Materials preparation to the practical classes
for the students of pharmaceutical faculty
LESSON № 18
Theme 25. Fivemember heterocyclic compounds with two heteroatoms (pyrazole, imidazole, thiazole, oxazole, isoxazole).
1.Fivemembered heterocycles connections are with two heteroatoms.
Azoles are five-membered ring aromatic heterocycles containing two nitrogens, one nitrogen and one oxygen, or one nitrogen and one sulfur. They may be considered as aza analogs of furan, pyrrole, and thiophene, in the same way that pyridine is an aza analog of benze.
From a molecular orbital standpoint, the azoles are similar to the simpler aromatic heterocycles. For example, in imidazole, each carboneand nitrogen may be considered to be spa hybridized. One nitrogen makes two sp²-sp² σ bonds to carbone and one sp²-s σ bonds to hydrogen. The other nitrogen has its lone pair in the third spa orbital. The π molecular orbital system is made up from the рz–orbitals from each ring atom. Six p electrons (one from each carbon and from one nitrogen, two from the other nitrogen) complete the aromatic shell.
The most important azoles are:
All the heterocycles listed above are aromatic. The common heterocylic fragment of all these heterocycles is a nitrogen of the pyridine type. Such nitrogen atom donates only one electron in a p-orbital to form the aromatic π-electron system (sextet). The pyridine-type nitrogen lone-pair electrons are in sp2-orbital, which is in the same plane with the heterocyclic ring. The second heteroatom donates the lone pair of electrons to the aromatic sextet; its lone pair electrons are in the p-orbital. Thus, the contribution of each heteroatom to the aromatic π-electron system is different.
Azoles have high melting and boiling points, they are freely soluble in polar solvents, but poorly soluble ion-polar solvents. Let us consider some specific properties of azoles.
1. Acid-base properties. Azoles are weak bases due to the lone pair electrons of the pyridine-type nitrogen. They form salts with mineral acids. For example:
The addition of a proton to an azole molecule do not affect the aromaticity of heterocycle, so the cation formed is aromatic. A positive charge of the cation is delocalized over the whole cycle. This fact explains why azoles are not acidophobic, as well as their high stability for oxidation with strong mineral acids.
Besides of their basic properties pyrazole and imidazole are weak acids. Therefore, pyrazole and imidazole are amphoteric compounds, which may react with both acids and alkalis to form salts. For example:
Imidazole reacts similarly to pyrazole.
2. Azole tautomerism. Azole tautomerism is a type of prototropic tautomerism where a proton can occupy two or more positions of a heterocyclic system. Such tautomerism type is common for azoles (pyrazole and imidazole), therefore, it is also called azole tautomerism. Such tautomerism type refers to the relocation of NH-proton to the pyridine- type nitrogen and may be considered a subset of acid-base behaviour.
The migration of proton is so rapid that it is impossible to distinguish its position in the molecule of a diazole.
Azole tautomerism makes positions 3 and 5 of pyrazole similar- while 3-methylpyrazole and 5-methylpyrazole are just tautomeric forms of the same compound.
In the case of imidazole positions 4 and 5 are equal.
In the solution equilibrium is established so rapidly that the separate tautomers cannot be isolated. That is why such compounds are named 3(5)-methylpyrazole and 4(5)-methylimidazole.
2. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of imidazole. Histamine. Histidine.Benzimidazole.
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Imidazole (1,3-diazole) is a colourless crystalline substance, its melting point is 91 oC and its boiling point is 256 oC; it is soluble in water, alcohol and ether.
Imidazole is a organic compound with the formula C3H4N2. This aromatic heterocyclic is classified as an alkaloid. Imidazole refers to the parent compound whereas imidazoles are a class of heterocycles with similar ring structure but varying substituents.
Discovery
Imidazole was first synthesized by Heinrich 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 benzyl, formaldehyde and ammonia in glacial acetic acid forming 2,4,5-triphenylimidazole (Lophine).
Preparation
Imidazole is prepared by the condensation of glyoxal, ammonia and formaldehyde.
A ball-and-stick model of imidazole, showing carbon-carbon and a carbon-nitrogen double bonds.
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 catalyst, such as platinum on alumina, is required.
The (1,2) and (3,4) bonds can also be formed from N-substituted α–aminoketones and formamide 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. It is essentially an adaptation of the Debus method. 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
Structure and properties
Imidazole is a 5-membered planar ring, which is soluble in water and other polar solvents. It exists in two equivalent tautomeric forms because the hydrogen atom can be located on either of the two nitrogen atoms. The compound is classified as aromatic due to the presence of a sextet of π-electrons, consisting of a pair of electrons from the protonated nitrogen atom and one from each of the remaining four atoms of the ring.
Some resonance structures of imidazole are shown below:
Chemical properties
Imidazole undergoes similar to pyrazole reactions. Imidazole is an amphoteric compound (i.e. it can function as both an acid and as a base).
Alkyltion and acylation of imidazole occurs at the pyridine-type nitrogen atom. The quaternary salts that are formed initially usually undergo rapid deprotonation to N-alkylimidazoles.
Nitration and sulphonation of imidazole occur at position 4 and require forced conditions because the reactions take place in the acidic medium with the formation of an imidazolum cation, which is inactive for the attack of electrophile.
Imidazole is readily brominated to tribromoimidazole with bromine in water or chloroform.
Imidazole is stable towards oxidation and reduction. However, it undergoes the ring destruction by H202 to form oxamide.
Biological significance and applications
Imidazole is incorporated into many important biological molecules. The most pervasive is the amino acid histidine, which has an imidazole side chain. Histidine is present in many proteins and enzymes and plays a vital part in the structure and binding functions of hemoglobin. Histidine can be decarboxylated to histamine, which is also a common biological compound. It is a component of the toxin that causes urticaria, which is another name for allergic hives. The relationship between histidine and histamine are shown below:
One of the applications of imidazole is in the purification of His-tagged proteins in immobilised metal affinity chromatography(IMAC). Imidazole is used to elute tagged proteins bound to 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. It is present in the anticancer medication mercaptopurine, which combats leukemia by interfering with DNA activities.
Industrial applications
Imidazole has been used extensively as a corrosion inhibitor on certain transition metals, such as copper. Preventing copper corrosion is important, especially in aqueous systems, where the conductivity of the copper decreases due to corrosion. Many compounds of industrial and technological importance contain imidazole derivatives. The thermostable polybenzimidazole PBI contains imidazole fused to a benzene ring and linked to a benzene, and acts as a fire retardant. Imidazole can also be found in various compounds 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).
Histidine
Histidine is an amino acid that is used to develop and maintain healthy tissues in all parts of the body, particularly the myelin sheaths that coat nerve cells and ensure the transmission of messages from the brain to various parts of the body. It may be useful for treatment of mental disorders as well as certain types of sexual dysfunction. Histidine levels in the body must be balanced to ensure good mental and physical health. High levels of this amino acid have been linked to the presence of psychological disorders such as anxiety and schizophrenia, while low levels of histidine are thought contribute to the development of rheumatoid arthritis and the type of deafness that results from nerve damage. Taking histidine supplements may help relieve symptoms of rheumatoid arthritis. Histidine is important to normal sexual functioning, because it gets converted into histamine, a chemical needed to stimulate sexual arousal. When taken together with vitamin B3 (niacin) and vitamin B6 (pyridoxine), histidine can increase sexual pleasure by boosting histamine levels in the body. Histamine is also needed to help the immune system know when the body is experiencing an allergic reaction, and for the production of gastric juices needed for normal digestion. Research suggests that hsitidine also acts as a natural detoxifier, protecting against radiation damage, and removing heavy metals from the system. It may even help prevent the onset of AIDS—histidine is crucial to the production of both red and white blood cells. Like other amino acids, histidine is found in many high-protein foods, such as meat and dairy products, as well as grains such as rice, wheat, and rye. It is not certain if histidine is an essential or non-essential amino acid—most health experts agree that, although the body manufactures its own histidine, it is fairly easy for natural supplies to run short. The chronically ill, post-surgery, or arthritic individual may wish to consider supplementation with this amino acid. Histidine is available in both capsule and powder forms, as well as in combination amino acid formulas. Because it has a proven effect on the central nervous system and histamine production, people with manic (bipolar) depression should not take supplemental histidine without first consulting their physician. Anyone with liver or kidney disorders should not take histidine without first consulting with a licensed health care provider. Taking any one amino acid supplement may cause levels of nitrogen in the body to become imbalanced, as well as disrupt the Krebs cycle by which toxins are eliminated from the liver and kidneys.
Chemical properties
The imidazole sidechain of histidine has a pKa of approximately 6.0, and, overall, the amino acid has a pKa of 6.5. This means that, at physiologically relevant pH values, relatively small shifts in pH will change its average charge. Below a pH of 6, the imidazole ring is mostly protonated as described by the Henderson–Hasselbalch equation. When protonated, the imidazole 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.
Aromaticity
The imidazole ring of histidine is aromatic at all pH values. It contains six pi electrons: four from two double bonds and two from a nitrogen lone pair. It can form pi stacking interactions, but is complicated by the positive charge. It does not absorb at 280 nm in either state, but does in the lower UV range more than some amino acids.
Biochemistry
The imidazole sidechain of histidine is a common coordinating ligand in metalloproteins and is a part of catalytic sites in certain enzymes. In catalytic triads, the basic nitrogen of histidine is used to abstract 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, it 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. Histidine is also important in haemoglobin in helices E and F. Histidine assists in stabilising oxyhaemoglobin and destabilising CO-bound haemoglobin. As a result, carbon monoxide binding is only 200 times stronger in haemoglobin, compared to 20,000 times stronger in free haem.
Metabolism
Histamine forms colorless hygroscopic crystals that melt at
Tautomers of histamine
Histamine has two basic centres, namely the aliphatic amino group and whichever nitrogen atom of the imidazole ring does not already have a proton. Under physiological conditions, the aliphatic amino group will be protonated, whereas the second nitrogen of the imidazole ring will not be protonated. Thus, histamine is normally protonated to a singly-charged cation. Istidine was first isolated by German physician Albrecht Kossel in 1896.
Synthesis and metabolism
Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic vasoactive amine.
Conversion of histidine to histamine by histidine decarboxylase
Once formed, histamine is either stored or rapidly inactivated. Histamine released into the synapses is broken down by acetaldehyde dehydrogenase. It is the deficiency of this enzyme that triggers an allergic reaction as histamines pool in the synapses. Histamine is broken down by histamine-N-methyltransferase and diamine oxidase. Some forms of foodborne disease, so-called “food poisonings,” are due to conversion of histidine into histamine in spoiled food, such as fish. The most important pathophysiologic mechanism of mast cell and basophil histamine release is immunologic. These cells, if sensitized by IgE antibodies attached to their membranes, degranulate when exposed to the appropriate antigen. Certain amines and alkaloids, including such drugs as morphine, and curare alkaloids, can displace histamine in granules and cause its release. Antibiotics like polymyxin are also found to be stimulating histamine release.
Benzimidazole
Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene and imidazole. The most prominent benzimidazole compound iature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. Benzimidazole, in an extension of the well-elaborated imidazole system, has been used as carbon skeletons for N-heterocyclic carbenes. The NHCs are usually used as ligands for transition metal complexes. They are often prepared by deprotonating an N,N’–disubstituted benzimidazolium salt at the 2-position with a base.
Preparation
Benzimidazole and its derivatives are obtained by the reaction of o-phenylenediamine with carboxylic acids.
Benzimidazole is commercially available. The usual synthesis involves condensation of o-phenylenediamine with formic acid, or the equivalent trimethyl orthoformate:
C6H4(NH2)2 + HC(OCH3)3 → C6H4N(NH)CH + 3 CH3OH
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Benzimidazole |
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IUPAC name |
1H-benzimidazole |
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Properties |
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Molecular formula |
C7H6N2 |
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Molar mass |
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Melting point |
170–172 °C |
Chemical properties of benzimidazole are similar to imidazole. Benzimidazole is an amphoteric compound; it may undergo alkyla– tion of the pyridine-type nitrogen; azole tautomerism is possible for it. Benzimidazole undergoes electrophilic substitution of a hydrogen atom in position 5 of the benzene ring.
Spasmolytic drug dibazol is a derivative of benzimidazole. It is obtained by the reaction of o-phenylenediamine with phenylacetic acid.
Dibazol (bendazol) possesses a direct myotropic (papaverine-like action with a vasodilating, spasmolytic and hypotensive effect.
Submitted by E. C. Wagner and W. H. Millett.
Benzimidazoles are a large chemical family used to treat nematode and trematode infections in domestic animals. However, with the widespread development of resistance and the availability of more efficient and easier to administer compounds, their use is rapidly decreasing. They are characterized by a broad spectrum of activity against roundworms (nematodes), an ovicidal effect, and a wide safety margin. Those of interest are mebendazole, flubendazole, fenbendazole, oxfendazole, oxibendazole, albendazole, albendazole sulfoxide, thiabendazole, thiophanate, febantel, netobimin, and triclabendazole. Netobimin, albendazole, and triclabendazole are also active against liver flukes; however, unlike all the other benzimidazoles, triclabendazole has no activity against roundworms.
3. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of pyrazole. Analhine.
Pyrazole (1,2-diazole) is a crystalline substance with pyridine-like odour, melting at 70 °C; its boiling point is 87 °C. Pyrazole is freely soluble in water, soluble in alcohols, ether and benzene.
Pyrazole refers both to the class of simple aromatic ring organic compounds of the heterocyclic 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. Being so composed and having pharmacological effects on humans, they are classified as alkaloids, although they are rare iature.
Methods of preparation.
1. Cycloaddition of diazoalkanes to alkynes. This reaction is used for pyrazole and its derivatives synthesis. Diazomethane reacts with acetylene to give pyrazole.
2. Cyclocondensation of hydrazine, and alkyl- or arylhydrazines with 1 3-dicarbonyl compounds. This method is often used for synthesis of pyrazole homologues. The reaction of hydrazine with acetylacetone results in 3,5-dimethylpyrazole.
3. Pyrazoles are produced synthetically through the reaction of α,β-unsaturated aldehydes with hydrazine and subsequent dehydrogenation.
Chemical properties.
1. Acid-base properties. Pyrazole is an amphoteric compound because of two different nitrogen atoms in its structure (pyrrole– and pyridine-type nitrogen atoms).
Pyridine-type nitrogen makes pyrazole basic, while the pyrrole-type nitrogen makes it acidic.
2. Electrophilic substitution reactions. The direction of electrophilic substitution reactions for pyrazole depends much upon the electrophile and the conditions. Alkylation and acylation of pyrazole produces N-substituted pyrazoles. The reaction of pyrazole with methyl iodide in the neutral or basic media results in N-methylpyrazole.
Electrophilic substitution on the carbon atom proceeds only with the strong electrophiles (nitration, sulphonation, halogenation).
Electrophilic substitution on the C-atoms of pyrazole proceeds more slowly than for furan, pyrrole and thiophene because nitrogen of the pyridine type decreases the reactivity of pyrazole. Substitution occurs at position 4 (the most distant from nitrogen atoms).
Since pyrazole is not acidophobic, it may be nitrated and sulphonated with the concentrated nitric and sulphuric acids. The intermediate of both reactions is the pyrazolium cation, which is rather inactive for elec– trophile attack. This complicates nitration and sulphonation of pyrazole.
Pyrazole readily undergoes halogenation.
3. Reduction reactions. Depending upon the conditions reduction 0f pyrazole may produce either partially hydrogenated 2-pyrazoline or pvrazolidine — the product of complete hydrogenation.
Pyrazoles react with potassium borohydride to form a class of ligands known as Scorpionates. Structurally related compounds are pyrazoline and pyrazolidine.
Pyrazole derivatives
The most important pyrazole derivative is 5-pyrazolone, which is the core structure of a number of drugs. 5-Pyrazolone may exist in CHr, OH- and NH-tautomeric forms.
The preferable form of 5-pyrazolone is CH2-form.
The most important derivative of 5-pyrazolone is 3-methyl-l-phenyl- 5-pyrazolone, which is an intermediate for synthesis of analgesics and antipyretics, such as antipyrine (phenazone), amidopyrine, and analgin (metamizole sodium).
3-Methyl-l-phenyl-5-pyrazolone was first obtained by the German chemist Ludwig Knorr in 1883 by the reaction of acetoacetic ester with phenylhydrazine.
3-Methyl-l-phenyl-5-pyrazolone also exists in three tautomeric forms.
Antipyrine is obtained by methylation of 3-methyl-l-phenyls-pyrazolone (it is NH-form).
Antipyrine is an antipyretic (antifever) drug.
Amidopyrine. Hydrogen atom in the antipyrine CH-group is very acidic, due to the influence of the neighboring CO-group. This hydrogen atom is easily substituted with other atoms or atomic groups.
Amidopyrine is produced by the following scheme: first 4-nitroso- antipyrine is obtained by the reaction of antipyrine with sodium nitrite in the presence of HC1; then 4-nitrosoantipyrine is reduced to 4-aminoantipyrine, which is further alkylated with methyl iodide.
4-Nitrosoantipyrine is a compound of an emerald-green colour; its formation is a test reaction for antipyrine. Analgin is the derivative of antipyrine.
Heterocycle formation from 1,3-dinitroalkanes. A novel pyrazole synthesis
Aliphatic nitro compounds have proved to be useful starting materials in organic synthesis. When the nitro compounds are properly substituted they can cyclize, yielding heterocyclic compounds. 1,3-Dinitroalkanes can be viewed as synthetic equivalents for 1,3-dicarbonyl compounds through a Nef, or equivalent, reaction, and therefore could be ultimately converted into azole heterocycles. Application of the Nef reaction under the usual conditions (NaOH; conc. H2SO4) to 1,3-dinitroalknes gives only trace amounts of the anticipated dione, although the yields can be increased (up to 40%) using a secondary amine as the base. We now find that 1,3-dinitroalkanes react with hydrazines giving rise to pyrazoles.The title compounds are five-membered heterocycles having two adjacent nitrogen atoms within the ring. Pyrazoles have two endocyclic bonds and possess aromatic and tautomeric properties. Pyrazolones also have two double bonds, one of which is attached to an exocyclic oxygen atom. Pyrazolines have only one endocyclic double bond. The structural elucidation of pyrazoles and derivatives has been greatly aided by nuclear magnetic resonance spectroscopy, especially for distinguishing between isomeric structures. Pyrazoles are stable compounds and their boiling points increase with an increase in the number of alkyl groups on carbon; solubility in organic solvents is also increased. Substitution on nitrogen decreases the boiling point because of the elimination of hydrogen bonding. Pyrazolines are usually liquids having high boiling points and low water solubility, and are basic iature. Pyrazolones are often crystalline solids and their characteristics are strongly influenced by the predominant tautomeric form. Pyrazoles can react with both acids and bases, and can be halogenated, nitrated, and acylated on both N and C. Pyrazolines are much less stable, resulting in facile ring opening. Pyrazolones react with diazonium salts, an important process in the dye industry. The preferred synthetic method for the title compounds utilizes the reaction of hydrazines with bifunctional compounds, such as β–diketones and esters, and β–keto acetylenic compounds. In an alternative procedure, diazo compounds replace hydrazines and ring formation takes place via 1,3-dipolar cycloaddition. Pyrazoles and pyrazolones are widely used in the pharmaceutical industry to alleviate inflammation, fever, pain, and infections. To a lesser extent, they are also used as insecticides and herbicides. Pyrazolones linked to azo compounds are extensively used in the dye industry; some pyrazolines display insecticidal activity. In medicine, pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.
4. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of oxazole. Isoxazole.
Oxazole and isoxazole are colourless liquids boiling at 69 °C and 95 °C, respectively. Oxazole and isoxazole are aromatic. Electrophilic aromatic substitution reactions occur predominantly at position 4. Both heterocycles are weak bases.
Isoxazole is a parent structure of cycloserine, which is an antituberculosis drug.
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.
Preparation
Classical oxazole synthetic methods in organic chemistry are
- the Robinson-Gabriel synthesis by dehydration of 2-acylaminoketones
- the Fischer oxazole synthesis from cyanohydrins and aldehydes
- the Bredereck reaction with α–haloketones and formamide
- In one reported oxazole synthesis the reactants are a nitro-substituted benzoyl chloride and an isonitrile
The Fischer oxazole synthesis is a chemical synthesis of the aromatic heterocycle oxazole from cyanohydrins and aldehydes in the presence of anhydrous hydrochloric acid. This method was discovered by Hermann Emil Fischer in 1896.
Biosynthesis
In biomolecules, oxazoles result from the cyclization and oxidation of serine or threonine nonribosomal peptides:
Where X = H, CH3 for serine and threonine respectively, B = base.
(1) Enzymatic cyclization. (2) Elimination. (3) [O] = enzymatic oxidation.
Reactions
- Deprotonation of oxazoles at C2 is often accompanied by ring-opening to the isonitrile.
- Electrophilic aromatic substitution takes place at C5 requiring activating groups.
- Nucleophilic aromatic substitution takes place with leaving groups at C2.
- Diels-Alder reactions with oxazole dienes can be followed by loss of oxygen to form pyridines.
- The Cornforth Rearrangement of 4-acyloxazoles is a thermal rearrangement reaction with the organic acyl residue and the C5 substituent changing positions.
- Various oxidation reactions. One study] reports on the oxidation of 4,5-diphenyloxazole with 3 equivalents of CAN to the formamide and benzoic acid:
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Isoxazole |
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IUPAC name |
isoxazole |
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Properties |
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Molecular formula |
C3H3NO |
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Molar mass |
69.06202 |
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Density |
1.075 g/ml |
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Boiling point |
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Isoxazole is an azole with an oxygen atom next to the nitrogen. Isoxazoles are found in some natural products, such as ibotenic acid. Isoxazoles also form the basis for a number of drugs, including the COX-2 inhibitor valdecoxib (Bextra). Furoxan is a nitric oxide donor.
Structure, classification, nomenclature, izomery, methods of getting and chemical properties of thiazole. Thiamine. Isothiazole.
Thiazole (1,3-thiazole) is a colourless liquid with an unpleasant odour its boiling point is 117°C. It contains two different heteroatoms: sulphur and nitrogen.
Thiazole, or 1,3-thiazole, is a clear to pale yellow flammable liquid with a pyridine-like odor and the molecular formula C3H3NS. It is a 5-membered ring, in which two of the vertices of the ring are nitrogen and sulfur, and the other three are carbons . Thiazole is used for manufacturing biocides, fungicides, pharmaceuticals, and dyes. Thiazoles are a class of organic compounds related to azoles with a common thiazole functional group. Thiazoles are aromatic. The thiazole moiety is a crucial part of vitamin B1 (thiamine) and epothilone. Other important thiazoles are benzothiazoles, for example, the firefly chemical luciferin. Thiazoles are structurally similar to imidazoles. Like imidazoles, thiazoles have been used to give N-S free carbenes nd transition metal carbene complexes.
Structure of thiazoles (left) and thiazolium salts (right)
Preparation
The main method for thiazole preparation is cyclocondensation of a-halocarbonyl compounds with thioamides (the Hantzsch synthesis)
The reaction of thioformamide with chloroacetic aldehyde results in thiazole.
Various laboratory methods exist for the organic synthesis of thiazoles.
· The Hantzsch thiazole synthesis (1889) is a reaction between haloketones and thioamides. For example, 2,4-dimethylthiazole is synthesized from acetamide, phosphorus pentasulfide, and chloroacetone. Another example is given below:
- In an adaptation of the Robinson-Gabriel synthesis, a 2-acylamino-ketones reacts with phosphorus pentasulfide.
- In the Cook-Heilbron synthesis, an α–aminonitrile reacts with carbon disulfide.
- Certain thiazoles can be accessed though application of the Herz reaction.
Chemical properties
Thiazoles are characterized by larger pi-electron delocalization than the corresponding oxazoles and have therefore greater aromaticity. This is evidenced by the position of the ring protons in proton NMR (between 7.27 and 8.77 ppm), clearly indicating a strong diamagnetic ring current.
Due to the presence of the pyridine-type nitrogen thiazole is basic (reacts with HCl). The nitrogen atom of thiazole undergoes alkylation. Electrophilic substitution reactions occur at position 5 of thiazole ring while nucleophilic substitution reactions occur at position 2. Thiazole is stable towards oxidation and reduction.
The calculated pi-electron density marks C5 as the primary electrophilic site, and C2 as the nucleophilic site.
The reactivity of a thiazole can be summarized as follows:
- Deprotonation at C2: the negative charge on this position is stabilized as an ylide; Grignard reagents and organolithium compounds react at this site, replacing the proton
2-(trimethylsiliyl)thiazole (with a trimethylsilyl group in the 2-position) is a stable substitute and reacts with a range of electrophiles such as aldehydes, acyl halides, and ketenes
- Alkylation at nitrogen forms a thiazolium salt
- Electrophilic aromatic substitution at C5 requires activating groups such as a methyl group in this bromination:
- Nucleophilic aromatic substitution often requires an electrofuge at C2, such as chlorine with
- Organic oxidation at nitrogen gives the thiazole N-oxide; many oxidizing agents exist, such as mCPBA; a novel one is hypofluorous acid prepared from fluorine and water in acetonitrile; some of the oxidation takes place at sulfur, leading to a sulfoxide :
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Thiazole derivatives
2-Aminothiazole is of the great importance as the intermediate for synthesis of drugs.
2-Aminothaiazole is more basic than thiazole. The basic centre in the molecule of 2-aminothiazole is a heterocyclic nitrogen, since the lone pair of the NH2-group is conjugated with the aromatic system of thiazole.
Alkylation of 2-aminothiazole occurs at the heterocyclic nitrogen, while acylation takes place on the amino-group. 2-Aminothiazole also undergoes the diazotization reaction.
Antimicrobial drugs sulfanilamides, such as norsulfazole (sulfatiazole) and phthalazole, contain thiazole moiety.
Thiamin or thiamine, also known as vitamin B1 and aneurine hydrochloride, is the term for a family of molecules sharing a common structural feature responsible for its activity as a vitamin. It is one of the B vitamins. Its most common form is a colorless chemical compound with a chemical formula C12H17N4OS. This form of thiamin is soluble in water, methanol, and glycerol and practically insoluble in acetone, ether, chloroform, and benzene. Another form of thiamin known as TTFD has different solubility properties and belongs to a family of molecules often referred to as fat-soluble thiamins. Thiamin decomposes if heated. Its chemical structure contains a pyrimidine ring and a thiazole ring. Thiamin is one of only four nutrients associated with a pandemic human deficiency disease. It is essential for neural function and carbohydrate metabolism. Thiamin deficiency results in beriberi, a disease characterized by a bewildering variety of symptoms. Common symptoms often involve the nervous system and the heart. In less severe deficiency, nonspecific signs include malaise, weight loss, irritability and confusion.
Isothiazole
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IUPAC name |
Isothiazole |
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Other names |
1,2-thiazole |
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Properties |
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Molecular formula |
C3H3NS |
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Molar mass |
85.13 g/mol |
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Boiling point |
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An isothiazole is a type of organic compound containing a five-membered aromatic ring that consists of three carbon atoms, one nitrogen atom, and one sulfur atom. Isothiazole is a member of a class of compounds known as azoles. In contrast to the isomeric thiazole, the two heteroatoms are in adjacent positions. The ring structure of isothiazole is incorporated into larger compounds with biological activity such as the pharmaceutical drugs ziprasidone and perosiprone.
Supplement 1.
Pyrazole |
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Supplement 2.
Oxazole |
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Supplement 3.
Isoxazole |
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Supplement 4
Thiazole |
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