Useful Introductory Chemistry notes for class 11th students

1. CO-301 Heterocyclic
Chemistry
Convenor
Dr. Fawaz Aldabbagh
http://www.nuigalway.ie/chemistry/level2/staff/f_aldabbagh/Fawaz.htm
Cytotoxin- Inhibits DNA-topoisomerase enzymes
Happy Tree
(China)

2. Definition: Heterocyclic compounds are organic
compounds that contain a ring structure containing atoms
in addition to carbon, such as sulfur, oxygen or nitrogen,
as the heteroatom. The ring may be aromatic or non-
aromatic
Significance – Two thirds of all organic compounds are aromatic
heterocycles. Most pharmaceuticals are heterocycles.
Examples
Quinine
Pfizer: Viagra
Treatment of malaria for 400 years (Peru)
Erectile dysfunction

3. N
N
Me
N NHMe
N
NC
H
H
Ovarian & lung cancer
GSK - Topotecan
Pfizer - Irinotecan
Camptothecin Analogues
Treating stomach & intestinal ulcers
More soluble & less side-effects

4. When Is A Molecule Aromatic?
• For a molecule to be aromatic it must:
• Be cyclic
• Have a p-orbital on every atom in ring
• Be planar
• Posses 4n+2 p electrons (n = any integer)
benzene naphthalene
+
cyclopropenyl cation
[14]-Annulene
Erich Hückel

5. Six Membered Heterocycles: Pyridine
N N
H
pyridine piperidine
Pyridine replaces the CH of benzene by a N atom (and a pair of electrons)
Hybridization = sp2 with similar resonance stabilization energy
Lone pair of electrons not involved in aromaticity
N
H
H
H
H H
pyridine
8.5
7.1
7.5
1H NMR: d
Pyridinium ion: pKa = 5.5
Piperidine: pKa = 11.29
diethylamine : pKa = 10.28
Pyridine is a weak base
Pyridine is -electron deficient
Electrophilic aromatic substitution is
difficult
Nucleophilic aromatic substitution is easy

6. N
Me I
N
Me
+ I
_
O
O
O OH O
O
O
R X
O
R O
R
+ Pyr
+
Pyr
R1-OH 1
X = OAc, Cl, Br
Pyridine as a nucleophile
Use Pyridine as a solvent to make esters
N
O R
+
Acyl pyridinium ion
Reactive intermediate
E.g.

7. DMAP (DimethylAminoPyridine)
N
N
CH3
C
H3
N
N
H
N
NO2
+
i
i
i, HNO3, H2SO4
Whereas acylations “catalyzed” by pyridine are
normally carried out in pyridine as the reaction
solvent. Only small amounts of DMAP are required
to do acylations
Attempted Electrophilic Aromatic Substitution
N
N
AlCl3
N
R
O
+
ii
ii
ii, AlCl3, RCOCl
_
Unreactive, Stable

8. How can we nitrate pyridine?
N N
O
N
O
NO2
N
O
O N O
N
O
NO2
N
NO2
O PPh3
N
O
N H
O
O
+
_
H2O2, AcOH
Pyridine N-oxide
HNO3, H2SO4
+
_
85%
+
_
+
+
_
PPh3
+
75%
+
+
_
We now have an activating and protecting group
Mechanism

9. Third Period ; n2 = 32 = 9 orbitals
Ar [Ne]; 3s2, 3px
2, 3py
2, 3pz
2 3d0 3d0 3d0 3d0
3d0
n = 3

10. Nucleophilic Substitution at 2- and 4-positions of
pyridine is most favoured
N Cl N Cl
Nu
N Nu
_
_
Nu
N Cl N SPh
PhSH, NEt3
93%
E.g.
N
Br
Br
N
NH2
Br
NH3 (aq)
65%

11. Five Membered Heterocycles: Pyrrole
N
H
H
H
H
H
Pyrrole
6.5
6.2
1H NMR: d
Aromatic: Thus, 6 electrons
Sp2 hybridised and planar
Lone pair tied up in aromatic ring
Pyrrole is -electron excessive
Thus, Electrophilic Aromatic Substitution is Easy
Nucleophilic Substitution is Difficult

12. N
H
N
H
O
H
O
H NMe2
N
SO2Ph
N
SO2Ph
Me
O
N
H
Me
O
N
H
N
H
NO2
N
H
NO2
+
1. POCl3
2. Na2CO3, H2O
59%
Ac2O, AlCl3
rt
NaOH (aq)
82%
AcONO2, AcOH/ -10 C
+
51% 13%
Electrophilic Aromatic Substitution preferred at the 2-position
Normal acidic nitration causes polymerization
Vilsmeier Reaction
Electron-withdrawing group allows substitution at the 3-position

13. N
H
N
H
H
H N
H
N
H
H
H N
H
H+
+
+
reaction continues to give polymer
Organic Synthesis with Pyrrole should avoid strong acids
N
H
N
H
Cl
N
H
N
H
Cl
Cl
Cl
Cl
80%
80%
i; 1 X SO2Cl2, Et2O
ii; 4 X SO2Cl2, Et2O
i
ii

14. Indole
Lysergic acid (LSD) Strychnine
Indole Alkaloids
N
H
Indole
N
H
N
H
CHO
Vilsmeier
55%
Aromatic due to 10 -electrons
Benzene part is non-reactive
Electrophilic aromatic substitution
occurs at the 3-position
OCONH2
N
OMe
NH
N
H2
Me
O
O
Mitomycin C

15. Other Five Membered Heterocycles
N
H
S O
Pyrrole
Thiophene Furan
The least aromatic:
The O atom is too electronegative
Can give addition, as well as substitution products when
reacted with E+
Less reactive than pyrrole,
but substitution always at 2-
position
More aromatic than Furan
Electrophilic Substitution, not addition
Least reactive
Thiophene has similar reactivity to benzene

16. Avoid concentrated mineral acids or strong Lewis acids, e.g. AlCl3
Electrophilic Aromatic Substitution of Thiophene
S
S
O
H
O
H NMe2
S S
NO2
S S
Cl
S
Cl
Cl
+
1. POCl3
2. Na2CO3, H2O
68%
HNO3, AcOH, Ac2O / -10 C
85%
43%
SO2Cl2, heat
10%

17. S S
O
O
O
O
O O
O
O
O
O
+
ZnCl2, 100 C
+
ZnCl2, 0 C
83%
95%
Some Reactions of Furan
O
O
Br
Br
Br
Br O
OMe
MeO
H H
CHO
OHC
O
Ph3P OHC
CHO
CHO
OHC
Br2, CCl4
Br2, MeOH
H+, H2O
+
_
not a clean reaction
Furan is more reactive than thiophene
Addition product
Hydrolysis of acetal
Wittig reaction
Furan is easily cleaved to dicarbonyls

18. Furan is a source of 1,4-dicarbonyls in Organic Synthesis
O
OMe
MeO
H H
O O
H H
O
R H
O R
H
O R
H
R H
O O R
R
O
R R O O
R R
cis-butenediol
(too unstable to isolate)
H+, H2O
acetal acetal
+
1
1 1
1 - H2O
acetal
aldehyde + 2 x alcohol
H+, H2O
acid-catalysed

19. The Diels-Alder Reaction
Otto Diels
Kurt Alder
Noble Prize in 1950
O
O
O
O
O
O
+
100 C
benzene
100%
Diene
4 system
dienophile
2 system 4+2 cycloaddition
Electron rich
Electron poor
O
H
O
H
+
30 C
100%

20. H
H
O
O
OMe
OMe
H
H
CO2Me
CO2Me
H
H
O
OMe
O
MeO
H
H
CO2Me
CO2Me
+
+
The configuration of the dienophile is retained
Always reacts via the cis-diene
O
O
O
O
O
O
H
H
H
H
O
O
O
+
25 C
100%
endo product
(100%)
Under kinetic control

21. O
O
O
O
Thermodynamic
exo-product forms as the
temperature is raised
endo-product
Furan readily undergoes the Diels-Alder reaction with maleic anhydride
More stable due to less steric reasons
Aromaticity prevents thiophene from taking part in the Diels-Alder reaction
S
O
O
X
S O
O
X
X
+
- SO2
This sulfone is not aromatic & very reactive

22. Five-membered Rings with Two or More Nitrogens
Diazoles
N
N
H
N
N
H
Imidazole
Pyrazole
Imidazole is more basic than pyridine, but more acidic than pyrrole
N
N
H
H
N
N
H
H
N
N
N
N
+
_
_
Imidazole + H+
Imidazole - H+
NaOH
Properties: Very stable cation and anion of imidazole is formed
pKa = 14.5
(imidazole)
pKa = 16.5
(pyrrole)
- H2O

23. Histidine
Is one of the essential amino acids.
A relatively small change in cellular pH can result in a change in its charge
Some Natural Imidazole Compounds
Important ligand to many metalloproteins
histidine carboxylase
histamine
Carnosine
Dipeptide in high concentrations in the brain & muscles
- Improves social interactions & treatment of autism
Body neurotransmitter & local immune response

24. Synthesis of 2- and 5-Nitroimidazole Antibiotics
N
N
H
N
N
CPh3
N
N
CPh3
NO2 N
N
H
NO2
(i) (ii) (iii)
(i) ClCPh3, NEt3 (ii) Bu-Li, n-PrONO2
(iii) HCl (aq), MeOH
30%
2-Nitroimidazole, “azomycin”
5-Nitroimidazoles, “metronidazole” is used to treat anaerobic protozoan infections
N
N
H
Me N
N
H
Me
O2N O
N
N
Me
O2N
OH
N
N
Me
OH
O2N
+
Two tautomeric forms
metronidazole inactive
(i)
(i) HNO3, H2SO4
80% 5
4

25. Triazoles
N
N
N
H
N
N
N
H
N
N
N
H
N
N
N
H
1,2,3-Triazole
1,2,4-Triazole
Weakly basic like pyridine, but more acidic than imidazole
pKa = 10.3
Tetrazoles Only one isomer now possible
N
N
N
N
H
R
N
N
N
N
H
R
N
N
N
N
H
R
N
N
N
N
R N
N
N
N
R
_
_
etc
pKa ~ 5 ~ RCOOH

26. N
O
O
Me
O
Cl
H
N
O
Me
O
Cl
N
N
N
N
H
Indomethacin
Tetrazole derivative
Tetrazoles are used in drugs as replacements for CO2H
Anti-arthritis drug
- Non steroidal anti-inflammatory drug –
reduces fever, pain, stiffness, delays
premature labour & other uses
Indomethacin

27. N
H
N
H
NMe2
N
H
CN
N
H
N
N
N
N
H
N
N
N
N
N
O
Cl
H
98%
Me2NH, CH2=O NaCN
NaN3, NH4Cl, LiCl
DMF, 100 C
Synthesis of Indomethacin

28. Bioreductive Anti-Tumour Agents
OCONH2
N
OMe
NH
N
H2
Me
O
O
N
N
O
OR
O
O
N
Me
N
N
O
O
N
N N Tr
O
O
( )n
IC50 ≈ 1.0 µM
IC50 ≈ 0.001 µM
Mitomycin C
E. B. Skibo et al., J. Med. Chem., 2002, 45, 1211
K. Fahey, F. Aldabbagh, Tetrahedron Lett., 2008, 49, 5235
Pyrrolo[1,2-a]benzimidazole (PBI)
M. Lynch, S. Hehir, M. P. Carty, F. Aldabbagh, Chem. Eur. J. 2007, 13, 3218
S. Hehir, L. O’Donovan, M. P. Carty, F. Aldabbagh, Tetrahedron 2008, 64, 4196
1
10
L. O’Donovan, F. Aldabbagh, Chem. Commun., 2008, 5592.
Hypersensitive to Fanconi Anemia
More selective to hypoxia

29. Targeting Hypoxic Cells

30. Mitomycin C (MMC)
SET - activation
O
O
N
N
H2
Me
OCONH2
OMe
NH
O
O
N
N
H2
Me
OCONH2
NH
OMe
O
O
N
N
H2
Me
NH2
DNA
O
O
N
N
H2
Me
OCONH2
OMe
NH N
N
H2
Me
OCONH2
OMe
OH
OH
NH N
N
H2
Me
OH
OH NH2
DNA
+ 2 e-
+ 2 H+
CY P450 reductase
Two electron activation
DT-diaphorase
.
+ 1 e-
- 1 e-
- 1 e-
1
10
DNA alkylation
S. E. Wolkenberg and D. L. Boger, Chem Rev., 2002, 102, 2477
steps
DNA alkylation

31. Measuring the Effect of FANCD2 Expression on Cell Viability
N NH
OMe
OCONH2
O
O
N
H2
Me
N
N
OMe
OMe
N Tr
●, ● PD20i cells (lack FANCD2)
▲, ▲ PD20:RV (express FANCD2)
K. Fahey, L O’Donovan, M. Carr, M. P. Carty, F. Aldabbagh, Eur. J. Med Chem. 2010, 45, 1873-1879
0
20
40
60
80
100
0 2 4 6 8 10
Concentration (x 10
-3
µ M)
Cell
Viability
%