1,1'-Thiocarbonyldiimidazole CAS 6160-65-2

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1,1'-Thiocarbonyldiimidazole, CAS number 6160-65-2, molecular formula C7H6N4S, molecular weight 178.21. Also known as 1,1 '- thiocarbonate diimidazole or Methanethione, di-1H-imidazol-1-yl-. At room temperature, it appears as a white to light yellow powdery substance, and sometimes may also appear as light red crystals. This substance has a relatively stable form in its solid state and is not easily deformed or decomposed. Extremely soluble in water and ethanol, as well as in organic solvents such as tetrahydrofuran, toluene, and dichloromethane. It is mainly used as a thiocarbonyl transfer reagent in organic synthesis. It can react with hydroxyl or amino groups with active hydrogen to generate thiocarbonyl derivatives, which have important employ value in organic synthesis. For example, thiocarboxylic acid esters generated by hydroxyl groups can undergo deoxygenation reactions, while thiocarbonate esters generated by adjacent dihydroxy groups can undergo Corey Winter olefin formation reactions, etc.

N. N '- Thiocarbonyldiimidazole (TCDI, CAS number: 6160-65-2) is an organic compound with a unique chemical structure, with the molecular formula C7H6N4S and a molecular weight of 178.21. This compound is characterized by the thiol carbonyl group connecting two imidazole rings, and has shown wide employ value in the fields of medicine, biotechnology, and organic synthesis.

Core functional positioning

 

1.  Key reagents in biochemical reactions
The core function of TCDI is reflected in its chemical properties as a sulfur carbonyl transfer reagent. The thiocarbonyl group (- CS -) in its molecular structure is strongly activated by the imidazole ring, which can efficiently selectively react with compounds containing active hydrogen (such as hydroxyl and amino groups) to generate derivatives such as thioformate and thiocarbonate. This process has the following advantages:

Mild reaction conditions: can be carried out under neutral pH and room temperature conditions, avoiding the damage to sensitive sensory groups caused by strong acid/alkali environments in traditional methods.

 

High stereoselectivity: By controlling reaction conditions such as solvent and temperature, directional synthesis of specific conformational products can be achieved.
By product control: No harmful by-products such as hydrogen halide acid are produced during the reaction process, significantly improving product purity.

 

2. Key bonding agents in peptide synthesis
In solid-phase peptide synthesis (SPPS), 1,1'-Thiocarbonyldiimidazole serves as an activating reagent that can efficiently link amino acid residues. The mechanism of action is that TCDI reacts with the carboxyl group of an amino acid to form a thioformate intermediate, which then undergoes nucleophilic substitution with the amino group of another amino acid to form a stable peptide bond. This process has the following improvements compared to the traditional DCC (dicyclohexylcarbodiimide) method:

 

Improved reaction efficiency: The stability of the intermediate of thioformate ester is better than that of O-acylisourea generated by DCC, reducing the occurrence of side reactions.
Product purity optimization: Avoid residual dicyclohexylurea (DCU) generated in DCC method and simplify subsequent purification steps.
Scope of employ extension: It can effectively activate amino acids with steric hindrance (such as proline) and improve the success rate of complex peptide chain synthesis.

Reaction mechanism and product characteristics

 

1. Thioformate esterification of hydroxyl compounds
When TCDI reacts with alcohols, its thiocarbonyl group preferentially attacks the hydrogen atom of the alcohol hydroxyl group, producing thioformate and imidazole. This reaction has the following characteristics:

Regional selectivity: The reaction rate of primary alcohols is significantly higher than that of secondary alcohols, and selective modification of specific hydroxyl groups can be achieved by adjusting reaction conditions.
Functional compatibility: The reaction has no significant effect on functional groups such as adjacent carboxyl and ester groups, and is suitable for local modification of complex molecules.
Diversity of subsequent reactions: The generated thioformate esters can further participate in deoxygenation reactions, Corey Winter olefin formation reactions, etc., providing possibilities for molecular skeleton reconstruction.

 

2. Cyclic thiocarbonate esterification of dihydroxy compounds
When TCDI reacts with adjacent dihydroxy compounds (such as sugar derivatives), it can generate five or six membered cyclic thiocarbonates. The key value of this reaction lies in:

Stereoscopic configuration locking: The cyclic structure stabilizes the molecular configuration through conjugation, making it suitable for the synthesis and separation of chiral molecules.
Reaction selectivity: The steric hindrance effect of adjacent hydroxyl groups can regulate the type of cyclization products (five membered ring vs six membered ring).
Biological activity enhancement: Some cyclic thiocarbonate derivatives exhibit antibacterial, antiviral and other biological activities, and can be directly used as drug lead compounds.

 

3. Synthesis of Thiourea Derivatives of Amino Compounds
When TCDI reacts with diamine, cyclic thiourea derivatives can be generated. This reaction has important employ in the field of materials science:

Coordination chemistry employ: Cyclic thiourea ligands can form stable complexes with transition metals for catalytic reactions or the construction of metal organic frameworks (MOFs) materials.
Supramolecular self-assembly: Hydrogen bonding of thiourea groups can drive molecular self-assembly, forming nanostructures with specific functions.
Potential for drug design: Some thiourea derivatives exhibit anti-tumor, anti-inflammatory and other activities, providing structural templates for innovative drug development.

Specific application scenarios

 

1. Synthesis of pharmaceutical intermediates
Antibiotic compounds: TCDI can be used as a key intermediate for the synthesis of β - lactam antibiotics, introducing protective groups through thioformate reaction to improve synthesis efficiency.
Peptide drugs: used in solid-phase synthesis to replace traditional condensing agents for the synthesis of cyclic peptides, peptide hormones, and other drug molecules.
Chiral drug synthesis: Utilizing the stereoselectivity of TCDI to synthesize drug molecules with specific chiral centers, such as the key intermediate of antiviral drug oseltamivir.

 

3. Organic Synthesis Methodology
Corey Winter olefin formation reaction: The cyclic thiocarbonate generated by 1,1'-Thiocarbonyldiimidazole can be efficiently converted into olefins under the action of metal tin hydride, providing a new method for constructing carbon carbon double bonds.
Deoxygenation reaction: Used in combination with the Bu ∝ SnH AIBN system to achieve selective removal of hydroxyl groups, it is a key step in the total synthesis of natural products.
Synthesis of heterocyclic compounds: By reacting TCDI with hydroxyl amino compounds, sulfur-containing heterocycles such as thiazoles and oxazoles are constructed to enrich the drug molecule library.

 

2. Biotechnology field
Protein engineering: As a protein crosslinking agent, protein fragments are connected through thioformate ester bonds to construct fusion proteins with specific functions.
Enzyme immobilization: Enzyme molecules are immobilized on carrier materials after TCDI modification to enhance enzyme stability and reusability.
Biosensors: Utilizing TCDI modified electrode surfaces to construct highly sensitive and selective biosensors for disease biomarker detection.

 

4. Materials Science Applications
Polymer materials: TCDI derivatives can be used as crosslinking agents to prepare elastic materials with self-healing functions.
Metal organic frameworks (MOFs): Cyclic thiourea ligands coordinate with metal nodes to construct MOF materials with high specific surface area and gas adsorption properties.
Functional coating: Coating TCDI modified molecules on the surface of materials to endow them with antibacterial, anti fouling and other properties.

With breakthroughs in fields such as synthetic biology and precision medicine, the employ scenarios of TCDI will further expand. For example, in gene editing technology, TCDI derivatives may serve as novel linkers to efficiently couple the CRISPR-Cas9 system with targeted molecules; In AI driven drug design, the structural diversity of TCDI can provide rich training datasets for deep learning models. It is expected that by 2030, the global market size of TCDI will exceed 500 million US dollars, becoming an indispensable key link in the biopharmaceutical industry chain.

It is an organic intermediate, which can be prepared by one-step reaction from 1 - (trimethylsilyl) imidazole and thiophosgene. It has been reported in the literature that it can be used to prepare a kind of mud resistant polycarboxylic water reducer and an elastic material with ultra-high room temperature self-repairing efficiency.

N. Synthesis of N '- thiocarbonyl diimidazole: 1 - (trimethylsilyl) imidazole (7.7 g, 55 mmol) and 50 mL of dried benzene (distilled by CaH2) are placed in a flame drying flask equipped with a high-efficiency condenser. Fill the flask with nitrogen atmosphere and cool it to 0 ℃. Slowly add thiophosgene (3.2 g, 28 mmol) into the flask with a syringe. After addition, mix the mixture at 0 ℃ for another 1 hour. Remove the solvent under indoor vacuum to obtain yellow solid. The solid was dried under high vacuum for several days to obtain a yellow solid (4.81g) with a yield of 98% and mp of 98-100 degrees.

The production method is prepared using sulfur phosgene and 1- (trimethylsilyl) imidazole as raw materials.

It is used for group protection and protein peptide chain connection in biochemical synthesis reaction.

1,1'-Thiocarbonyldiimidazole (TCDI) is mainly used as a thiocarbonyl transfer agent in organic synthesis, and reacts with hydroxyl or amino groups with active hydrogen to generate thiocarbonyl derivatives. The thiocarboxylate formed by hydroxyl group can undergo deoxidation reaction, and the thiocarbonate formed by o-dihydroxy group can undergo Corey-Winter olefinization reaction. The thiocarbonyl group in TCDI molecule is activated by imidazole and has very high thioformylation activity. The reagent can release imidazole to form a new C-N bond after meeting the amino group with active hydrogen. Diamine reacts with TCDI to form cyclic thiourea derivatives. If the substrate molecule is a hydroxy-amino compound, the corresponding heterocyclic derivative is generated. Because many of these products have important biological activities or are used as separation reagents for chiral derivatives, this reaction has quite important synthetic significance. The reaction of TCDI with hydroxyl compounds can easily generate thiocarbamate compounds, and the reaction with dihydroxy substrates can generate cyclic thiocarbonate derivatives. Because these compounds are synthesized under neutral and very mild conditions, they have no obvious effect on many other functional groups and have a wide range of applications. If this reaction is continuously used with metal tin hydride reductant, the deoxidation of hydroxyl can be completed. The deoxidation of thiocarbonate derivatives is highly selective, and the steric hindrance effect may be one of the main influencing factors.

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