rapidly hydrolyze and release carbon dioxide, which may cause an increase in pressure inside a sealed container. Therefore, it must be operated and stored in an anhydrous inert atmosphere such as nitrogen or argon. Meanwhile, CDI itself is highly irritating and can corrode the eyes, skin and respiratory tract. Appropriate protective equipment (goggles, gloves, fume hoods) must be worn during operation.

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