Imidazole is an
organic compoundAn organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
with the formula C
3H
4N
2. This aromatic heterocyclic is a
diazoleDiazole refers to either one of a pair of isomeric chemical compounds with molecular formula C3H4N2, having a five-membered ring consisting of three carbon atoms and two nitrogen atoms.The two isomers are:...
and is classified as an
alkaloidAlkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents. This ring system is present in important biological building-blocks, such as
histidineHistidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
, and the related hormone
histamineHistamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
. Imidazole can serve as a
baseFor the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...
and as a weak
acidAn acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...
. Many drugs contain an imidazole ring, such as
antifungal drugAn antifungal medication is a medication used to treat fungal infections such as athlete's foot, ringworm, candidiasis , serious systemic infections such as cryptococcal meningitis, and others...
s and
nitroimidazole4-Nitroimidazole is an imidazole derivative that contains a nitro group.Several derivatives of nitroimidazole constitute the class of nitroimidazole antibiotics that have been used to combat anaerobic bacterial and parasitic infections. Perhaps the most common example is metronidazole . Other...
.
Discovery
Imidazole was first synthesized in 1858, but various imidazole derivatives had been discovered as early as the 1840s. Its synthesis, as shown below, used
glyoxalGlyoxal is an organic compound with the formula OCHCHO. This yellow colored liquid is the smallest dialdehyde . Its tautomer acetylenediol is unstable.-Production:...
and
formaldehydeFormaldehyde is an organic compound with the formula CH2O. It is the simplest aldehyde, hence its systematic name methanal.Formaldehyde is a colorless gas with a characteristic pungent odor. It is an important precursor to many other chemical compounds, especially for polymers...
in
ammoniaAmmonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
to form imidazole (or glyoxaline, as it was originally named). This synthesis, while producing relatively low yields, is still used for creating C-substituted imidazoles.
In one
microwaveMicrowave chemistry is the science of applying microwave irradiation to chemical reactions. Microwaves act as high frequency electric fields and will generally heat any material containing mobile electric charges, such as polar molecules in a solvent or conducting ions in a solid...
modification, the reactants are
benzilBenzil is the organic compound with the formula 2, generally abbreviated 2. This yellow solid is one of the most common diketones...
,
benzaldehydeBenzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...
and
ammoniaAmmonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
in glacial acetic acid, forming 2,4,5-triphenylimidazole (Lophine).
Structure and properties
Imidazole is a 5-membered planar ring, which is soluble in water and other
polarIn chemistry, polarity refers to a separation of electric charge leading to a molecule or its chemical groups having an electric dipole or multipole moment. Polar molecules interact through dipole–dipole intermolecular forces and hydrogen bonds. Molecular polarity is dependent on the difference in...
solvents. It exists in two equivalent
tautomerTautomers are isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond...
ic forms, 1
H-imidazole and 3
H-imidazole, because the
hydrogenHydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
atomThe atom is a basic unit of matter that consists of a dense central nucleus surrounded by a cloud of negatively charged electrons. The atomic nucleus contains a mix of positively charged protons and electrically neutral neutrons...
can be located on either of the two
nitrogenNitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
atoms. Imidazole is a highly polar compound, as evidenced by a calculated dipole of 3.61
DThe debye is a CGS unit of electric dipole momentElectric dipole moment is defined as charge times displacement: Historically the debye was defined as the dipole moment resulting from two charges of opposite sign but an equal magnitude of 10-10 statcoulomb10-10 statcoulomb is approximately 0.2083...
, and is entirely soluble in water. The compound is classified as
aromaticIn organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...
due to the presence of a sextet of
π-electronIn chemistry, pi bonds are covalent chemical bonds where two lobes of one involved atomic orbital overlap two lobes of the other involved atomic orbital...
s, consisting of a pair of electrons from the protonated nitrogen atom and one from each of the remaining four atoms of the ring.
Some
resonanceIn chemistry, resonance or mesomerism is a way of describing delocalized electrons within certain molecules or polyatomic ions where the bonding cannot be expressed by one single Lewis formula...
structures of imidazole are shown below:
Amphotericity
Imidazole is amphoteric. That is, it can function as both an acid and as a base. As an acid, the p
Ka 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 p
Ka of the conjugate acid (cited above as p
KBH+ to avoid confusion between the two) is approximately 7, making imidazole approximately sixty times more basic than
pyridinePyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
. The basic site is N-3.
Preparation
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 simply by varying the functional groups on the reactants. In literature, 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
amidineAmidines are a class of oxoacid derivatives.The oxoacid from which an amidine is derived must be of the form RnEOH, where R is a substituent...
to imidazole. The example below applies to imidazole when R=R
1=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
alcoholIn chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
,
aldehydeAn aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
, or
carboxylic acidCarboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
. A dehydrogenating catalyst, such as
platinumPlatinum is a chemical element with the chemical symbol Pt and an atomic number of 78. Its name is derived from the Spanish term platina del Pinto, which is literally translated into "little silver of the Pinto River." It is a dense, malleable, ductile, precious, gray-white transition metal...
on alumina, is required.
The (1,2) and (3,4) bonds can also be formed from N-substituted α-aminoketones and
formamideFormamide, also known as methanamide, is an amide derived from formic acid. It is a clear liquid which is miscible with water and has an ammonia-like odor. It is used primarily for manufacturing sulfa drugs and synthesizing vitamins and as a softener for paper and fiber...
with heat. The product will be a 1,4-disubstituted imidazole, but here since R=R
1=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 synthesisThe Debus-Radziszewski imidazole synthesis is an organic reaction describing the synthesis of an imidazole from a diketone, an aldehyde and ammonia...
. 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-vinyltetrazoleTetrazoles are a class of synthetic organic heterocyclic compound, consisting of a 5-member ring of four nitrogen and one carbon atom . The simplest is tetrazole itself, CN4H2. They are unknown in nature...
. 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=R
1=R
2=Hydrogen.
Imidazole can also be formed in a vapor-phase reaction. The reaction occurs with
formamideFormamide, also known as methanamide, is an amide derived from formic acid. It is a clear liquid which is miscible with water and has an ammonia-like odor. It is used primarily for manufacturing sulfa drugs and synthesizing vitamins and as a softener for paper and fiber...
, ethylenediamine, and hydrogen over platinum on alumina, and it must take place between 340 and 480°C. This forms a very pure imidazole product.
Biological significance and applications
Imidazole is incorporated into many important biological molecules. The most pervasive is the
amino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
histidineHistidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
, 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
hemoglobinHemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
. Histidine can be decarboxylated to
histamineHistamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
, which is also a common biological compound. It is a component of the
toxinA toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...
that causes
urticariaUrticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...
, which is another name for
allergicAn Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
hives. The relationship between histidine and histamine are shown below:
One of the applications of imidazole is in the purification of His-tagged
proteinProteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s in immobilised metal affinity chromatography (IMAC). Imidazole is used to elute tagged proteins bound to
NiNickel is a chemical element with the chemical symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel belongs to the transition metals and is hard and ductile...
ionAn ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s 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 co-ordination, freeing the His-tagged proteins.
Imidazole has become an important part of many pharmaceuticals. Synthetic imidazoles are present in many
fungicideFungicides are chemical compounds or biological organisms used to kill or inhibit fungi or fungal spores. Fungi can cause serious damage in agriculture, resulting in critical losses of yield, quality and profit. Fungicides are used both in agriculture and to fight fungal infections in animals...
s and antifungal, antiprotozoal, and
antihypertensiveThe antihypertensives are a class of drugs that are used to treat hypertension . Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from...
medications. Imidazole is part of the
theophyllineTheophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
molecule, found in tea leaves and coffee beans, that stimulates the
central nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. It is present in the anticancer medication
mercaptopurineMercaptopurine is an immunosuppressive drug.It is a thiopurine.-Uses:...
, which combats
leukemiaLeukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
by interfering with
DNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
activities.
Pharmaceutical derivatives
The substituted imidazole derivatives are valuable in treatment of many systemic fungal infections. Imidazoles belong to the class of Azole antifungals, which includes
ketoconazoleKetoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
,
miconazoleMiconazole is an imidazole antifungal agent, developed by Janssen Pharmaceutica, commonly applied topically to the skin or to mucus membranes to cure fungal infections. It works by inhibiting the synthesis of ergosterol, a critical component of fungal cell membranes...
, and
clotrimazoleClotrimazole is an antifungal medication commonly used in the treatment of fungal infections such as vaginal yeast infections, oral thrush, and ringworm...
.
For comparison, another group of azoles is the triazoles, which includes
fluconazoleFluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. It is commonly marketed under the trade...
,
itraconazoleItraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...
, and
voriconazoleVoriconazole is a triazole antifungal medication that is generally used to treat serious, invasive fungal infections. These are generally seen in patients who are immunocompromised, and include invasive candidiasis, invasive aspergillosis, and certain emerging fungal infections.-Invasive...
. 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.
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
benzeneBenzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....
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
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
protonationIn chemistry, protonation is the addition of a proton to an atom, molecule, or ion. Some classic examples include*the protonation of water by sulfuric acid:*the protonation of isobutene in the formation of a carbocation:2C=CH2 + HBF4 → 3C+ + BF4−*the protonation of ammonia in the...
or substitution at
nitrogenNitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
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 possible; these salts are known as
imidazolide salts (for example, sodium imidazolide).
Related heterocycles
- Benzimidazole
Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene and imidazole. The most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. Benzimidazole, in...
, an analog with a fused benzeneBenzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....
ring
- Dihydroimidazole or benzimidazoline, an analog where 4,5-double bond
A double bond in chemistry is a chemical bond between two chemical elements involving four bonding electrons instead of the usual two. The most common double bond, that between two carbon atoms, can be found in alkenes. Many types of double bonds between two different elements exist, for example in...
is saturated
- Pyrrole
Pyrrole is a heterocyclic aromatic organic compound, a five-membered ring with the formula C4H4NH. It is a colourless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., N-methylpyrrole, C4H4NCH3...
, an analog with only one nitrogenNitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
atomThe atom is a basic unit of matter that consists of a dense central nucleus surrounded by a cloud of negatively charged electrons. The atomic nucleus contains a mix of positively charged protons and electrically neutral neutrons...
in position 1
- Oxazole
Oxazole is the parent compound for a vast class of heterocyclic aromatic organic compounds. These are azoles with an oxygen and a nitrogen separated by one carbon. Oxazoles are aromatic compounds but less so than the thiazoles...
, an analog with the nitrogen atom in position 1 replaced by oxygenOxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
- 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 formula C3H3NS...
, an analog with the nitrogen atom in position 1 replaced by sulfurSulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...
- Pyrazole
Pyrazole refers both to the class of simple aromatic ring organic compounds of the heterocyclic diazole series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions, and to the unsubstituted parent compound...
, an analog with two adjacent nitrogenNitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
atoms
- Triazole
Triazole refers to either one of a pair of isomeric chemical compounds with molecular formula C2H3N3, having a five-membered ring of two carbon atoms and three nitrogen atoms.The two isomers are:*1,2,3-Triazole 100px*1,2,4-Triazole 100px...
s, analogs with three nitrogen atoms