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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)
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
N
N
Me
N NHMe
NNC
H
H
Ovarian & lung cancer
GSK - TopotecanPfizer - Irinotecan
Camptothecin Analogues
Treating stomach & intestinal ulcers
More soluble & less side-effects
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
Six Membered Heterocycles: Pyridine
N N
Hpyridine 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
HH
H H
pyridine
8.5
7.1
7.5
1H NMR: Pyridinium ion: pKa = 5.5
Piperidine: pKa = 11.29
diethylamine : pKa = 10.28
Pyridine is a weak basePyridine is -electron deficientElectrophilic aromatic substitution is difficultNucleophilic aromatic substitution is easy
N
Me I
N
Me+ I
_
O
O
O OH O
O
O
R X
O
R OR
+ 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 ionReactive intermediate
E.g.
DMAP (DimethylAminoPyridine)
N
NCH3CH3
NN
H
N
NO2
+
ii
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
NN
AlCl3
N
R
O
+
iiii
ii, AlCl3, RCOCl_
Unreactive, Stable
How can we nitrate pyridine?
N N
ON
O
NO2
N
O
O N O
N
O
NO2
N
NO2
O PPh3
N
O
N HO
O
+_
H2O2, AcOH
Pyridine N-oxide
HNO3, H2SO4
+_
85%
+_
+
+_
PPh3+
75%
+
+
_We now have an activating and protecting group
Mechanism
Third Period ; n2 = 32 = 9 orbitals
Ar [Ne]; 3s2, 3px2, 3py
2, 3pz2 3d0 3d0 3d0 3d0 3d0
n = 3
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
BrNH3 (aq)
65%
Five Membered Heterocycles: Pyrrole
N
H
H
H
H
H
Pyrrole
6.5
6.2
1H NMR: 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
N
HN
H O
H
O
H NMe2
N
SO2Ph
N
SO2Ph
Me
O
N
H
Me
O
N
H
N
H
NO2N
H
NO2
+
1. POCl32. 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
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
ClCl
ClCl
80%
80%
i; 1 X SO2Cl2, Et2O
ii; 4 X SO2Cl2, Et2O
i
ii
Indole
Lysergic acid (LSD) Strychnine
Indole Alkaloids
N
H
Indole
N
HN
H
CHOVilsmeier
55%
Aromatic due to 10 -electrons
Benzene part is non-reactive
Electrophilic aromatic substitution
occurs at the 3-position
OCONH2
N
OMe
NH
NH2
Me
O
O
Mitomycin C
Other Five Membered Heterocycles
N
HS 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
Avoid concentrated mineral acids or strong Lewis acids, e.g. AlCl3
Electrophilic Aromatic Substitution of Thiophene
SS
O
H
O
H NMe2
S S NO2
S S ClS Cl
Cl
+
1. POCl32. Na2CO3, H2O
68%
HNO3, AcOH, Ac2O / -10 C
85%
43%
SO2Cl2, heat
10%
S SO
O
O
O
O OO
O
O
O
+ZnCl2, 100 C
+ZnCl2, 0 C
83%
95%
Some Reactions of Furan
OO
Br
Br
Br
Br O
OMeMeO
H H
CHOOHC
OPh3P
OHC
CHO
CHOOHC
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
Furan is a source of 1,4-dicarbonyls in Organic Synthesis
O
OMeMeO
H H
O OH H
O
R H
O RH
O RHR H
O O RR
OR R O OR R
cis-butenediol(too unstable to isolate)
H+, H2O
acetal acetal
+1
1 11 - H2O
acetalaldehyde + 2 x alcohol
H+, H2O
acid-catalysed
The Diels-Alder Reaction
Otto Diels
Kurt Alder
Noble Prize in 1950
O
O
O
O
O
O
+100 C
benzene
100%Diene
4 systemdienophile2 system 4+2 cycloaddition
Electron rich
Electron poor
O
H
O
H+
30 C
100%
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
HH
OO
O
+25 C
100%
endo product(100%)
Under kinetic control
OO
O
O
Thermodynamicexo-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
OX
S OO
X
X
+- SO2
This sulfone is not aromatic & very reactive
Five-membered Rings with Two or More Nitrogens
Diazoles
N
N
H
NN
H
ImidazolePyrazole
Imidazole is more basic than pyridine, but more acidic than pyrrole
N
N
H
H
N
NH
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
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
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
Triazoles
NN
N
H
NN
N
H
N
NN
H
N
NN
H
1,2,3-Triazole1,2,4-Triazole
Weakly basic like pyridine, but more acidic than imidazole
pKa = 10.3
Tetrazoles Only one isomer now possible
NN
NN
H
RN
N
NN
H
R
NN
NN
H
RN
N
NN
R NN
NN
R_
_
etc
pKa ~ 5 ~ RCOOH
N
O
OMe
O
Cl
H
N
OMe
O
Cl
NN
NNH
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
N
HN
H
NMe2
N
H
CN
NH
NN
NN
H
N
NN
NN
O
Cl
H
98%
Me2NH, CH2=O NaCN
NaN3, NH4Cl, LiCl
DMF, 100 C
Synthesis of Indomethacin
Bioreductive Anti-Tumour AgentsOCONH2
N
OMe
NH
NH2
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 AnemiaMore selective to hypoxia
Targeting Hypoxic Cells
Mitomycin C (MMC)
SET - activation
O
O
N
NH2
Me
OCONH2
OMe
NH
O
O
N
NH2
Me
OCONH2
NH
OMe
O
O
N
NH2
MeNH2
DNA
O
O
N
NH2
Me
OCONH2
OMe
NH N
NH2
Me
OCONH2
OMe
OH
OH
NH N
NH2
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
Measuring the Effect of FANCD2 Expression on Cell Viability
N NH
OMe
OCONH2O
O
NH2
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 10-3µ M)
Ce
ll V
iab
ility
%
