EC / List no.: 200-745-3
CAS no.: 71-00-1
Histidine (symbol His or H) is an α-amino acid that is used in the biosynthesis of proteins.
Histidine contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the deprotonated –COO− form under biological conditions), and an imidazole side chain (which is partially protonated), classifying it as a positively charged amino acid at physiological pH.
Initially thought essential only for infants, it has now been shown in longer-term studies to be essential for adults also.
Histidine is encoded by the codons CAU and CAC.
Histidine was first isolated by German physician Albrecht Kossel and Sven Gustaf Hedin in 1896.
Histidine is also a precursor to histamine, a vital inflammatory agent in immune responses.
The acyl radical is histidyl.
Properties of the imidazole side chain
The conjugate acid (protonated form) of the imidazole side chain in histidine has a pKa of approximately 6.0.
Thus, below a pH of 6, the imidazole ring is mostly protonated (as described by the Henderson–Hasselbalch equation).
The resulting imidazolium ring bears two NH bonds and has a positive charge.
The positive charge is equally distributed between both nitrogens and can be represented with two equally important resonance structures.
Above pH 6, one of the two protons is lost.
The remaining proton of the imidazole ring can reside on either nitrogen, giving rise to what are known as the N1-H or N3-H tautomers.
The N3-H tautomer, shown in the figure above, is protonated on the #3 nitrogen, farther from the amino acid backbone bearing the amino and carboxyl groups, whereas the N1-H tautomer is protonated on the nitrogen nearer the backbone.
The imidazole/imidazolium ring of histidine is aromatic at all pH values.
The acid-base properties of the imidazole side chain are relevant to the catalytic mechanism of many enzymes.
In catalytic triads, the basic nitrogen of histidine abstracts a proton from serine, threonine, or cysteine to activate it as a nucleophile.
In a histidine proton shuttle, histidine is used to quickly shuttle protons.
Histidine can do this by abstracting a proton with its basic nitrogen to make a positively charged intermediate and then use another molecule, a buffer, to extract the proton from its acidic nitrogen.
In carbonic anhydrases, a histidine proton shuttle is utilized to rapidly shuttle protons away from a zinc-bound water molecule to quickly regenerate the active form of the enzyme.
In helices E and F of haemoglobin, histidine influences binding of dioxygen as well as carbon monoxide.
This interaction enhances the affinity of Fe(II) for O2 but destabilizes the binding of CO, which binds only 200 times stronger in haemoglobin, compared to 20,000 times stronger in free haem.
The tautomerism and acid-base properties of the imidazole side chain has been characterized by 15N NMR spectroscopy.
The two 15N chemical shifts are similar (about 200 ppm, relative to nitric acid on the sigma scale, on which increased shielding corresponds to increased chemical shift).
NMR spectral measurements shows that the chemical shift of N1-H drops slightly, whereas the chemical shift of N3-H drops considerably (about 190 vs. 145 ppm).
This change indicates that the N1-H tautomer is preferred, possibly due to hydrogen bonding to the neighboring ammonium.
The shielding at N3 is substantially reduced due to the second-order paramagnetic effect, which involves a symmetry-allowed interaction between the nitrogen lone pair and the excited π* states of the aromatic ring.
At pH > 9, the chemical shifts of N1 and N3 are approximately 185 and 170 ppm.
Histidine forms complexes with many metal ions.
The imidazole sidechain of the histidine residue commonly serves as a ligand in metalloproteins.
One example is the axial base attached to Fe in myoglobin and hemoglobin.
Poly-histidine tags (of six or more consecutive H residues) are utilized for protein purification by binding to columns with nickel or cobalt, with micromolar affinity.
Natural poly-histidine peptides, found in the venom of the viper Atheris squamigera have been shown to bind Zn(2+), Ni(2+) and Cu(2+) and affect the function of venom metalloproteases.
Furthermore, histidine-rich low-complexity regions are found in metal-binding and especially nickel-cobalt binding proteins.
Histidine is an essential amino acid that is not synthesized de novo in humans.
Humans and other animals must ingest histidine or histidine-containing proteins.
The biosynthesis of histidine has been widely studied in prokaryotes such as E. coli.
Histidine synthesis in E. coli involves eight gene products (His1, 2, 3, 4, 5, 6, 7, and 8) and it occurs in ten steps.
This is possible because a single gene product has the ability to catalyze more than one reaction.
For example, as shown in the pathway, His4 catalyzes 4 different steps in the pathway.
Histidine is synthesized from phosphoribosyl pyrophosphate (PRPP), which is made from ribose-5-phosphate by ribose-phosphate diphosphokinase in the pentose phosphate pathway.
The first reaction of histidine biosynthesis is the condensation of PRPP and adenosine triphosphate (ATP) by the enzyme ATP-phosphoribosyl transferase.
ATP-phosphoribosyl transferase is indicated by His1 in the image.
His4 gene product then hydrolyzes the product of the condensation, phosphoribosyl-ATP, producing phosphoribosyl-AMP (PRAMP), which is an irreversible step.
His4 then catalyzes the formation of phosphoribosylformiminoAICAR-phosphate, which is then converted to phosphoribulosylformimino-AICAR-P by the His6 gene product.
His7 splits phosphoribulosylformimino-AICAR-P to form d-erythro-imidazole-glycerol-phosphate.
After, His3 forms imidazole acetol-phosphate releasing water.
His5 then makes l-histidinol-phosphate, which is then hydrolyzed by His2 making histidinol.
His4 catalyzes the oxidation of l-histidinol to form l-histidinal, an amino aldehyde.
In the last step, l-histidinal is converted to l-histidine.
Just like animals and microorganisms, plants need histidine for their growth and development.
Microorganisms and plants are similar in that they can synthesize histidine.
Both synthesize histidine from the biochemical intermediate phosphoribosyl pyrophosphate.
In general, the histidine biosynthesis is very similar in plants and microorganisms.
Regulation of biosynthesis
This pathway requires energy in order to occur therefore, the presence of ATP activates the first enzyme of the pathway, ATP-phosphoribosyl transferase (shown as His1 in the image on the right).
ATP-phosphoribosyl transferase is the rate determining enzyme, which is regulated through feedback inhibition meaning that it is inhibited in the presence of the product, histidine.
Histidine is one of the amino acids that can be converted to intermediates of the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle).
Histidine, along with other amino acids such as proline and arginine, takes part in deamination, a process in which its amino group is removed.
In prokaryotes, histidine is first converted to urocanate by histidase.
Then, urocanase converts urocanate to 4-imidazolone-5-propionate.
Imidazolonepropionase catalyzes the reaction to form formiminoglutamate (FIGLU) from 4-imidazolone-5-propionate.
The formimino group is transferred to tetrahydrofolate, and the remaining five carbons form glutamate.
Overall, these reactions result in the formation of glutamate and ammonia.
Glutamate can then be deaminated by glutamate dehydrogenase or transaminated to form α-ketoglutarate.
Conversion to other biologically active amines
The histidine amino acid is a precursor for histamine, an amine produced in the body necessary for inflammation.
The enzyme histidine ammonia-lyase converts histidine into ammonia and urocanic acid.
A deficiency in this enzyme is present in the rare metabolic disorder histidinemia, producing urocanic aciduria as a key diagnostic finding.
Histidine can be converted to 3-methylhistidine, which serves as a biomarker for skeletal muscle damage, by certain methyltransferase enzymes.
Histidine is also a precursor for carnosine biosynthesis, which is a dipeptide found in skeletal muscle.
In Actinobacteria and filamentous fungi, such as Neurospora crassa, histidine can be converted into the antioxidant ergothioneine.
White crystalline or crystalline powder,odorless,slightly bitter taste.
Melting and decomposition at about 277~288 ℃.
The imidazole and metal ions are easy to form complex salt.
Dissolve in water (4.3g/100ml, 25 ℃), very difficult to dissolve in ethanol, insoluble in ether.
Histidine is commonly used for its hydrochloride, because of minimal solubility and other reasons.
(1) nutritional supplements.
Histidine is the very important components of Amino acid infusion and comprehensive amino acid preparations.
Histidine can be used in the treatment of gastric ulcer, anemia, allergies and so on.
(2) Histidine is used for biochemical research, medicine for the treatment of gastric ulcer, anemia, allergies and so on.
(3) Histidine is used as amino acid drugs.
Histidine is the main components of amino acid infusion and amino acid preparations, for the treatment of gastric ulcer, anemia and angina, aortitis, heart failure and other cardiovascular system disorders.
Adverse reactions and contraindications: low toxicity, adult poisoning>64g/day, such as the injection of hydrochloric acid histidine with headache, flushing and heat.
(4) Histidine is used as a nutrient enhancer, the important component of amino acid infusion and amino acid preparations.
Histidine can be used for the treatment of gastric ulcer and biochemical researchment.
(5) Histidine is used for pharmaceutical raw materials and food additives.
(1) Histidine is eatracted from pig blood, bovine blood.
Pig blood is spraied drying and then obtained blood powder, 100kg pig blood have 18kg blood power.
Histidine is commonly used as its hydrochloride salt ([7048-02-4]).
The Histidine containing eluent was concentrated to the appearance of crystals, adjusted to pH 2.5 with hydrochloric acid, and immediately added with 2 times the amount of ethanol in the solution, standing, precipitating and filtering to obtain L-group ammonia Acid hydrochloride crude, after decolorization, recrystallization, drying in the finished product.
Histidine can also be extracted from hydrolysates of defatted soybeans.
There are two main production methods.
First one is direct fermentation, with carbon source of glucose and an inducible drug-resistant strain of corynebacterium glutamicum. Second one is protein hydrolysis.
The hydrolysis method is described in detail below.
Pig and cattle blood , pig hair or hoof were raw materials, hydrolyzed by acid , separated and purificated to get L-histidine.
Hydrolysis:50kg of pig blood powder and 4 times amout of 6mol/L HCl were put into a hydrolysis tank and heated at 110-120 ℃ for 24 hours.
Preparation of the dilution of the column: The hydrolysis solution of the previous step was concentrated under reduced pressure, distilled water was added again, and the acid was repeatedly distilled for 3-4 times until the distillate did not flow out of the hydrochloric acid.
Concentrated solution diluted with distilled water to 500L,adjusted pH to 3.5-4 with concentrated ammonia, plused 20% of the amount of blood powder activated carbon, heated, decolorizated and stirred at 90 ℃ for 6h.
Then filtered when it is hot, and take the filtrate standing overnight precipitate.
Filtering again, the filtrate was diluted with distilled water to 2.5% (according to the blood powder dosage), and adjusted to pH 2.5 with concentrated HCl, which was column dilution.
The column dilution was separated, washed with water and eluted.
Column is Ф300mm×2000 mm, PVC material, packed with 001 × 7 (732) strong acidic styrene cation exchange resin 1730mm, flow rate 1L/ min, stopping to upper column until the outflow of L histidine.
Washing with water 500L, flow rate 1.5L /min.
The pH 7.0-10.0 fraction was collected. After the collection, the resin was recoated for 15 min, and then regenerated with twice the amount of 1.5-2 mol/L HCl, the flow rate was 5-13 L/min.
After regeneration, Washing with water untill PH 4 or so, waiting for the next column.
Purification: Histidine acid eluent, removing ammonia with vacuum, concentrated to dry, and then dissolved with 40L distilled water, adjusted pH with 3-3.26 mol/L HCl, add 1kg activated carbon, heated and decolorizated at 90 ℃ for 30min.
The filtrate was concentrated in a thin film evaporator and allowed to stand for 48 hours to precipitate crystals.
The crystals were collected by filtration, washed with 95% ethanol and dried at 80 oC with vacuum for 4 hours to give Histidine hydrochloride.
(2) Dry flour and hydrochloric acid as raw material reflux for several hours, filtrated,washed and handled with activated carbon to get Histidine monohydrochloride crude, then purified to obtain the pure product.
(3) separated with ion exchange resin from the protein hydrolyzate of the basic amino acid.
Sample is accurately weighed about 105 rag, dried at 105 ℃ for 3h, then dissolved in 3ml formic acid and 50ml glacial acetic acid, and titrated with 0.1mol/L perchloric acid, and the end point was determined by potentiometric method.
At the same time a blank test and the necessary amendments should be made.
Per Ml0.1mol/L perchloric acid equates to 15.52mg Histidine (C6H9N3O2).
White, odorless crystals or crystalline powder having a slightly bitter taste.
Histidine is soluble in water, very slightly soluble in alcohol, and insoluble in ether.
Histidine melts with decomposition between about 277° and 288°C.
Histidine is an odorless powder with slightly bitter taste
White or almost white, crystalline powder or colourless crystals
Reported found in water bread, macaroni, egg noodles, corn flakes, corn grits, oatmeal, wheat bran, wheat flakes, shredded wheat, barley, brown rice, rye flour, whole grain wheat flour, buttermilk, blue cheese, cheddar cheese, cottage cheese, cream cheese, Parmesan cheese, bacon, cured ham, frankfurters, pork sausage, canned red kidney beans, canned sweet corn, canned peas, canned lima beans, canned potatoes, almonds, cashews, peanuts, dates, beef, lamb, veal, chicken, turkey and other natural sources.
Histidine is an essential amino acid for human development which the body cannot produce on its own. Histidine is one of the 22 proteinogenic amino acids.
Histidine precursor to histamine (H4365 00) and a component of carnosine.
ChEBI: The L-enantiomer of the amino acid histidine.
Histidine is grouped with the aromatic amino acids, but the metabolic route diverges at an early stage from the other members of the group.
Histidine is produced in C. glutamicum in a 10-step sequence starting from phosphoribosyl pyrophosphate.
Originally production titers of up to 10.5 g/L were reported, but this has since been increased by workers at Kyowa Hakko to 22.5 g/L.
In a parallel development, the fermentation of Histidine using E. coli has been reported by Ajinomoto, with titers up to 19.1 g/L.
Both the titer and the carbon yield for Histidine are lower than those reported for L-phenylalanine and L-tryptophan, and Histidine remains one of the more challenging amino acids to produce on an industrial scale.
A likely impurity is arginine.
S-Histidine is adsorbed from aqueous solution onto a Dowex 50-H+ ion-exchange resin, washed with 1.5M HCl (to remove other amino acids), then eluted with 4M HCl as the dihydrochloride.
This purified dihydrochloride (see below) is finally dissolved in water, the pH adjusted to 7.0, and the free zwitterionic base crystallises out on addition of EtOH.
Its solubility in H2O is 4.2% at 25o.
Use and Manufacturing
Medicine, feed additive, biochemical research, dietary supplement
Infusion solutions/diagnostic aids; raw material (peptide drugs)
Histidine is a nutritionally essential amino acid that is also a precursor for several hormones (e.g., thyrotropin-releasing hormone), and critical metabolites affecting renal function, neurotransmission, gastric secretion, and the immune system.
Its unique acid/base properties make it a versatile catalytic residue in many enzymes, as well as for those proteins and enzymes that coordinate metal ions.
Histidine is an amino acid. Amino acids are the building blocks of protein in our bodies.
People use histidine as medicine.
Some people take histidine by mouth for metabolic syndrome, diarrhea caused by cholera infection, rheumatoid arthritis, allergic diseases, ulcers, and anemia caused by kidney failure or kidney dialysis.
Uses & Effectiveness ?
Possibly Ineffective for
Anemia associated with kidney failure or kidney dialysis.
Taking histidine by mouth does not seem to treat anemia caused by kidney failure or kidney dialysis.
Taking histidine by mouth does not seem to treat rheumatoid arthritis.
Insufficient Evidence for Cholera.
Early research shows that drinking a rehydration solution containing histidine may slightly reduce the duration of diarrhea in people with cholera who are also receiving antibiotics.
Metabolic syndrome (increased risk for diabetes and heart disease). ).
Early research shows that taking histidine for 12 weeks decreases body mass index and insulin resistance in obese women with metabolic syndrome.
Histidine is an amino acid; amino acids are used to make proteins and enzymes in the body.
Histidine is sometimes referred to as a “semiessential amino acid” because it is nonessential in adults, but essential in the diet of infants and those with a kidney disorder called uremia.
Histidine is also called Histidine and a-amino-b-[4-imidazole]-propionic acid.
Function of Histidine
Histidine is used by the body to make specific hormones and metabolites that impact kidney function, transmission of nerves, stomach secretions, and the immune system.1
Histidine also has an impact on the repair and growth of tissue, making blood cells and helping to protect nerve cells.
Histidine is also used to make histamine in the body.1
A primary function of histidine in the body is to regulate and help metabolize (break down and use for energy) trace elements. These trace elements include:
Histidine also helps to form many different enzymes and compounds in the body.
In addition, histidine works to formulate a compound called metallothionein inside of the cells of the brain, liver, and kidneys; metallothionein protects the brain cells and requires histidine to be formed.
If a person’s body is toxic with heavy metals (such as mercury and lead), it may result in a depletion of adequate stores of histidine.
histidine, an amino acid obtainable by hydrolysis of many proteins.
A particularly rich source, hemoglobin (the oxygen-carrying pigment of red blood cells) yields about 8.5 percent by weight of histidine.
First isolated in 1896 from various proteins, histidine is one of several so-called essential amino acids for human beings; they cannot synthesize it and require dietary sources.
In microorganisms histidine is synthesized from the sugar ribose and the nucleotide adenosine triphosphate.
Histamine, a compound involved in the physiological processes associated with allergic reactions, is formed in the human body by decarboxylation of histidine.
Histidine is an amino acid. Amino acids are the building blocks of protein in our bodies.
People use histidine as medicine.
Histidine is used for rheumatoid arthritis, allergic diseases, ulcers, and anemia caused by kidney failure or kidney dialysis.
Histidine is registered under the REACH Regulation and is manufactured in and / or imported to the European Economic Area, at ≥ 10 to < 100 tonnes per annum.
Histidine is used by consumers, in articles, by professional workers (widespread uses), in formulation or re-packing, at industrial sites and in manufacturing.
Histidine is used in the following products: washing & cleaning products, adhesives and sealants, air care products, anti-freeze products, biocides (e.g. disinfectants, pest control products), coating products, fillers, putties, plasters, modelling clay, leather treatment products, lubricants and greases, perfumes and fragrances, polishes and waxes and cosmetics and personal care products.
Other release to the environment of Histidine is likely to occur from: indoor use (e.g. machine wash liquids/detergents, automotive care products, paints and coating or adhesives, fragrances and air fresheners), outdoor use as processing aid and indoor use in long-life materials with low release rate (e.g. flooring, furniture, toys, construction materials, curtains, foot-wear, leather products, paper and cardboard products, electronic equipment).
Article service life
Other release to the environment of Histidine is likely to occur from: indoor use as processing aid and indoor use in long-life materials with high release rate (e.g. release from fabrics, textiles during washing, removal of indoor paints).
Histidine is intended to be released from scented: clothes, paper products and CDs.
Widespread uses by professional workers
Histidine is used in the following products: washing & cleaning products, laboratory chemicals, adhesives and sealants, air care products, anti-freeze products, biocides (e.g. disinfectants, pest control products), coating products, fillers, putties, plasters, modelling clay, leather treatment products, lubricants and greases, photo-chemicals, polishes and waxes and cosmetics and personal care products.
Histidine is used in the following areas: health services and scientific research and development.
Histidine is used for the manufacture of: chemicals.
Other release to the environment of Histidine is likely to occur from: indoor use (e.g. machine wash liquids/detergents, automotive care products, paints and coating or adhesives, fragrances and air fresheners) and outdoor use as processing aid.
Formulation or re-packing
Histidine is used in the following products: pH regulators and water treatment products, laboratory chemicals and pharmaceuticals.
Release to the environment of Histidine can occur from industrial use: formulation of mixtures.
Uses at industrial sites
Histidine is used in the following products: laboratory chemicals, pharmaceuticals, cosmetics and personal care products, perfumes and fragrances and washing & cleaning products.
Histidine has an industrial use resulting in manufacture of another substance (use of intermediates).
Histidine is used in the following areas: formulation of mixtures and/or re-packaging, scientific research and development, health services and mining.
Histidine is used for the manufacture of: chemicals and electrical, electronic and optical equipment.
Release to the environment of Histidine can occur from industrial use: as an intermediate step in further manufacturing of another substance (use of intermediates), in the production of articles, in processing aids at industrial sites and as processing aid.
Release to the environment of Histidine can occur from industrial use: manufacturing of the substance.
USES & EFFECTIVENESS
Possibly Ineffective for...
Anemia associated with kidney failure or kidney dialysis.
Insufficient Evidence to Rate Effectiveness for...
Histidine has been used for the selection of transformed cells.
Histidine has also been used to study its effects on the formation of verteporfin cross-linked oligomers in cellular homogenates.
Histidine is an essential amino acid.
Histidine binds to metal ions and may aid in the transport of copper. Histidine is widely present at the active sites of enzymes.
Histidine also has a role in binding of heme groups, macromolecules and phosphate groups in the binding sites of proteins.
Precursor of histamine by action of histidine decarboxylase.
Since the actions of supplemental Histidine are unclear, any postulated mechanism is entirely speculative.
However, some facts are known about Histidine and some of its metabolites, such as histamine and trans-urocanic acid, which suggest that supplemental Histidine may one day be shown to have immunomodulatory and/or antioxidant activities.
Low free histidine has been found in the serum of some rheumatoid arthritis patients.
Serum concentrations of other amino acids have been found to be normal in these patients.
Histidine is an excellent chelating agent for such metals as copper, iron and zinc.
Copper and iron participate in a reaction (Fenton reaction) that generates potent reactive oxygen species that could be destructive to tissues, including joints.
Histidine is the obligate precursor of histamine, which is produced via the decarboxylation of the amino acid.
In experimental animals, tissue histamine levels increase as the amount of dietary Histidine increases.
Histidine is likely that this would be the case in humans as well.
Histamine is known to possess immunomodulatory and antioxidant activity.
Suppressor T cells have H2 receptors, and histamine activates them.
Promotion of suppressor T cell activity could be beneficial in rheumatoid arthritis.
Further, histamine has been shown to down-regulate the production of reactive oxygen species in phagocytic cells, such as monocytes, by binding to the H2 receptors on these cells.
Decreased reactive oxygen species production by phagocytes could play antioxidant, anti-inflammatory and immunomodulatory roles in such diseases as rheumatoid arthritis.
This latter mechanism is the rationale for the use of histamine itself in several clinical trials studying histamine for the treatment of certain types of cancer and viral diseases.
In these trials, down-regulation by histamine of reactive oxygen species formation appears to inhibHistidine the suppression of natural killer (NK) cells and cytotoxic T lymphocytes, allowing these cells to be more effective in attacking cancer cells and virally infected cells.
This amino acid is suitable for use in tissue culture systems requiring additives.
Histidine is a basic amino acid with side chains, which is an essential for the rapid growth
and health maintenance of animals.
The addition of Histidine is an essential when replacing animal protein sources in the feed, especially blood meal.
The imidazole group of Histidine accounts for a large part of the buffering capacity of tissues
and plasma proteins and is active in response to catalytic sites of numerous enzymes.
Histidine is an essential amino acid for synthesis of carnosine, homocarnosine and anserine
for maintaining physiological homeostasis (fatigue recovery, antioxidation) and palatability promoting.
In particular, there is a cataract prevention function by regulating osmotic pressure in salmon.
What Is Histidine?
Histidine is an essential amino acids.
Amino acids are are chemicals that are very important to life on Earth.
These chemicals are what creates proteins and enzymes that allow life on the planet to occur.
An amino acid has a very simple structure that is made up of an amino acid back bone and side group, or 'R' group.
The backbone of an amino acid is made up of an amine group or an -NH2 attached to a central carbon molecule followed by a carboxylic acid group, -COOH.
The amine and carboxylic acid groups can donate hydrogen molecules or oxygen and hydrogen molecules to bind to other amino acids.
The side chain, or R group, is located off of the central carbon and is essentially a finger print for every amino acid.
Each R group is unique to the amino acid that is forms.
Histidine (abbreviated as His or H) is one of the 20 most common natural amino acids present in proteins.
In the nutritional sense, in humans, histidine is considered an essential amino acid, but mostly only in children.
Its codons are CAU and CAC.
Imidazole was first synthesized by H. Debus in 1858, but various imidazole derivatives had been discovered as early as the 1840s.
His synthesis, as shown below, used glyoxal and formaldehyde in ammonia to form imidazole.
This synthesis, while producing relatively low yields, is still used for creating C-substituted imidazoles.
In one microwave modification the reactants are benzil, formaldehyde and ammonia 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 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 immediate 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 agent, such as platinum with alumina, must be present in the reaction for the imidazole to form.
The example below applies to imidazole when R=Hydrogen.
The (1,2) and (3,4) bonds can also be formed from N-substituted α-aminoketones and formamide and 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 which is able to give good yields for substituted imidazoles.
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 only give substantial yields 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.
Structure and properties
Imidazole is a 5-membered planar ring, which is soluble in water and polar solvents.
The compound has an aromatic sextet, which consists of one π electron from the =N- atom and one from each carbon atom, and two from the NH nitrogen.
Some resonance structures of imidazole are shown below.
Imidazole is a base and an excellent nucleophile.
Histidine reacts at the NH nitrogen, attacking alkylating and acylating compounds.
Histidine is not particularly susceptible to electrophilic attacks at the carbon atoms, and most of these reactions are substitutions that keep the aromaticity intact.
One can see from the resonance structure that the carbon-2 is the carbon most likely to have a nucleophile attack it, but in general nucleophilic substitutions are difficult with imidazole.
Biological significance and applications
Imidazole is incorporated into many important biological molecules.
The most obvious 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.
Histidine can be decarboxylated to histamine, which is also a common biological compound.
Histidine is a component of the toxin that causes urticaria, which is basically an allergic reaction.
The structures of both histidine and histamine are:
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 Ni 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 co-ordination, 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, which stimulates the central nervous system.
Histidine is present in the anticancer medication mercaptopurine, which combats leukemia by interfering with DNA activities.
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.
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 which 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 protonation or substitution at nitrogen of imidazole.
These salts have been used as ionic liquids and precursors to stable carbenes.
Salts where a deprotanated imidazole is an anion are also possible; these salts are known as imidazolide salts (for example, sodium imidazolide).
(2S)-2-Amino-3-(1H-imidazol-4-yl) Propanoic acid
1H-Imidazole-4-propanoic acid, alpha-amino-, (S)-
L-ALPHA-AMINO-4(OR 5)-IMIDAZOLE-PROPIONIC ACID
L-HIS = H-His-OH
L-HISTIDINE FREE BASE CELL CULTURE*TESTE D
L-HISTIDINE HYDROCHLORIDE HISTAMINE PREC URSOR
L-HISTIDINE-15N3 95 ATOM % 15N
L-HISTIDINE, REAGENTPLUS TM, >= 99%
L-Histidine, extra pure, USP, BP, Ph Eur
L-HISTIDINE BASE RESEARCH GRADE
L-Histidine (200 mg)
MultiPharM (TM) L-Histidine, USP, Ph Eur
L-Histidine, 98% 25GR
1448: PN: EP2071334 SEQID: 1532 claiMed protein
1448: PN: WO2009077864 SEQID: (S)-1H-IMidazole-4-alanine
PN: WO2009046220 SEQID: 343 claiMed sequence
Aldo-keto reductase family member B10
L-Histidine Vetec(TM) reagent grade, >=99%
DEVELOPER SOLUTION PHE
FIXING SOLUTION PHE
FEMA No. 3694
alpha-Amino-4(or 5)-imidazolepropionic acid
alpha-Amino-1H-imidazole-4-propionic acid, (S)-
1H-Imidazole-4-propanoic acid, alpha-amino-, (S)-
(2S)-2-amino-3-(1H-imidazol-4-yl)propanoic acid hydrochloride
L-Histidine, non-animal source
Imidazole C-4(5) deriv. 5
L-Histidine, p.a., 98.5%
L-Histidine, Cell Culture Reagent
L-Histidine, BioUltra, >=99.5% (NT)
L-Histidine, SAJ special grade, >=98.5%
L-Histidine, ReagentPlus(R), >=99% (TLC)
L-Histidine, Vetec(TM) reagent grade, >=99%
Histidine, European Pharmacopoeia (EP) Reference Standard
L-Histidine, United States Pharmacopeia (USP) Reference Standard
L-Histidine, Pharmaceutical Secondary Standard; Certified Reference Material
L-Histidine, cell culture tested, meets EP, USP testing specifications, from non-animal source
L-Histidine, PharmaGrade, Ajinomoto, EP, USP, manufactured under appropriate GMP controls for Pharma or Biopharmaceutical production, suitable for cell culture