Basic information chemical properties Physical characteristics Main application Preparation method Uses Production method Safety Related Supplier
Imidazole Chemical Properties
- Melting point:88-91 °C(lit.)
- Boiling point:256 °C(lit.)
- Density 1.01 g/mL at 20 °C
- vapor pressure <1 mm Hg ( 20 °C)
- refractive index 1.4801
- Flash point:293 °F
- storage temp. 2-8°C
- solubility H2O: 0.1 M at 20 °C, clear, colorless
- form crystalline
- pka6.953(at 25℃)
- color white
- Specific Gravity1.03
- OdorAmine like
- PH9.5-11.0 (25℃, 50mg/mL in H2O)
- PH Range9.5 - 11
- Water Solubility 633 g/L (20 ºC)
- λmaxλ: 260 nm Amax: 0.10
λ: 280 nm Amax: 0.10
- Sensitive Hygroscopic
- Merck 14,4912
- BRN 103853
- Stability:Stable. Incompatible with acids, strong oxidizing agents. Protect from moisture.
- CAS DataBase Reference288-32-4(CAS DataBase Reference)
- NIST Chemistry Reference1H-Imidazole(288-32-4)
- EPA Substance Registry SystemImidazole (288-32-4)
- Hazard Codes C,Xi,T
- Risk Statements 36/38-63-34-22-20/21/22-61
- Safety Statements 26-36/37/39-45-22-36-27-53
- RIDADR UN 2923 8/PG 3
- WGK Germany 1
- RTECS NI3325000
- Autoignition Temperature480 °C
- TSCA Yes
- HazardClass 8
- PackingGroup III
- HS Code 29332990
- ToxicityLD50 in mice (mg/kg): 610 i.p.; 1880 orally (Nishie)
Imidazole Usage And Synthesis
- chemical properties Imidazole is between the two nitrogen atoms of five membered heterocyclic compounds containing. The unshared electron pair of 1-bit nitrogen atom in imidazole ring participates in the cyclic conjugation, reduces the electron density of the nitrogen atom, and makes hydrogen of the nitrogen atom easily leave in the form of hydrogen. Therefore imidazole has weak acidity, and can form salt with strong base.
The unshared electron pair of 3-bit nitrogen atom in imidazole ring doesn’t participates in the cyclic conjugation, while it occupies the sp2 hybridized orbital, can accept protons, and form salt with strong acid. Alkaline of imidazole is slightly stronger than pyrazole and pyridine.
There is tautomerism in the imidazole ring. The hydrogen on the 1-bit nitrogen atom can be transferred to the 3-atom, therefore, imidazole derivatives with same substituent respectively on 4-bit and 5-bit are tautomers.
Imidazole is stable to acid, and has antioxidant activity. Imidazole derivatives are widely found in nature, such as histamine, histidine and benzimidazole, etc.
There are some interesting reagents in acyl imidazole compounds. For example, 1-acetyl imidazole is a stable acylating agent, after reaction with pyrrole, it becomes 1-acetyl pyrrole. Furthermore, in general, 1-acetyl imidazole can get ketones and aldehydes using Grignard reagent and reducing agent. Reaction of N, N-carbonyldimidazole and carboxyl will get useful reagent acyl imidazole. The relationship between imidazole and natural compounds is very close. For example, pyrimidine ring turns into purine derivatives after condensation. In addition to being like 6-amino purine and guanine the nucleic acid bases, it also exists in the organisms of uric acid, caffeine and theophylline. The catalytic action of imidazole, such as accelerated enzyme hydrolysis, still under study. As the cause of allergic skin, its toxicity is similar todiamine. Rat oral LD501880mg/kg.
- Physical characteristicsIn nature, there are only imidazole derivatives and no free imidazole. The precipitation from benzene is a colorless crystalline prism, with scents of ammonia. Relative molecular mass 68.08. Relative density 1.0303(101/4℃) . Melting point 89～91℃，boiling point 257℃，165℃～168℃(2.67×103Pa) and 138.2℃(1.60×103Pa). Flash point 145℃. Refractive index 1.4801(101℃). Viscosity 2.696mPa·s(100℃). Slightly soluble in benzene, petroleum ether, soluble in ether, acetone, chloroform and pyridine, easily soluble in water (at normal temperature 70) and ethanol. It appears weak alkaline. As the-NH-bond on 1 bite and-N= bond on 3 bit forms hydrogen bond, the boiling point is quite high; when 1 bit hydrogen is substituted, hydrogen bond cannot be formed, hence the boiling point decreases. As to thermal stability, it rarely dissolves under 250℃ (decomposition temperature is 590℃). It is also very stable to reducing agent and oxidant, but can form stable salt with inorganic acid. Owning some certain aromatic properties, also could get halogenation, nitration, sulfonation and hydroxymethylation in the presence of catalyst. Can be coupled with the heavy nitrogen salt in 2 bit. In addition, due to the =NH (1 bit) connected to the two double bonds, with some of the "acid", it can be replaced by metal to get salt. In addition, 3 bit nitrogen ions have coordination effect on metal ions, which can form chelate compounds. Although it is difficult to restore, but can be combined with the proton to generate cation type with resonance structure, and get of a stable form. Tautomers of imidazole ring are very easy to change, so it is hard to tell isomers on 4 bit or 5 bit.
The above information is edited by the Chemicalbook He Liao Pu.
- Main applicationImidazole can be used as epoxy curing agent, improve the mechanical properties such as bending, stretching and compression etc., improve the electrical properties of the insulation, and improve performance of chemical resistance properties, which is widely used in computers and electrical appliances;
Used as an anti-rust agent for copper in printed circuit boards and integrated circuits;
Used as pharmaceutical raw materials for manufacturing anti-fungal drugs, antifungal agents, drug for treatment of hypoglycemia, artificial plasma, trichomonad drug, bronchial asthma drug, macula agent, etc.;
Used as pesticide raw material for synergist, insecticides and fungicides of boric acid agent;
In addition, imidazole is also used as raw material of urea-formaldehyde resin curing agent, photographic medicine, adhesive, coating, vulcanizer, antistatic agent, etc.; intermediate for organic synthesis.
- Preparation methodWith glyoxal as raw material, reactive in formaldehyde and ammonium sulfate (or ammonia) in 85~90℃, and get imidazole sulfate and then neutralized with calcium hydroxide to get imidazole crude product. Filtering, water washing, combining filtrate and washings, decompression evaporation concentration and crystallization, then it’s done. If using ammonia directly, then there should be no sulfate processing steps and it can be prepared at once. Either with ammonium sulfate or ammonia, the yield is relatively low, approximately 45%.
With o-phenylenediamine and formic acid as raw material, via cyclization to benzimidazole, and then through oxidation in the sulfuric acid solution to generate dicarbonyl imidazole; later in the effect of copper oxidation, via decarboxylation from 100 to 150℃ to get crude; And then in benzene solution recrystallization to get imidazole finished products.
With d-tartrate acid as raw material, in sulfuric acid, nitric acid was used to carry out nitrification, and get 2, 3-dinitro tartrate acid; and then in the formaldehyde and ammonia reaction, to get dicarboxylic imidazole; finally decarboxylation to get it.
- Uses1.Used as intermediate of bactericide for imazalil, prochloraz, etc., and that of pharmaceutical anti-fungal drug, econazole, ketoconazole, and clotrimazole as well.
2.Used as organic synthetic materials and intermediates for the preparation of drugs and pesticides.
3.Used as analytical reagent, as well as in organic synthesis.
4.Imidazole is mainly used as curing agent for epoxy resin. In Japan the imidazole accounts for less than half of the consumption. For imidazole compounds whose dosage is 0.5 to 10 percent of epoxy resin, it can be used in antifungal drug, ant mildew agent, hypoglycemic drug, artificial plasma, etc., also can be used in medicines to cure trichomoniasis and turkey blackhead. Imidazole is also one of the main raw material during production of imidazole antifungal miconazole, econazole, clotrimazole and ketoconazole. By imidazole and 2, 4, ω-trichloroacetophenon as the main raw material, it can get fruit fungicide enilconazde. Add 2, 4, ω-trichloroacetophenon into absolute methanol, with heating reflux, adding bromine. Wait until the solution color gradually disappeared, cooling to 0℃, and then intensely mixing it for 3h. And the vacuum distillation of methanol. Put the remaining liquid into the water, to extract it with dichloromethane. After the extract recovered with dichloromethane, add dilute nitric acid to get salt; recrystallization with water and then treated with ammonia to get 2', 4'-dichloro-2-imidazole acetophenone. Furthermore use sodium borohydride reduction into the corresponding alcohols, and then in the presence of sodium hydroxide and dimethyl formamide, use allyl chloride based to get enilconazde (also known as enilconazole). the after adding dilute nitric acid salt and water after recrystallization using ammonia water treatment of 2,2 ', 4'-dichloro 2-methyl imidazole phenyl ethyl ketone. It has something in common of the structure and production methods between enilconazde and miconazole. Miconazole is a broad-spectrum antifungal agent, and enilconazde is also antifungal agent, which is widely used in imazalil.
5.Agrochemical intermediates, bactericide intermediates, triazole fungicide.
- Production method1.It can be made via cyclization and neutralization by glyoxal. Put glyoxal, formaldehyde and ammonium sulfate into reaction pot, stir and heat up to 85-85℃ with heat preservation 4h. Cool it to 50-60℃, with limewater neutralization to pH for more than 10. Heat up to 85-90℃, ammonia excretion for more than 1h, cool it slightly, filter and filter cake washing with hot water; Combined wash, filtrate, and vacuum concentration until anhydrous steamed out; continue to vacuum distillation until low boiling substances all steamed out, collect 105-160℃ (0.133-0.267kPa) fractions and then imidazole is done. The yield is about 45%. Another method is to make cyclization of o-diaminobenzene and formic acid to get benzimidazole, followed by 4, 5-dyhydroxy imidazole via reaction and open-loop of hydrogen peroxide, and finally get imidazole via decarboxylation. 4, 5-dyhydroxy imidazole also can be made by d-tartrate through nitration and cyclization. The process of getting imidazole via decarboxylation of 4, 5-dyhydroxy imidazole is as below: mix 4, 5-dyhydroxy imidazole with copper oxide, heat up to 100-280℃, emit lots of carbon dioxide gas, then the collected distillate is crude product, and at last recrystallize it with benzene to get the product, and the yield is 76%.
2.The production method is to put glyoxal, formaldehyde and ammonium sulfate into reaction pot, stir and heat up to 85-85℃ with heat preservation 4h. Cool it to 50-60℃, with limewater neutralization to pH for more than 10. Heat up to 85-90℃, ammonia excretion for more than 1h, cool it slightly, filter and filter cake washing with hot water; Combined wash, filtrate, and vacuum concentration until anhydrous steamed out; continue to vacuum distillation until low boiling substances all steamed out, collect 105~160℃/133~266Pa fractions and then imidazole is done.
With o-phenylenediamine as raw material, put it into formic acid, stir and heat up, heat preservation at 95~98℃ for 2h, cool it to 50~60℃, adjust PH value to 10 with 10%NaOH; When it reaches room temperature, with filtering, washing and drying to get benzimidazole. Put benzimidazole into concentrated sulfuric acid, heat up to 100℃, and slowly drop in H2O2. Reaction while stirring under 140~150℃ for 1h, cooling to 40℃, water dilution, precipitation, crystallization, filtration, washing, drying, and then 4, 5-dyhydroxy imidazole is done. Mix 4, 5-dyhydroxy imidazole with copper oxide, heat up to 100-280℃, emit lots of carbon dioxide gas, then the collected distillate is white block crude product, and at last recrystallize it with benzene to get the fine imidazole.
- Chemical PropertiesImidazole is a heterocyclic compound with a five-membered planar ring. It is amphoteric and highly polar.The pharmacophore of imidazole exists in bioactive compounds including amino acids, plant growth regulators and therapeutic agents.
- UsesExcellent for buffers in the range of pH 6.2-7.8
Imidazole has been used
- in the lysis, wash and elution buffer for the purification of histidine tagged Sonic Hedgehog(shh-N) protein.
- in elution buffer in stepwise gradient for the purification of histidine tagged aldo keto reductases using nickel affinity chromatography.
- as a component of homogenization buffer for the purification of phagosomal compartments from dendritic cell.
- UsesImidazole is a versatile heterocycle used in the preparation of various biologically active compounds such as the amino acid histidine and is present in many antifungal medication. It is also used ext ensively as a corrosion inhibitor on transition metals such as copper.It is used in organic synthesis and as an antiirradiationagent.
- DefinitionChEBI: An imidazole tautomer which has the migrating hydrogen at position 1.
- Health HazardIt is less toxic relative to pyrrole and otherfive-membered heterocyclic compounds ofnitrogen. Intraperitoneal administration ofimidazole caused somnolence, muscle contractions,and convulsions in mice. Theoral LD50 value in mice is in the range900 mg/kg.
- Fire HazardNoncombustible solid.
- Purification MethodsCrystallise imidazole from *benzene, CCl4, CH2Cl2, EtOH, pet ether, acetone/pet ether and distilled de-ionized water. Dry it at 40o under vacuum over P2O5. Distil it at low pressure. It is also purified by sublimation or by zone melting. [Snyder et al. Org Synth Coll Vol III 471 1955, Bredereck et al. Chem Ber 97 827 1964, Caswell & Spiro J Am Chem Soc 108 6470 1986.] 15N-imidazole crystallises from *benzene [Scholes et al. J Am Chem Soc 108 1660 1986]. [Beilstein 23 II 34, 23 III/IV 564, 23/4 V 191.]
Imidazole Preparation Products And Raw materials
- Raw materialsHydrochloric acidPotassium hydroxide Ammonium hydroxideHydrogen peroxideAmmonium chloride Formaldehydeo-PhenylenediamineGlyoxalCupric oxideBenzimidazole4,5-Imidazoledicarboxylic acid
- Preparation Products5-(AMINOMETHYL)-1-METHYLPYRROLIDIN-2-ONE(S)-4-BOC-MORPHOLINE-3-CARBOXYLIC ACID1-Boc-3-(Amino)azetidinebeta-Methyl vinyl phosphate (MAP)6-FLUORO-1H-PYRAZOLO[3,4-B]PYRIDINE-3-CARBONITRILE1-Methylimidazole5-Bromoindazole6-FLUORO-1H-PYRAZOLO[3,4-B]PYRIDINE-3-CARBOXYLIC ACID2-CYANOPYRIDINE-4-CARBOXALDEHYDEImazalil4-(HYDROXYMETHYL)PICOLINITRILE2-(1H-IMIDAZOL-1-YL)BENZOIC ACIDClotrimazoleEconazoleMiconazole nitrate SisthsneKetoconazole1-[4-(BROMOMETHYL)PHENYL]-1H-PYRAZOLEImidazole-2-carboxaldehyde2,6-Dihydroxypurine4-Chloroimidazole4-(IMIDAZOL-1-YL)PHENOL2-Bromo-4-nitroimidazoleOxiconazole nitrateTRIFLUMIZOLE1-BENZYL-2-IMIDAZOLECARBOXYLIC ACID1-Phenylimidazole4-(1H-Imidazol-1-yl)benzaldehyde2-Imidazol-1-ylethanamineN-(3-Aminopropyl)-imidazole4-(1H-IMIDAZOL-1-YL)BENZOIC ACIDClimbazoleOrazamide1-[(4-Methylphenyl)sulfonyl]-1H-imidazoleimidazol-2-ylamine sulphate 1-(1-2-HYDROXYPHENYL)ETHENYL)-1H-IMIDAZOLEchloroalcohol type homogeneous strongly basic anion exchange membrane1-METHYL-5-NITROIMIDAZOLE4-NitroimidazoleDetergent,industrial
- IMIDAZOLE-15N2 Sorafenib IMpurity Phenol, 4-(hydroxyamino)- Methyl 4-chloropicolinate 2-Chloro-5-nitrobenzotrifluoride 2-Chlorobenzotrifluoride Sorafenib β-D-Glucuronide 2-Pyridinecarboxamide,N-methyl-(9CI) Sorafenib Related Compound 22 Sorafenib-d3 4-(2-Aminophenoxy)-N-methylpicolinamide IFLAB-BB F2108-0089 3-(Trifluoromethyl)phenyl isocyanate Sorafenib Related Compound B 4-HYDROXYPHENYLFORMAMIDE 1-(4-chloro-3-(trifluoromethyl)phenyl)urea 3-Amino-2-chlorobenzotrifluoride 1,4-Benzoquinoneimine
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