C 22J

1
C 22J

• Lecture 6

2
Lecture Outline

• Reactions of amines with nitrous acid
• Polynuclear aromatics
• Reactions of simple heterocyclic compounds

3
So far..
4
Reaction of amines with Nitrous Acid
Primary Amines (R-NH2) react with nitrous acid to
give diazonium salts.
The overall reaction is-
and proceeds via the N-nitrosoamine and the
diazahydroxide
5
Secondary Amines react with HONO to give
secondary
N-nitrosoamines.
Secondary N-nitrosoamines stable will usually
just separate from the reaction mixture as an
oily liquid.
Tertiary Amines react with HONO to give
N-nitrosoammonium
salts.
6
Polynuclear Aromatics
Naphthalene
2 fused benzene rings, 10 pi-electrons.
cf. 2 isolated benzene rings, 12 pi-electrons.
Smaller amt. of electron density, then, results
in naphthalene having less than 2 x resonance
energy of benzene.
Naphthalene 252 kJ/mol or 126 kJ/benzene ring.
Benzene 152 kJ/mol
Resonance energy/ kcal/ mol
7
Polynuclear Aromatics
Polycyclic aromatic hydrocarbons, particularly
naphthalene, anthracene, phenanthrene and their
simple derivatives are generally more reactive
than benzene in EAS because Eact for the
?-complex formation is lower than for benzene.
For naphthalene, position 1 is the preferred site
for attack. Bulky substituents or heating
(thermodynamic control) may favour attack at C-2
Both phenanthrene and anthracene react
preferentially in the center as a consequence of
resonance stabilization of the ?-complex.
8
Reactions of Polynuclear aromatics

• Generally more reactive towards oxidation,
  reduction, and electrophilic substitution than
  benzene
• Can undergo rxn at one ring and retain one or
  more intact benzenoid rings in the intermediate
  and the product
• Electrophilic aromatic substitution

9
Reactions of Polynuclear aromatics
Anthracene

• Reduction

10
Phenanthrene
14 pi-electrons
These compounds are not as strongly stabilised as
benzene and will undergo addition reactions.
Prod. has 2 isolated benzene rings.
11
Heterocyclic Aromatic Compounds
Carbocyclic ring system made up entirely of
carbon atoms.
Heterocyclic ring system made up of carbon and
at least one other element, commonly N, O, S.
Some simple heterocyclic compounds-
12
Of the known aromatic compounds, about half have
structures that incorporate a heterocyclic
component.
13
Heterocyclic chemistry
There are two types of heterocyclic cpds.

• ?-excessive heterocyclics have an e- - donating
  heteroatom eg. O, NH, S
• ?-deficient heterocyclics have an e- - accepting
  heteroatom eg. N or N

Looking at Pyridine
NB i) The molecule is not a regular hexagon.
The C-C bond lengths gt the C-N bond lengths.
ii) 6 e-s are delocalized over the ring by
the overlap of p-orbitals of C and N. The lone
e--pair of N is located in a sp2 orbital.
iii) The molecule has a dipole moment as the
e- - distribution is uneven.
14
Heterocyclic chemistry
Hantzsch Dihydropyridine (Pyridine) Synthesis
This reaction allows the preparation of
dihydropyridine derivatives by condensation of
an aldehyde with two equivalents of a
ß-ketoester in the presence of ammonia.
Subsequent O (or dehydrogenation) gives
pyridine-3,5-dicarboxylates, which may also be
decarboxylated to yield the corresponding
pyridines.
15
Heterocyclic chemistry
Mechanism
The reaction can be visualized as proceeding
through a Knoevenagel Condensation product as a
key intermediate
Mechanism?
A second key intermediate is an ester enamine,
which is produced by condensation of the second
equivalent of the ß-ketoester with ammonia
Mechanism?
16
(No Transcript)
17
Pyridine in nature
Pyridine - water-miscible, polar solvent, with
unpleasant odour. Basic - pKa 5.23
Naturally occurring substituted pyridines include
18
Pyridine Discoveries
PH.D. CANDIDATES Hans Meyer and Josef Mally of
German Charles University in Prague first
synthesized isoniazid in 1912 as part of their
doctoral requirements, completely unaware of the
enormous potential their compound held for
treating TB.
19
Nicotinamide adenine dinucleotide NAD (R H)
and its phosphate NADP(R PO(OH)2. very
important coenzymes in biological redox reactions.
20
NAD as part of a liver enzyme called alcohol
dehydrogenase, will oxidise alcohols to
aldehydes as shown below. Can be considered to
be Natures equivalent of Cr(VI).
The hydride adds to the 4-position
Active site of enzyme
21
The chemistry of pyridines
Pyridine most benzene-like of the simple aromatic
heterocyclic compounds. N-atom in ring.
How does this affect the reactivity of pyridine?

• N more electronegative than C, and distorts the
• electron distribution in the ring.
• Pyridine is like a deactivated benzene ring,
  with the
• electron withdrawing group at the position
  of the N-atom,
• e.g.

22
Would you expect pyridine to be more or less
susceptible to EAS than benzene?
At what position would you expect EAS to occur?
23

• Pyridine acts somewhat like a carbonyl compound

24

• What effect will the lone pair of electrons on
  the N-atom have on the reactivity of pyridine?

Would you expect the pyridinium ion to be
susceptible to attack by E?

• EAS of pyridine must involve either -
• a) attack of E on a pyridinium cation very
  highly unfavoured, or

• attack on the free pyridine, which is available
  only in very low
• equilibrium concn. When attack does occur
  here, very small amts.
• of meta-substd. product.

25
Heterocyclic chemistry
The e- - distribution is uneven because of
induction and resonance
Induction
3 or ?- substituted product is usual for EAS
Pyridine is less reactive towards EAS than C6H6.
This is because 1) N is more electronegative
than C and is a net acceptor of ?-density and so
makes the ?-cloud less available.
In other words, N deactivates the ring,
especially in positions 2 and 4.
26
Heterocyclic chemistry
N is basic and in the presence of an
electrophile, rxn occurs at N first.
Aromaticity is not affected but e- - distribution
is. Pyridinium ion is highly unreactive. H-atom
can be removed by base at end of rxn.
Special rxn conditions are usually required for
EAS
27
Heterocyclic chemistry
Pyridines do not undergo Friedel crafts
alkylation or acylation or coupling with
diazonium cpds.
Rxns include
28
Heterocyclic chemistry
Electrophilic attack in positions 2 or 4 is
unfavourable because of an especially unstable
resonance structure contributes to the hybrid.
Esp. unstable contributor
No such contributor exists for attack at position
3, hence it is preferred.
29
Activation towards EAS

• Pyridine derivatives with an ER group on the ring
  activate it towards EAS
• Rxns occur under milder conditions
• When o,p-groups are in the 3-position, the
  strength of the directing group is of relevance

30
Nucleophilic aromatic substitution
Pyridine is appreciably reactive to NAS The
N-atom, being more electronegative, makes the
ring better able to accommodate the ve charge
that the aromatic ring must accept in NAS.
NAS gives substituted products in positions 2 and
4.
31
Nucleophilic aromatic substitution
Nucleophilic attack at position-3.
Nucleophilic attack at this position therefore,
not observed.
32
Nucleophilic aromatic substitution
33
Pyridine N-Oxides in EAS

• Milder reaction conditions required
• Substitution occurs at the 4-position instead of
  the 3-position

Resonance forms of pyridine N-oxide
34
Pyridine N-Oxides in EAS
Use of Pyridine N-Oxides allows formation of 2-
and 4-substituted pyridines.
Attack at position-2/ 3?
35
Substituted pyridine-N-oxide is reconverted to
pyridine.
Overall
36
Pyrrole

• Weakly basic but has greater aromatic character
• Electron pair NOT available to act as base
• Review aromaticity of pyrrole
• Protonation would destroy aromaticity

37

• Pyrrole is extremely reactive towards EAS
• 2- substitution
• 3-substitution

38
Pyrrole
For five membered heterocycles
pyrrolegtfurangtthiophene
Pyrrole, unlike pyridine, is highly reactive
towards EAS. Five membered heterocycles give
mainly 2-substituted products in EAS.
Esp. stable, every atom has an octet
For substitution at position 2, three resonance
structures contribute to the hybrid. For
position 3, only two such structures arise.
Esp. stable, every atom has an octet