302 Chem _ March 5, 2012
(Damha/Sleiman)
Masad J. Damha
Otto Maass Building
My office
(OM413A)
[e-mail]
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Pyridine Poor reactivity towards electrophiles
C3-substitution is preferred
Pyridine undergoes
electrophilic aromatic
substitution reactions,
but reluctantly!
WHY?
Instead, N-substitution is observed
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Chem 302 _ March 5, 2012
(Damha/Sleiman)
Pyridine Poor reactivity towards electrophiles
N-substitution maintains aromaticity of pyridine ring
N-acetyl pyridinium chloride
(a good acylating agent)
N-ethyl pyridinium bromide
(this is a good brominating agent)
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bromination of benzene with pyridinium bromide - mechanism:
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Chem 302 _ March 5, 2012
(Damha/Sleiman)
Pyridine Poor reactivity towards electrophiles
The fact that pyridine undergoes N-substitution with E+s explains, in part,
why it is reluctant to undergo electrophilic aromatic substitution.
a)
Very difficult!
2 +ve charges!
b)
Nitrogen is more electronegative than carbon. This results in polarization of the
pi-system, resulting in decreased electron density on the ring carbons.
(Relative reactivity towards E+)
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Pyridine Poor reactivity towards electrophiles
C3-substitution is preferred
Pyridine undergoes
electrophilic aromatic
substitution reactions,
but reluctantly!
WHY?
Instead, N-substitution is observed
3
Chem 302 _ March 5, 2012
(Damha/Sleiman)
Pyridine Poor reactivity towards electrophiles
Orientation when electrophilic aromatic substitutions do occur:
C3:
..
..
..
preferred
..
C2:
..
..
N (6 electrons; sextet)
Pyridine reacts preferentially with E+ at C3.
This maximizes the resonance forms in the intermediate
(greater charge delocalization, making it more stable).
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So, how do we carry out reactions under less rigorous conditions, and at C4?
e.g.,
This requires a trick!: One first prepares a Py N-oxide (by derivative reaction with H2O2);
then add the desired E+, and finally reduce the Py-oxide ring into the Py derivative. A minor
product is the C2-nitro derivative, less favored because of steric effects and due to electrostatic
repulsion between N+ and NO2+.
Py N-oxide
-OH-
-H+
a zwitterion
Trimethyl phosphite
Trimethyl phosphate
-H+
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+ some C2-nitro derivative
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Chem 302 _ March 5, 2012
(Damha/Sleiman)
Trimethyl phosphite
Trimethyl phosphate
+
+
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Basicity
Why is pyridine a weaker base than piperidine?
(or, why is a pyridinium ion a stronger acid than a piperidinium ion?)
sp3
sp2
sp3
sp2
N has a greater s character
N is more electronegative.
Hence, it is more electronegative
Hence, N-H bond more polarized
Hence, es on N are more tightly held
(since its lone pair of es is less
available, pyridine is a weaker base)
Hence, easier to break
Hence, this is a stronger acid
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5
Chem 302 _ March 5, 2012
(Damha/Sleiman)
Same rationale for:
The most polarized bond;
easier to break
sp
Increasing acidity
(as this sp carbon is the most electronegative,
its es are more tightly held; i.e., they are
less available; hence this C is the least basic)
(es more loosely
held; hence C is
more basic)
Increasing basicity
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Basicity
Why is pyridine a weaker base than piperidine?
(or, why is a pyridinium ion a stronger acid than a piperidinium ion?)
sp3
sp2
sp3
sp2
1
12
6
Chem 302 _ March 5, 2012
(Damha/Sleiman)
Pyridine N-Oxides are useful intermediates
Nucleophilic Substitution of Pyridine:
Pyridine is activated towards nucleophilic substitution
Charge well accommodated by N
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Chem 302 _ March 5, 2012
(Damha/Sleiman)
Try this synthesis
Nifluminic acid a drug to treat joint and muscular pain
Also called niflumic acid
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Pyridine N-Oxides are useful intermediates
Try these 3 mechanisms:
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