Imidazole

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Imidazole
Full structural formula
Skeletal formula with numbers
Ball-and-stick model
Space-filling model
Names
Preferred IUPAC name
1H-Imidazole[1]
Other names
1,3-Diazole
Glyoxaline (archaic)
Identifiers
3D model (
JSmol
)
103853
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
 100.005.473 Edit this at Wikidata
EC Number
  • 206-019-2
1417
KEGG
RTECS number
  • NI3325000
UNII
UN number 3263
  • InChI=1S/C3H4N2/c1-2-5-3-4-1/h1-3H,(H,4,5) checkY
    Key: RAXXELZNTBOGNW-UHFFFAOYSA-N checkY
  • InChI=1/C3H4N2/c1-2-5-3-4-1/h1-3H,(H,4,5)
  • c1cnc[nH]1
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)
633 g/L
Acidity (pKa) 6.95 (for the
conjugate acid) [2]
UV-vis (λmax) 206 nm
Structure
Monoclinic
Planar 5-membered ring
3.61 D
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Corrosive
GHS labelling:[4]
GHS05: CorrosiveGHS07: Exclamation markGHS08: Health hazard
Danger
H302, H314, H360D
P263, P270, P280, P301+P310, P305+P351+P338, P308+P313[3]
Flash point 146 °C (295 °F; 419 K)
Safety data sheet (SDS) External MSDS
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Imidazole (ImH) is an

heterocycle, classified as a diazole, and has non-adjacent nitrogen atoms in meta-substitution
.

Many natural products, especially

antibiotics, and the sedative midazolam.[5][6][7][8][9]

When fused to a pyrimidine ring, it forms a purine, which is the most widely occurring nitrogen-containing heterocycle in nature.[10]

The name "imidazole" was coined in 1887 by the German chemist Arthur Rudolf Hantzsch (1857–1935).[11]

Structure and properties

Imidazole is a planar 5-membered ring, that exists in two equivalent tautomeric forms because hydrogen can be bound to one or another nitrogen atom. Imidazole is a highly polar compound, as evidenced by its electric dipole moment of 3.67 D,[12] and is highly soluble in water. The compound is classified as aromatic due to the presence of a planar ring containing 6 π-electrons (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, which is to say that it can function both as 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 the one bound to nitrogen. Deprotonation gives the imidazolide anion, which is symmetrical. 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 the nitrogen with the lone pair (and not bound to hydrogen). Protonation gives the imidazolium cation, which is symmetrical.

Preparation

Imidazole was first reported in 1858 by the German chemist

Heinrich Debus, although various imidazole derivatives had been discovered as early as the 1840s. It was shown that glyoxal, formaldehyde, and ammonia condense to form imidazole (glyoxaline, as it was originally named).[13]
This synthesis, while producing relatively low yields, is still used for generating C-substituted imidazoles.

In one

glacial acetic acid, forming 2,4,5-triphenylimidazole ("lophine").[14]

Imidazole can be synthesized by numerous methods besides 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. The example below applies to imidazole when R1 = R2 = hydrogen.

Formation of one bond
Formation of one bond

Formation of two bonds

The (1,2) and (2,3) bonds can be formed by treating a 1,2-diamino

alumina
, is required.

Formation of two bonds
Formation of two bonds

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 R1 = R2 = 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 three bonds
Formation of three bonds

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.[15]

Arduengo imidazoles
Arduengo imidazoles

Formation from other heterocycles

Imidazole can be synthesized by the

organotin compound
, such as 2-tributylstannyltetrazole. The reaction, shown below, produces imidazole when R1 = R2 = R3 = hydrogen.

Imidazole can also be formed in a vapor-phase reaction. The reaction occurs with

alumina
, and it must take place between 340 and 480 °C. This forms a very pure imidazole product.

Van Leusen reaction[16]

The

aldimine
. The Van Leusen Imidazole Synthesis allows the preparation of imidazoles from aldimines by reaction with tosylmethyl isocyanide (TosMIC). The reaction has later been expanded to a two-step synthesis in which the aldimine is generated in situ: the Van Leusen Three-Component Reaction (vL-3CR).

Biological significance and applications

Imidazole is incorporated into many important biological compounds. The most pervasive is the

enzymes, e.g. by binding metal cofactors, as seen in hemoglobin
.

Imidazole-based histidine compounds play a very important role in intracellular buffering.

urticaria (hives) when it is produced during allergic
reaction.

Imidazole substituents are found in many pharmaceuticals. Synthetic imidazoles are present in many

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.[18][19] Other biological activities of the imidazole pharmacophore relate to the downregulation of intracellular Ca2+ and K+ fluxes, and interference with translation initiation.[20]

Pharmaceutical derivatives

The substituted imidazole derivatives are valuable in treatment of many systemic

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.[22]

Some imidazole derivatives show effects on insects, for example

econazole nitrate with the common clothes moth Tineola bisselliella.[23]

Industrial applications

Imidazole itself has few direct applications. It is instead a precursor to a variety of agrichemicals, including enilconazole, climbazole, clotrimazole, prochloraz, and bifonazole.[24]

agrichemicals
.

Coordination chemistry

Main article: Transition metal imidazole complex

Imidazole and its derivatives have high affinity for metal cations. 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.

Use in biological research

Imidazole is a suitable buffer for pH 6.2 to 7.8,[25]. Pure imidazole has essentially no absorbance at protein relevant wavelengths (280 nm),[26][27] however lower purities of imidazole can give notable absorbance at 280 nm. Imidazole can interfere with the Lowry protein assay.[28]

Salts of imidazole

Simple imidazolium cation

Salts of imidazole where the imidazole ring is the

anion are also well known; these salts are known as imidazolates
(for example, sodium imidazolate, NaC3H3N2).

Related heterocycles

Safety

Imidazole has low acute toxicity as indicated by the LD50 of 970 mg/kg (Rat, oral).[24]

See also

References

  1. ISBN 978-0-85404-182-4
    .
  2. doi:10.1021/jo01066a039
    .
  3. ^ "Imidazole". molekula.com. Molekula Group. Archived from the original on 2018-10-19. Retrieved 2018-10-19.
  4. ^ "Imidazole". pubchem.ncbi.nlm.nih.gov. Archived from the original on 10 May 2023. Retrieved 17 February 2024.
  5. ISBN 978-0-08-042072-1
    .
  6. ISBN 978-0-08-053445-9
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    .
  9. ISBN 978-0-582-01421-3
    .
  10. S2CID 12416667
    .
  11. ^ Hantzsch, A. and Weber, J. H. (1887) "Ueber Verbindungen des Thiazols (Pyridins der Thiophenreihe)" Archived 2020-05-30 at the Wayback Machine (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" Archived 2020-05-30 at the Wayback Machine (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.
  12. S2CID 3522351
    .
  13. doi:10.1002/jlac.18581070209. Archived
    from the original on 2020-05-30. Retrieved 2016-10-01. 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".)
  14. doi:10.1021/ed083p1658
    .
  15. Arduengo, A. J.
    , "Process for Manufacture of Imidazoles", issued 2001-01-23     
  16. doi:10.1021/jo00427a012
    .
  17. ^ Hochachka, P. W.; Somero, G. N. (2002). Biochemical Adaptation: Mechanisms and Process in Physiological Evolution. New York: Oxford University Press.
  18. PMID 18477512. Archived
    (PDF) from the original on 2023-03-06. Retrieved 2018-07-24.
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    .
  20. PMID 16121977
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  21. ISBN 9780781765619
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  22. ISBN 978-0-8138-2061-3
    .
  23. S2CID 135799368
    .
  24. ^
    ISBN 978-3527306732.{{cite encyclopedia}}: CS1 maint: multiple names: authors list (link
    )
  25. OCLC 11865673
    .
  26. ^ "1H-Imidazole". Archived from the original on 25 April 2021. Retrieved 13 May 2021.
  27. ^ "Optimizing Purification of Histidine-Tagged Proteins". Archived from the original on 13 May 2021. Retrieved 13 May 2021.
  28. PMID 8851751
    .
  29. PMID 22409592
    .
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