Imidazole

Imidazole
Full structural formula
Skeletal formula with numbers
Ball-and-stick model
Space-filling model
Names
IUPAC name
1H-Imidazole
Other names
1,3-diazole
glyoxaline (archaic)
1,3-diazacyclopenta-2,4-diene
Identifiers
288-32-4 YesY
3D model (Jmol) Interactive image
ChEBI CHEBI:16069 YesY
ChEMBL ChEMBL540 YesY
ChemSpider 773 YesY
ECHA InfoCard 100.005.473
EC Number 206-019-2
KEGG C01589 YesY
PubChem 795
RTECS number NI3325000
Properties
C3H4N2
Molar mass 68.077 g/mol
Appearance white or pale yellow solid
Density 1.23 g/cm3, solid
Melting point 89 to 91 °C (192 to 196 °F; 362 to 364 K)
Boiling point 256 °C (493 °F; 529 K)
Soluble
Acidity (pKa) 14.5 (for imidazole) and 7.05 (for the conjugate acid) [1]
UV-vis (λmax) 280 nm
Structure
monoclinic
planar 5-membered ring
3.61 D
Hazards
Main hazards Corrosive
Safety data sheet External MSDS
R-phrases R20 R22 R34 R41
S-phrases S26 S36 S37 S39 S45
Flash point 146 °C (295 °F; 419 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Imidazole 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, and having non-adjacent nitrogen atoms.

Many natural products, especially alkaloids, contain the imidazole ring. These imidazoles share the 1,3-C3N2 ring but feature varied substituents. This ring system is present in important biological building blocks, such as histidine and the related hormone histamine. Many drugs contain an imidazole ring, such as certain antifungal drugs, the nitroimidazole series of antibiotics, and the sedative midazolam.[2][3][4][5][6]

When fused to a pyrimidine ring, it forms purine, which is the most widely occurring nitrogen-containing heterocycle in nature.[7]

The name "imidazole" was coined in 1887 by the German chemist Arthur Rudolf Hantzsch (1857–1935).[8]

Structure and properties

Imidazole is a planar 5-membered ring. It exists in two equivalent tautomeric forms, because the positive charge can be located on either of the two nitrogen atoms. Imidazole is a highly polar compound, as evidenced by its electric dipole moment of 3.67 D.[9] It is highly soluble in water. The compound is classified as aromatic due to the presence of a sextet of π-electrons, consisting of a pair of electrons from the protonated nitrogen atom and one from each of the remaining four atoms of the ring. Some resonance structures of imidazole are shown below:

Amphoterism

Imidazole is amphoteric. That is, it can function as both an acid and as a base. As an acid, the pKa of imidazole is 14.5, making it less acidic than carboxylic acids, phenols, and imides, but slightly more acidic than alcohols. The acidic proton is located on N-1. As a base, the pKa of the conjugate acid (cited as pKBH+ to avoid confusion between the two) is approximately 7, making imidazole approximately sixty times more basic than pyridine. The basic site is N3. Protonation gives the imidazolium cation, which is symmetrical.

Preparation

Imidazole was first reported in 1858 by the German-British chemist Heinrich Debus, although various imidazole derivatives had been discovered as early as the 1840s. Its synthesis, as shown below, used glyoxal and formaldehyde in ammonia to form imidazole (or glyoxaline, as it was originally named).[10] This synthesis, while producing relatively low yields, is still used for creating C-substituted imidazoles.

In one microwave modification, the reactants are benzil, benzaldehyde and ammonia in glacial acetic acid, forming 2,4,5-triphenylimidazole (lophine).[11]

Imidazole can be synthesized by numerous methods besides the Debus method. Many of these syntheses can also be applied to different substituted imidazoles and imidazole derivatives by varying the functional groups on the reactants. These methods are commonly categorized by which and how many bonds form to make the imidazole rings. For example, the Debus method forms the (1,2), (3,4), and (1,5) bonds in imidazole, using each reactant as a fragment of the ring, and thus this method would be a three-bond-forming synthesis. A small sampling of these methods is presented below.

Formation of one bond
The (1,5) or (3,4) bond can be formed by the reaction of an imidate and an α-aminoaldehyde or α-aminoacetal, resulting in the cyclization of an amidine to imidazole. The example below applies to imidazole when R = R1 = hydrogen.
Formation of two bonds
The (1,2) and (2,3) bonds can be formed by treating a 1,2-diaminoalkane, at high temperatures, with an alcohol, aldehyde, or carboxylic acid. A dehydrogenating catalyst, such as platinum on alumina, is required.
The (1,2) and (3,4) bonds can also be formed from N-substituted α-aminoketones and formamide with heat. The product will be a 1,4-disubstituted imidazole, but here since R = R1 = hydrogen, imidazole itself is the product. The yield of this reaction is moderate, but it seems to be the most effective method of making the 1,4 substitution.
Formation of four bonds
This is a general method that is able to give good yields for substituted imidazoles. In essence, it is an adaptation of the Debus method called the Debus-Radziszewski imidazole synthesis. The starting materials are substituted glyoxal, aldehyde, amine, and ammonia or an ammonium salt.[12]
Formation from other heterocycles
Imidazole can be synthesized by the photolysis of 1-vinyltetrazole. This reaction will give substantial yields only if the 1-vinyltetrazole is made efficiently from an organotin compound, such as 2-tributylstannyltetrazole. The reaction, shown below, produces imidazole when R = R1 = R2 = hydrogen.
Imidazole can also be formed in a vapor-phase reaction. The reaction occurs with formamide, ethylenediamine, and hydrogen over platinum on alumina, and it must take place between 340 and 480 °C. This forms a very pure imidazole product.
Van Leusen reaction
The Van Leusen reaction can also be employed to form imidazoles starting from TosMIC and an aldimine.

Biological significance and applications

Imidazole is incorporated into many important biological molecules. The most pervasive is the amino acid histidine, which has an imidazole side-chain. Histidine is present in many proteins and enzymes and plays a vital part in the structure and binding functions of hemoglobin. Imidazole-based histidine compounds play a very important role in intracellular buffering.[13] Histidine can be decarboxylated to histamine, which is also a common biological compound. It can cause urticaria (hives), when histamine is produced during allergic reaction. The relationship between histidine and histamine are shown below:

One of the applications of imidazole is in the purification of His-tagged proteins in immobilised metal affinity chromatography (IMAC). Imidazole is used to elute tagged proteins bound to nickel ions attached to the surface of beads in the chromatography column. An excess of imidazole is passed through the column, which displaces the His-tag from nickel coordination, freeing the His-tagged proteins.

Imidazole has become an important part of many pharmaceuticals. Synthetic imidazoles are present in many fungicides and antifungal, antiprotozoal, and antihypertensive medications. Imidazole is part of the theophylline molecule, found in tea leaves and coffee beans, that stimulates the central nervous system. It is present in the anticancer medication mercaptopurine, which combats leukemia by interfering with DNA activities.

A number of substituted imidazoles, including clotrimazole, are selective inhibitors of nitric oxide synthase, which makes them interesting drug targets in inflammation, neurodegenerative diseases and tumors of the nervous system.[14][15] Other biological activities of the imidazole pharmacophore relate to the downregulation of intracellular Ca2+ and K+ fluxes, and interference with translation initiation.[16]

Pharmaceutical derivatives

The substituted imidazole derivatives are valuable in treatment of many systemic fungal infections.[17] Imidazoles belong to the class of azole antifungals, which includes ketoconazole, miconazole, and clotrimazole.

For comparison, another group of azoles is the triazoles, which includes fluconazole, itraconazole, and voriconazole. The difference between the imidazoles and the triazoles involves the mechanism of inhibition of the cytochrome P450 enzyme. The N3 of the imidazole compound binds to the heme iron atom of ferric cytochrome P450, whereas the N4 of the triazoles bind to the heme group. The triazoles have been shown to have a higher specificity for the cytochrome P450 than imidazoles, thereby making them more potent than the imidazoles.[18]

Some imidazole derivatives show effects on insects, for example sulconazole nitrate exhibits a strong anti-feeding effect on the keratin-digesting Australian carpet beetle larvae Anthrenocerus australis, as does econazole nitrate with the common clothes moth Tineola bisselliella.[19]

Industrial applications

Imidazole has been used extensively as a corrosion inhibitor on certain transition metals, such as copper. Preventing copper corrosion is important, especially in aqueous systems, where the conductivity of the copper decreases due to corrosion.

Many compounds of industrial and technological importance contain imidazole derivatives. The thermostable polybenzimidazole (PBI) contains imidazole fused to a benzene ring and linked to a benzene, and acts as a fire retardant. Imidazole can also be found in various compounds that are used for photography and electronics.

Salts of imidazole

Simple imidazolium cation

Salts of imidazole where the imidazole ring is in the cation are known as imidazolium salts (for example, imidazolium chloride). These salts are formed from the protonation or substitution at nitrogen of imidazole. These salts have been used as ionic liquids and precursors to stable carbenes. Salts where a deprotonated imidazole is an anion are also well known; these salts are known as imidazolates (for example, sodium imidazolate, NaC3H3N2).

See also

References

  1. ↑ Walba, H.; Isensee, R. W. (1961). "Acidity constants of some arylimidazoles and their cations". J. Org. Chem. 26 (8): 2789–2791. doi:10.1021/jo01066a039.
  2. ↑ Karitzky, A. R.; Rees (1984). Comprehensive Heterocyclic Chemistry. 5. p. 469–498.
  3. ↑ Grimmett, M. Ross (1997). Imidazole and Benzimidazole Synthesis. Academic Press.
  4. ↑ Brown, E. G. (1998). Ring Nitrogen and Key Biomolecules. Kluwer Academic Press.
  5. ↑ Pozharskii, A. F.; et al. (1997). Heterocycles in Life and Society. John Wiley & Sons.
  6. ↑ Gilchrist, T. L. (1985). Heterocyclic Chemistry. Bath Press. ISBN 0-582-01421-2.
  7. ↑ Rosemeyer, H. (2004). "The Chemodiversity of Purine as a Constituent of Natural Products". Chemistry & Biodiversity. 1 (3): 361. doi:10.1002/cbdv.200490033.
  8. ↑ Hantzsch, A. and Weber, J. H. (1887) "Ueber Verbindungen des Thiazols (Pyridins der Thiophenreihe)" (On compounds of thiazole (pyridines of the thiophene series), Berichte der deutschen chemischen Gesellschaft, 20 : 3118–3132, see p. 3119. See also: Hantzsch, A. (1888) "Allegemeine Bemerkungen über Azole" (General observations about azoles), Annalen der Chemie, 249 : 1–6. Hantzsch proposed a reform of the nomenclature of azole compounds, including a proposal to call the heterocyclic ring C3H3(NH)N "imidazole" ; see pp. 2 and 4.
  9. ↑ Christen, Dines; Griffiths, John H.; Sheridan, John (1981). "The Microwave Spectrum of Imidazole; Complete Structure and the Electron Distribution from Nuclear Quadrupole Coupling Tensors and Dipole Moment Orientation". Zeitschrift für Naturforschung A. 36 (12): 1378–1385. Bibcode:1981ZNatA..36.1378C. doi:10.1515/zna-1981-1220.
  10. ↑ Debus, Heinrich (1858). "Ueber die Einwirkung des Ammoniaks auf Glyoxal" [On the reaction of ammonia upon glyoxal]. Annalen der Chemie und Pharmacie. 107 (2): 199–208. doi:10.1002/jlac.18581070209. From p. 205: "Die gereinigte Substanz stellt das oxalsaure Salz einer Basis dar, die ich mit Glyoxalin bezeichenen werde." (The purified substance constitutes the oxalic salt of a base, which I will designate as "glyoxaline".)
  11. ↑ Crouch, R. David; Howard, Jessica L.; Zile, Jennifer L.; Barker, Kathryn H. (2006). "Microwave-Mediated Synthesis of Lophine: Developing a Mechanism To Explain a Product". J. Chem. Educ. 83 (11): 1658. doi:10.1021/ed083p1658.
  12. ↑ US patent 6,177,575, Arduengo, A. J., "Process for Manufacture of Imidazoles", issued 2001-01-23
  13. ↑ Hochachka, P. W.; Somero, G. N. (2002). Biochemical Adaptation: Mechanisms and Process in Physiological Evolution. New York: Oxford University Press.
  14. ↑ Castaño, T.; Encinas, A.; Pérez, C.; Castro, A.; Campillo, N. E.; Gil, C. (2008). "Design, synthesis, and evaluation of potential inhibitors of nitric oxide synthase". Bioorg. Med. Chem. 16 (11): 6193–6206. doi:10.1016/j.bmc.2008.04.036. PMID 18477512.
  15. ↑ Bogle, R. G.; Whitley, G. S.; Soo, S. C.; Johnstone, A. P.; Vallance, P. (1994). "Effect of anti-fungal imidazoles on mRNA levels and enzyme activity of inducible nitric oxide synthase". Br. J. Pharmacol. 111 (4): 1257–1261. doi:10.1111/j.1476-5381.1994.tb14881.x. PMC 1910171Freely accessible. PMID 7518297.
  16. ↑ Khalid, M. H.; Tokunaga, Y.; Caputy, A. J.; Walters, E. (2005). "Inhibition of tumor growth and prolonged survival of rats with intracranial gliomas following administration of clotrimazole". J. Neurosurg. 103 (1): 79–86. doi:10.3171/jns.2005.103.1.0079. PMID 16121977.
  17. ↑ Leon Shargel. Comprehensive Pharmacy Review (6th ed.). p. 930.
  18. ↑ Riviere and Papich. Veterinary Pharmacology and Therapeutics (9th ed.). pp. 1019–1020.
  19. ↑ Sunderland, M. R.; Cruickshank, R. H.; Leighs, S. J. (2014). "The efficacy of antifungal azole and antiprotozoal compounds in protection of wool from keratin-digesting insect larvae". Textile Res. J. 84 (9): 924–931. doi:10.1177/0040517513515312.
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