Rajah
Serfoji Govt. College (Autonomous),
Thanjavur – 613 005
M.Sc., Chemistry SEMESTER – III Thanjavur – 613 005
Organic Chemistry - III Code: R3PCH6
UNIT - V Heterocyclics
Ø
A heterocyclic compound is a cyclic compound that
has atoms of at least two different elements as
members of its ring(s). The
counterparts of heterocyclic compounds are homocyclic compounds, the rings of which
are made of a single element.
Ø
Although
heterocyclic compounds may
be inorganic, most contain at least one carbon. Since in organic chemistry non-carbons
usually are considered to replace carbon atoms, they are called heteroatoms, meaning 'different
from carbon and hydrogen' (rings of heteroatoms of the same element are
homocyclic). The IUPAC recommends the Hantzsch-Widman nomenclature for naming heterocyclic compounds.
Ø
Heterocyclic
chemistry is the branch of
chemistry dealing with synthesis, properties, and applications of heterocycles
Pyrazole
Pyrazole is the organic compound with the formula C3H3N2H. It is a heterocycle characterized by a 5-membered ring of
three carbonatoms
and two adjacent nitrogen centres. Pyrazoles are also the class of compounds
that have the ring C3N2 with adjacent nitrogen centres.[1] A notable drug containing a pyrazole
ring is Celebrex.
uses
In medicine,
derivatives of pyrazoles are used for their analgesic, anti-inflammatory,
antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic
and antibacterial activities.
Pyrazoles are synthesized by the reaction of
α,β-unsaturated aldehydes with hydrazine and
subsequent dehydrogenation
Substituted pyrazoles are prepared by condensation of
1,3-diketones with
hydrazine. For example, acetylacetone and hydrazine gives
3,5-dimethylpyrazole:
CH3C(O)CH2C(O)CH3 +
N2H4 →
(CH3)2C3HN2H
+ 2 H2O
Imidazole
Imidazole is an organic compound with
the formula (CH)2N(NH)CH. It is a colourless solid that dissolves in
water to give mildly alkaline solution. In chemistry, it is an aromatic heterocycle,
classified as a diazole and
as an alkaloid.
Derivatives of
imidazole, called imidazoles, form a common family of heterocycles that share
the 1,3-C3N2 ring but feature varied substituents. This ring system is present
in important biological building-blocks, such as histidine,
and the related hormone histamine. Many drugs contain
an imidazole ring, such as antifungal drugs, nitroimidazole,
and the sedative midazolam.
Structure and properties
o
Imidazole is a
planar 5-membered ring. It exists in two equivalent tautomeric forms, because
the proton can be located on either of the two nitrogen atoms. Imidazole is a
highly polar compound, as evidenced by a calculated dipole of 3.61D. It is
highly soluble in water. 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:
Amphoterism
o Imidazole is amphoteric. That is, it can function as both an acid and as a base. As an acid, the pKa of imidazole is 14.5, making it less acidic than carboxylic acids, phenols, and imides, but slightly more acidic than alcohols. The acidic proton is located on N-1. As a base, the pKa of the conjugate acid (cited above as pKBH+ to avoid confusion between the two) is approximately 7, making imidazole approximately sixty times more basic than pyridine. The basic site is N-3. Protonation gives the imidazolium cation, which is symmetrical.
Biological significance and applications
o 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. Imidazole-based histidine compounds play a very
important role in intracellular buffering. 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.
o
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.
o
Imidazole has
become an important part of many pharmaceuticals. Synthetic imidazoles are
present in many fungicides and antifungal, antiprotozoal, and antihypertensivemedications.
Imidazole is part of the theophylline molecule,
found in tea leaves and coffee beans, that stimulates the central nervous system. It is present in the anticancer medication mercaptopurine,
which combats leukemia by interfering with DNA activities.
o
A number of
substituted imidazoles, including clotrimazole,
are selective inhibitors of nitric oxide synthase, which makes them interesting drug targets in inflammation, neurodegenerative
diseases and tumors of the nervous system. Other biological activities of the
imidazole pharmacophore relate to the downregulation of
intracellular Ca++ and K+ fluxes, and interference with translation initiation
Industrial applications
v
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.
v
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 that are used for photography and electronics.
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. Oxazole is a weak base; itsconjugate
acid has a pKa of 0.8, compared
to 7 for imidazole.
oxazole
synthetic methods
the Bredereck reaction with α-haloketones and formamide
Oxazolines
can also be obtained from cycloisomerization of certain propargyl amides.
In one study oxazoles were prepared via aone-pot synthesis consisting of the condensation of propargyl amine and benzoyl chloride to the amide,
followed by aSonogashira
coupling of
the terminal alkyne end with another equivalent of
benzoylchloride, and concluding with p-toluenesulfonic acid catalyzed cycloisomerization:
Biosynthesis
In biomolecules,
oxazoles result from the cyclization and oxidation of serine or threonine nonribosomal peptides:
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. The thiazole ring is notable as a
component of the vitamin thiamine.
Synthesis
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.
In
an adaptation of the Robinson-Gabriel
synthesis, a 2-acylamino-ketones
reacts with phosphorus
pentasulfide.
Certain
thiazoles can be accessed through application of the Herz
reaction.
Several biosynthesis routes lead to the
thiazole ring as required for the formation of thiamine. Sulfur of the
thiazole is derived from cysteine. In anaerobic bacteria, the CN group is
derived from dehydroglycine.
Reactions
§
Deprotonation at C2: the negative charge on
this position is stabilized as an ylide; Hauser bases 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, acylhalides,
and ketenes.
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. The thiazole ring is notable as a
component of the vitamin thiamine.
Synthesis
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.
In
an adaptation of the Robinson-Gabriel
synthesis, a 2-acylamino-ketones
reacts with phosphorus
pentasulfide.
Certain
thiazoles can be accessed through application of the Herz
reaction.
Several biosynthesis routes lead to the
thiazole ring as required for the formation of thiamine. Sulfur of the
thiazole is derived from cysteine. In anaerobic bacteria, the CN group is
derived from dehydroglycine.
Reactions
§
Deprotonation at C2: the negative charge on
this position is stabilized as an ylide; Hauser bases 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, acylhalides,
and ketenes.
§ Electrophilic aromatic substitution at C5 requires activating
groups such as a methyl group in this bromination:
§ Electrophilic aromatic substitution at C5 requires activating
groups such as a methyl group in this bromination:
§
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 inacetonitrile;
some of the oxidation takes place at sulfur, leading to sulfoxide/sulfone.
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