HOME

TheInfoList



OR:

Imidazole (ImH) is an
organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon- hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. Th ...
with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly
alkali In chemistry, an alkali (; from ar, القلوي, al-qaly, lit=ashes of the saltwort) is a basic, ionic salt of an alkali metal or an alkaline earth metal. An alkali can also be defined as a base that dissolves in water. A solution of ...
ne solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non-adjacent
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at seve ...
atoms in meta-substitution. Many natural products, especially
alkaloid Alkaloids are a class of basic BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Th ...
s, 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 Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the ...
and the related hormone histamine. Many drugs contain an imidazole ring, such as certain antifungal drugs, the nitroimidazole series of
antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
, and the sedative midazolam. When fused to a pyrimidine ring, it forms a
purine Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purin ...
, which is the most widely occurring nitrogen-containing heterocycle in nature. The name "imidazole" was coined in 1887 by the German chemist
Arthur Rudolf Hantzsch Arthur Rudolf Hantzsch (7 March 1857 – 14 March 1935) was a German chemist. Life and work Hantzsch studied chemistry in Dresden and graduated at the University of Würzburg under Johannes Wislicenus. As a professor, he taught at the Univers ...
(1857–1935).


Structure and properties

Imidazole is a planar 5-membered ring, that exists in two equivalent
tautomer Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hyd ...
ic forms because hydrogen can be bound to one or another
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at seve ...
atom. Imidazole is a highly polar compound, as evidenced by its electric dipole moment of 3.67  D, and is highly soluble in water. The compound is classified as aromatic due to the presence of a planar ring containing 6
π-electron In chemistry, pi bonds (π bonds) are covalent chemical bonds, in each of which two lobes of an orbital on one atom overlap with two lobes of an orbital on another atom, and in which this overlap occurs laterally. Each of these atomic orbitals ...
s (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 p''K''a 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 p''K''a of the conjugate acid (cited as p''K''BH+ to avoid confusion between the two) is approximately 7, making imidazole approximately sixty times more basic than
pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakl ...
. 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 Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogeno ...
condense to form imidazole (glyoxaline, as it was originally named). This synthesis, while producing relatively low yields, is still used for generating ''C''-substituted imidazoles. : In one
microwave Microwave is a form of electromagnetic radiation with wavelengths ranging from about one meter to one millimeter corresponding to frequency, frequencies between 300 MHz and 300 GHz respectively. Different sources define different fre ...
modification, the reactants are benzil, benzaldehyde and
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogeno ...
in glacial acetic acid, forming 2,4,5-triphenylimidazole ("lophine"). 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-amino
aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl group ...
or α-amino acetal. The example below applies to imidazole when R1 = R2 = hydrogen. ::


Formation of two bonds

The (1,2) and (2,3) bonds can be formed by treating a 1,2-diamino
alkane In organic chemistry Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms tha ...
, at high temperatures, with an alcohol,
aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl group ...
, or
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyl ...
. A dehydrogenating catalyst, such as
platinum Platinum is a chemical element with the symbol Pt and atomic number 78. It is a dense, malleable, ductile, highly unreactive, precious, silverish-white transition metal. Its name originates from Spanish , a diminutive of "silver". Pla ...
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 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 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. :


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 R1 = R2 = R3 = hydrogen. : Imidazole can also be formed in a vapor-phase reaction. The reaction occurs with formamide,
ethylenediamine Ethylenediamine (abbreviated as en when a ligand) is the organic compound with the formula C2H4(NH2)2. This colorless liquid with an ammonia-like odor is a basic amine. It is a widely used building block in chemical synthesis, with approximately ...
, and hydrogen over
platinum Platinum is a chemical element with the symbol Pt and atomic number 78. It is a dense, malleable, ductile, highly unreactive, precious, silverish-white transition metal. Its name originates from Spanish , a diminutive of "silver". Pla ...
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. 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
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the ...
, which has an imidazole side-chain. Histidine is present in many proteins and enzymes, e.g. by binding metal cofactors, as seen in
hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
. Imidazole-based histidine compounds play a very important role in intracellular buffering. Histidine can be
decarboxylated Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is t ...
to histamine. Histamine can cause urticaria (hives) when it is produced during allergic reaction. Imidazole substituents are found in many pharmaceuticals. Synthetic imidazoles are present in many fungicides and antifungal, antiprotozoal, and
antihypertensive Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests that ...
medications. Imidazole is part of the theophylline molecule, found in tea leaves and coffee beans, that stimulates the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
. It is present in the anticancer medication mercaptopurine, which combats
leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...
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 Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
, neurodegenerative diseases and tumors of the nervous system. Other biological activities of the imidazole pharmacophore relate to the downregulation of intracellular Ca2+ and K+ fluxes, and interference with translation initiation.


Pharmaceutical derivatives

The substituted imidazole derivatives are valuable in treatment of many systemic fungal
infections An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...
. 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. Some imidazole derivatives show effects on insects, for example
sulconazole nitrate Sulconazole (trade name Exelderm) is an antifungal medication of the imidazole class. It is available as a Cream (pharmaceutical), cream or Solution (chemistry), solution to treat skin infections such as athlete's foot, ringworm, jock itch, and t ...
exhibits a strong anti-feeding effect on the
keratin Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. Alpha-keratin (α-keratin) is a type of keratin found in vertebrates. It is the key structural material making up scales, hair, nails, feathers, ...
-digesting Australian carpet beetle larvae '' Anthrenocerus australis'', as does
econazole nitrate Econazole is an antifungal medication of the imidazole class. It was patented in 1968, and approved for medical use in 1974. Medical uses Econazole is used as a cream to treat skin infections such as athlete's foot, tinea, pityriasis versicol ...
with the common clothes moth '' Tineola bisselliella''.


Industrial applications

Imidazole itself has few direct applications. It is instead a precursor to a variety of agrichemicals, including
enilconazole Enilconazole (synonyms imazalil, chloramizole) is a fungicide widely used in agriculture, particularly in the growing of citrus fruits. Trade names include Freshgard, Fungaflor, and Nuzone. Enilconazole is also used in veterinary medicine as a to ...
,
climbazole Climbazole is a topical antifungal agent commonly used in the treatment of human fungal skin infections such as dandruff and eczema. Climbazole has shown a high ''in vitro'' and ''in vivo'' efficacy against '' Malassezia spp.'' that appear to pla ...
, clotrimazole, prochloraz, and bifonazole. 144px, Prochloraz is one of several imidazole-derived agrichemicals.">agrichemical.html" ;"title="Prochloraz is one of several imidazole-derived agrichemical">Prochloraz is one of several imidazole-derived agrichemicals.


Coordination chemistry

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 Affinity chromatography#Immobilized metal ion affinity chromatography, 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 In chemical analysis, chromatography is a laboratory technique for the separation of a mixture into its components. The mixture is dissolved in a fluid solvent (gas or liquid) called the ''mobile phase'', which carries it through a system ( ...
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 6.2-7.8,. Pure imidazole has essentially no absorbance at protein relevant wavelenths (280 nm), however lower purities of imidazole can give notable absorbance at 280 nm. Imidazole can interfere with the Lowry protein assay.


Salts of imidazole

Salts of imidazole where the imidazole ring is the
cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
are known as imidazolium salts (for example, imidazolium
chloride The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride s ...
or nitrate). These salts are formed from the protonation or substitution at
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at seve ...
of imidazole. These salts have been used as ionic liquids and precursors to stable carbenes. Salts where a deprotonated imidazole is an
anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
are also well known; these salts are known as imidazolates (for example, sodium imidazolate, NaC3H3N2).


Related heterocycles

* Benzimidazole, an analog with a fused
benzene Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen ato ...
ring *
Dihydroimidazole Imidazoline is a class of heterocycles formally derived from imidazoles by the reduction of one of the two double bonds. Three isomers are known, 2-imidazolines, 3-imidazolines, and 4-imidazolines. The 2- and 3-imidazolines contain an imine center ...
or imidazoline, an analog where the 4,5-
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
is saturated * Pyrrole, an analog with only one
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at seve ...
atom Every atom is composed of a nucleus and one or more electrons bound to the nucleus. The nucleus is made of one or more protons and a number of neutrons. Only the most common variety of hydrogen has no neutrons. Every solid, liquid, gas ...
in position 1 * Oxazole, an analog with the nitrogen atom in position 1 replaced by
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as we ...
*
Thiazole Thiazole, or 1,3-thiazole, is a heterocyclic compound that contains both sulfur and nitrogen. The term 'thiazole' also refers to a large family of derivatives. Thiazole itself is a pale yellow liquid with a pyridine-like odor and the molecular fo ...
, an analog with the nitrogen atom in position 1 replaced by
sulfur Sulfur (or sulphur in British English) is a chemical element with the symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms form cyclic octatomic molecules with a chemical formul ...
*
Pyrazole Pyrazole is an organic compound with the formula C3H3N2H. It is a heterocycle characterized by a 5-membered ring of three carbon atoms and two adjacent nitrogen atoms, which are in ortho-substitution. Pyrazole is a weak base, with p''K''b 11.5 ( ...
, an analog with two adjacent
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at seve ...
atoms *
Triazole A triazole is a heterocyclic compound featuring a five-membered ring of two carbon atoms and three nitrogen atoms with molecular formula C2H3N3. Triazoles exhibit substantial isomerism, depending on the positioning of the nitrogen atoms within th ...
s, analogs with three nitrogen atoms


Safety

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


See also

* 1-Methylimidazole * 4-Methylimidazole


References

{{Authority control Imidazoles Alkaloids Simple aromatic rings Aromatic bases