Six-heterocyclic Aromatic rings with 6 Pi electrons

PowerPoint PresentationProf. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 1
Structure of pyridine
1. Pyridine is a six membered heterocyclic compound with molecular
formula of C 6 H 5 N and it is obtained from coal tar.
2. I t may be formally derived from the structure of benzene through the exchange
of one ring carbon for a sp2 hybridized nitrogen.
3. Pyridine is an aromatic compound, however, the nitrogen’s lone pair of
electrons is in an sp2 orbital orthogonal to the p orbitals of the ring, therefore it is
not involved in maintaining aromaticity but it is available to react with protons thus
pyridine is basic.
4. Pyridine can be considered a hybrid of the Kekulé structures I and II. We shall
represent it as structure III in which the circle represents the aromatic sextet. 3/25/2023
Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/ Pharmacy College
2
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 3
Because of this electronic configuration, the nitrogen atom makes pyridine a much
stronger base than pyrrole, and affects the reactivity of the ring in a quite different way.
Source of pyridine compounds
Along with it are found a number of methylpyridines, the most important of which are the
monomethyl compounds, known as picolines. Oxidation of the picolines yields the
pyridine carboxylic acids.
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 4
The 3-isomer (nicotinic acid or niacin) is a vitamin. The 4-isomer (isonicotinic acid) has been
used, in the form of its hydrazide, in the treatment of tuberculosis.
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 5
Reactions of pyridine
The ring undergoes the substitution, both electrophilic and nucleophilic, typical of aromatic rings;
our interest will lie chiefly in the way the nitrogen atom affects these reactions.
There is another set of reactions in which pyridine acts as a base or nucleophile; these reactions
involve nitrogen directly and are due to its unshared pair of electrons.
Electrophilic substitution in pyridine
1. the negative pole in pyridine ring is at N while the positive pole is at carbon skeleton which
is opposite to what happens in pyrrole.
2. This is due to the greater electronegativity of nitrogen(relative to carbons) it tends to
withdraw the electron density from carbon atoms at positions 2, 4 and 6 which therefore acquire
partial positive charges while the N atom acquires partial negative charge and the carbons at
positions 3 and 5 (β-position) remain neutral therefore these positions are the most
preferred for electrophilic attack. 3/25/2023
Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/ Pharmacy College
6
3. Also as a consequence of electron deficiency on pyridine ring , pyridine is less reactive
towards electrophiles than pyrrole and benzene (it resembles highly deactivated benzene
derivatives), where it does not undergo Friedel-Craft’s alkylation or acylation or
coupling with diazonium salts.
4. Moreover, electrophilic substitution reactions of pyridine require very harsh conditions
(e.g. v. high temp.) to take place and are low yielding
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 7
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 8
Nucleophilic substitution on carbon
1. Pyridine is very reactive towards nucleophiles than benzene it resembles benzene having strong
E.W.G due to the withdrawing effect of the electronegative N atom .
2. AS appeared from the canonical structures of pyridine positions 2, 4 and 6 carry
partial positive charges thus ncleophilic substitution proceeds readily at the 2-position followed
by 4-position but not at the 3-position.
3. Additionally, attack at positions 2, 4 or 6 results in resonance structure in which the negative
charge is delocalized at N thus it is more preferred while attack at position 3 or 5 results in
resonance structures in which the negative charge is delocalized over carbons only.
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 9
Orientation of nucleophilic substitution in pyridine
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 10
Nucleophilic substitution in pyridine
In electrophilic substitution, the pyridine ring resembles a benzene ring that contains strongly
electron-withdrawing groups. Nucleophilic substitution takes place readily, particularly at the 2- and
4-positions. For example:
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 11
The reactivity of pyridine toward nucleophilic substitution is so great that even the powerfully basic
hydride ion, :H- , can be displaced. Two important examples of this reaction are amination by
sodium amide (Chichibabin reaction), and alkylation or arylation by organolithium compounds.
1. The Chichibabin reaction.
R can be o-, m-, or p- substituent
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 12
Nucleophilic attack at the 4-position yields a carbanion that is a hybrid of structures I, II, and III:
Attack at the 3-position yields a carbanion that is a hybrid of structures IV, V, and VI:
(As before, attack at the 2-position resembles attack at the 4-position.)
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 13
Basicity of pyridine
Pyridine is a base much stronger than pyrrole but much weaker than aliphatic amines.
Pyridine has a pair of electrons (in an sp2n orbital) that is available for sharing with acids; pyrrole
has not, and can accept an acid only at the expense of the aromatic character of the ring.
we have the following sequences of acidity of hydrocarbons and basicity of
their anions:
In the alkyl, phenyl, and acetylide anions, the unshared pair of electrons occupies
respectively an sp3, an sp2, and an sp orbital.
The availability of this pair for sharing with acids determines the basicity of the particular anion.
As we proceed along the series sp3, sp2, sp, the p character of the orbital decreases and the s
character increases.
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 14
Like other amines, pyridine has nucleophilic properties, and reacts with alkyl halides to form
quaternary ammonium salts.
N-oxide pyridine
1. N-oxide pyridine is more activated for electrophilic and nucleophilic attack at these positions
than pyridine itself.
2. N-oxide pyridines are very important intermediates for preparing pyridine derivatives that are
difficult to prepare due to the easiness of removal of oxygen atom by reduction.
3. Nitration of pyridine is very difficult and low yielding reaction and it occurs at position 3,
however using N-oxide pyridine will direct the nitration to position 4 and then the oxygen can be
easily removed by reduction as shown in the following scheme.
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 15
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 16
Reduction of pyridine
Catalytic hydrogenation of pyridine yields the aliphatic heterocyclic compound piperidine, C 5 H 11 N.
3/25/2023 Prof. Dr. Nadhir N. A. Jafar/ Al-Zahraa University for Women/
Pharmacy College 17