6-Membered Hetero Cyclic Compound

Nomenclature Examples
(1) Six-Membered Rings With One Heteroatom

Heteroatom Saturated Unsaturated Ions

Antimony Stibinin

Arsenic Arsinane Arsinine

Bismuth Bismin

Boron Borinane Borinine Boratabenzene anion

Germanium Germinane Germine

Piperidine (Azinane is not Pyridine (Azine is not

Nitrogen Pyridinium cation
used) used)

Pyran (2H-Oxine is not

Oxygen Tetrahydropyran Pyrylium cation
used)

Phosphorus Phosphinane Phosphinine

Selenium Selenopyrylium cation

Silicon Silinane Siline

 Thiopyran (2H-Thiine is
Sulfur Thiane Thiopyrylium cation
not used)

Tin Stanninane Stannine

(2)Six-Membered Rings With Two Heteroatoms

Heteroatom Saturated Unsaturated

Nitrogen / nitrogen Piperazine Diazine

Oxygen / nitrogen Morpholine Oxazine

Sulfur / nitrogen Thiomorpholine Thiazine

Oxygen / oxygen Dioxane Dioxine

Sulfur / sulfur Dithiane Dithiin

Six-Membered Rings With Three Heteroatoms

Heteroatom Saturated Unsaturated

Nitrogen Hexahydro-1,3,5-triazine Triazine

Oxygen Trioxane

Sulfur Trithiane
Six-Membered Rings With Four Heteroatoms

Heteroatom Saturated Unsaturated

Nitrogen Tetrazine

Six-Membered Rings With Five Heteroatoms

Heteroatom Saturated Unsaturated

Nitrogen Pentazine

Six-Membered Rings With Six Heteroatoms

The hypothetical compound with six nitrogen heteroatoms would
be hexazine.
Note :
Borazine is a six-membered ring with three nitrogen heteroatoms and three
boron heteroatom.
 Synthesis of pyridine

(1) The Hantzsch pyridine synthesis or Hantzsch dihydropyridine synthesis is a multi-

component organic reaction between an aldehyde such as formaldehyde, 2 equivalents
of a β-keto ester such as ethyl acetoacetate and a nitrogen donor such
as ammonium acetate or ammonia.
The initial reaction product is a dihydropyridine which can be oxidized in a subsequent
step to a pyridine. The driving force for this second reaction step is aromatization. This
reaction was reported in 1881 by Arthur Rudolf Hantzsch.
A 1,4-dihydropyridine dicarboxylate is also called a 1,4-DHP compound or a Hantzsch
compound. These compounds are an important class of calcium channel blockers and as
such commercialized in for instance nifedipine, amlodipine or nimodipine.

The reaction has been demonstrated to proceed in water as reaction solvent and with
direct aromatization by ferric chloride, Manganese Dioxide or potassium
permanganate in a one-pot synthesis.

(3) kröhnkite reaction

(6) Guareschi Reaction
Chemical and physical properties
of pyridine

Because of the electronegative nitrogen in the pyridine ring, the molecule is

relatively electron deficient. It, therefore, enters less readily into electrophilic
aromatic substitution reactions than benzene derivatives. Correspondingly
pyridine is more prone to nucleophilic substitution, as evidenced by the ease
of metalation by strong organometallic bases. The reactivity of pyridine can be
distinguished for three chemical groups. With electrophiles, electrophilic
substitution takes place where pyridine expresses aromatic properties.
With nucleophiles, pyridine reacts at positions 2 and 4 and thus behaves similar
to imines and carbonyls. The reaction with many Lewis acids results in the
addition to the nitrogen atom of pyridine, which is similar to the reactivity of
tertiary amines. The ability of pyridine and its derivatives to oxidize,
forming amine oxides (N-oxides), is also a feature of tertiary amines.
The nitrogen center of pyridine features a basic lone pair of electrons. This lone
pair does not overlap with the aromatic π-system ring, consequently pyridine is
a basic, having chemical properties similar to those of tertiary
amines. Protonation gives pyridinium, C5H5NH+.The pKa of the conjugate
acid (the pyridinium cation) is 5.25. The structures of pyridine and pyridinium are
almost identical.
The pyridinium cation is isoelectronic with benzene. Pyridinium p-
toluenesulfonate (PPTS) is an illustrative pyridinium salt; it is produced by
treating pyridine with p-toluenesulfonic acid. In addition to protonation, pyridine
undergoes N-centered alkylation, acylation, and N-oxidation.
Bonding

Pyridine with its free electron pair

Pyridine has a conjugated system of six π electrons that are delocalized over the
ring. The molecule is planar and, thus, follows the Hückel criteria for aromatic
systems. In contrast to benzene, the electron density is not evenly distributed
over the ring, reflecting the negative inductive effect of the nitrogen atom. For this
reason, pyridine has a dipole moment and a weaker resonant stabilization than
benzene (resonance energy 117 kJ·mol−1 in pyridine vs. 150 kJ·mol−1 in
benzene).
The ring atoms in the pyridine molecule are sp2-hybridized. The nitrogen is
involved in the π-bonding aromatic system using its unhybridized p orbital.
The lone pair is in an sp2 orbital, projecting outward from the ring in the same
plane as the σ bonds. As a result, the lone pair does not contribute to the
aromatic system but importantly influences the chemical properties of pyridine,
as it easily supports bond formation via an electrophilic attack. However,
because of the separation of the lone pair from the aromatic ring system, the
nitrogen atom cannot exhibit a positive mesomeric effect.
Many analogues of pyridine are known where N is replaced by other heteroatoms
(see figure below). Substitution of one C–H in pyridine with a second N gives rise
to the diazine heterocycles (C4H4N2), with the names pyridazine, pyrimidine,
and pyrazine.

Bond lengths and angles of benzene, pyridine, phosphorine, arsabenzene, stibabenzene,

and bismabenzene

Resonance structures of pyridine

Electrophilic substitutions
Owing to the decreased electron density in the aromatic system, electrophilic substitutions are
suppressed in pyridine and its derivatives. Friedel–Crafts alkylation or acylation, usually fail for
pyridine because they lead only to the addition at the nitrogen atom. Substitutions usually
occur at the 3-position, which is the most electron-rich carbon atom in the ring and is,
therefore, more susceptible to an electrophilic addition.

Direct nitration of pyridine is sluggish. Pyridine derivatives wherein the nitrogen atom is
screened sterically and/or electronically can be obtained by nitration with nitronium
tetrafluoroborate (NO2BF4). In this way, 3-nitropyridine can be obtained via the synthesis of
2,6-dibromopyridine followed by debromination.
Sulfonation of pyridine is even more difficult than nitration. However, pyridine-3-sulfonic acid
can be obtained. Reaction with the SO3 group also facilitates addition of sulfur to the nitrogen
atom, especially in the presence of a mercury(II) sulfate catalyst.
In contrast to the sluggish nitrations and sulfonations, the bromination and chlorination of
pyridine proceed well.

Pyridine-N-oxide
Structure of pyridine N-oxide
Oxidation of pyridine occurs at nitrogen to give pyridine-N-oxide. The oxidation can be
achieved with peracids:
C5H5N + RCO3H → C5H5NO + RCO2H
Some electrophilic substitutions on the pyridine are usefully effected using pyridine-N-oxide
followed by deoxygenation. Addition of oxygen suppresses further reactions at nitrogen
atom and promotes substitution at the 2- and 4-carbons. The oxygen atom can then be
removed, e.g. using zinc dust.
Nucleophilic substitutions
In contrast to benzene ring, pyridine efficiently supports several nucleophilic substitutions.
The reason for this is relatively lower electron density of the carbon atoms of the ring.
These reactions include substitutions with elimination of a hydride ion and elimination-
additions with formation of an intermediate aryne configuration, and usually proceed at the
2- or 4-position.

Many nucleophilic substitutions occur more easily not with bare pyridine but with pyridine
modified with bromine, chlorine, fluorine, or sulfonic acid fragments that then become a
leaving group. So fluorine is the best leaving group for the substitution with organolithium
compounds. The nucleophilic attack compounds may be alkoxides, thiolates, amines, and
ammonia (at elevated pressures).
In general, the hydride ion is a poor leaving group and occurs only in a few heterocyclic
reactions. They include the Chichibabin reaction, which yields pyridine
derivatives aminated at the 2-position. Here, sodium amide is used as the nucleophile
yielding 2-aminopyridine. The hydride ion released in this reaction combines with a proton
of an available amino group, forming a hydrogen molecule.
Analogous to benzene, nucleophilic substitutions to pyridine can result in the formation
of pyridyne intermediates as heteroaryne. For this purpose, pyridine derivatives can be
eliminated with good leaving groups using strong bases such as sodium and potassium
tert-butoxide. The subsequent addition of a nucleophile to the triple bond has low
selectivity, and the result is a mixture of the two possible adducts.
Radical reactions
Pyridine supports a series of radical reactions, which is used in its dimerization to
bipyridines. Radical dimerization of pyridine with elemental sodium or Raney
nickel selectively yields 4,4′-bipyridine, or 2,2′-bipyridine, which are important precursor
reagents in the chemical industry. One of the name reactions involving free radicals is
the Minisci reaction. It can produce 2-tert-butylpyridine upon reacting pyridine with pivalic
acid, silver nitrate and ammonium in sulfuric acid with a yield of 97%.

Reactions on the nitrogen atom

Additions of various Lewis acids to pyridine

Lewis acids easily add to the nitrogen atom of pyridine, forming pyridinium salts. The
reaction with alkyl halides leads to alkylation of the nitrogen atom. This creates a positive
charge in the ring that increases the reactivity of pyridine to both oxidation and reduction.
The Zincke reaction is used for the selective introduction of radicals in pyridinium
compounds (it has no relation to the chemical element zinc).
Hydrogenation and reduction

Reduction of pyridine to piperidine with Raney nickel

Piperidine is produced by hydrogenation of pyridine with a nickel-, cobalt-, or ruthenium-
based catalyst at elevated temperatures. The hydrogenation of pyridine to piperidine
releases 193.8 kJ·mol−1, which is slightly less than the energy of the hydrogenation
of benzene (205.3 kJ·mol−1).
Partially hydrogenated derivatives are obtained under milder conditions. For example,
reduction with lithium aluminium hydride yields a mixture of 1,4-dihydropyridine, 1,2-
dihydropyridine, and 2,5-dihydropyridine. Selective synthesis of 1,4-dihydropyridine is
achieved in the presence of organometallic complexes of magnesium and zinc, and (Δ3,4)-
tetrahydropyridine is obtained by electrochemical reduction of pyridine.
Lewis basicity and coordination compounds
Pyridine is a Lewis base, donating its pair of electrons to a Lewis acid. One example is
the sulfur trioxide pyridine complex (melting point 175 °C), which is a sulfation agent used
to convert alcohols to sulfate esters. Pyridine-borane (C5H5NBH3, melting point 10–11 °C)
is a mild reducing agent.

structure of the Crabtree's catalyst

Pyridine forms numerous complexes with transition metals. Typical octahedral complexes
have the stoichiometry MCl2(py)4 and MCl3(py)3. Octahedral homoleptic complexes of the
type M(py)6+ are rare or tend to dissociate pyridine. Numerous square planar complexes
are known, such as Crabtree's catalyst. The pyridine ligand replaced during the reaction is
restored after its completion.
The η6 coordination mode, as occurs in η6 benzene complexes, is observed only
in sterically encumbered derivatives that block the nitrogen center.

Applications
Pesticides
The main use of pyridine is as a precursor to the herbicides paraquat and diquat. The first
synthesis step of insecticide chlorpyrifos consists of the chlorination of pyridine. Pyridine is
also the starting compound for the preparation of pyrithione-
based fungicides. Cetylpyridinium and laurylpyridinium, which can be produced from
pyridine with a Zincke reaction, are used as antiseptic in oral and dental care
products. Pyridine is easily attacked by alkylating agents to give N-alkylpyridinium salts.
One example is cetylpyridinium chloride.

Synthesis of paraquat
Solvent
Pyridine is used as a polar, basic, low-reactive solvent, for example in Knoevenagel
condensations. It is especially suitable for the dehalogenation, where it acts as the base of
the elimination reaction and bonds the resulting hydrogen halide to form a pyridinium salt.
In esterifications and acylations, pyridine activates the carboxylic acid halides or
anhydrides. Even more active in these reactions are the pyridine derivatives 4-
dimethylaminopyridine (DMAP) and 4-(1-pyrrolidinyl) pyridine. Pyridine is also used as a
base in condensation reactions.
Elimination reaction with pyridine to form pyridinium
It is also used in the textile industry to improve network capacity of cotton.

Synthesis of 4H pyran

(1) A Diels-Alder adduct formed by reaction of acrolein with vinyl

acetate is decomposed on a column of glass beads at 350°C
leading to the generation of 4H-pyran and acetic acid.906 This
compound was unstable in air and hence disproportionate to
dihydropyran and pyrylium ion.

(2) Stable polyfunctionalized 4H-pyrans are synthesized by the

reaction of formaldehyde with ethyl acetoacetate in the
presence of piperidine, yielding diketone, which on reaction with
zinc chloride cyclized to a 4H-pyran derivative.
 (3) Mesityl oxide condenses with ethyl acetoacetate to yield 4H-
pyran.

(4) The unsubstituted pentanedial yields the parent 4H-pyran on

successive treatment with hydrogen chloride and N,N-
diethylaniline . This two-step approach involving elimination of
hydrogen chloride from the initially formed tetrahydropyran has
been extended to the synthesis of substituted 4H-pyrans .

Chemical and physical properties

of pyran

Chemical Reactivity
(1) Pyrylium tetraborate is obtained as a crystalline solid by reaction
of 4H-pyran with triphenylmethane tetrafluoroborate.
 (2) Lithium aluminum hydride reduction of 3-carbethoxy-2,4,4,6-
tetramethyl-4H-pyran afforded 3-hydroxymethyl-2,4,4,6-
tetramethyl-4H-pyran. Reaction of this alcohol with chromic
trioxide oxidizes it to an aldehyde. Base-catalyzed aldol
condensation of the aldehyde with acetone yields an unsaturated
ketone.

(3) When 2,4-dinitrophenylhydrazine (DNP) reacts with 4H-pyrans, a

ring-opening reaction takes place leading to the generation of
bis-2,4-dinitrophenylhydrazone derivatives.

Thiopyran

is a heterocyclic compound with the chemical formula C5H6S. There are two
isomers, 2H-thiopyran and 4H-thiopyran, which differ by the location of double
bonds. Thiopyrans are analogous to pyrans in which the oxygen atoms have
been replaced by sulfur atoms.
** An environmentally benign synthesis of substituted 4H-thiopyrans was carried out
by the condensation of aromatic aldehydes, malononitrile, carbon disulfide and
primary amines. Constant potential electro synthesis was carried out in an undivided
cell at room temperature in the presence of lithium perchlorate as a supporting
electrolyte. Clean synthesis, use of electricity instead of chemical reagents and atom
economy are attractive features of the present protocol.