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. Ovarian & lung cancer GSK - TopotecanPfizer - 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) Erich Hückel

5. Six Membered Heterocycles: Pyridine Pyridine replaces the CH of benzene by a N atom (and a pair of electrons) Hybridization = sp 2 with similar resonance stabilization energy Lone pair of electrons not involved in aromaticity 1 H NMR:  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. Pyridine as a nucleophile Use Pyridine as a solvent to make esters Acyl pyridinium ion Reactive intermediate E.g.

7. DMAP (DimethylAminoPyridine) 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 Unreactive, Stable

8. How can we nitrate pyridine? We now have an activating and protecting group Mechanism

9. Third Period ; n 2 = 3 2 = 9 orbitals Ar [Ne]; 3s 2, 3p x 2, 3p y 2, 3p z 2 3d 0 3d 0 3d 0 3d 0 3d 0 n = 3

10. Nucleophilic Substitution at 2- and 4-positions of pyridine is most favoured E.g.

11. Five Membered Heterocycles: Pyrrole 1 H NMR:  Aromatic: Thus, 6  electrons Sp 2 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. 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. Organic Synthesis with Pyrrole should avoid strong acids i; 1 X SO 2 Cl 2, Et 2 O ii; 4 X SO 2 Cl 2, Et 2 O i ii

14. Indole Lysergic acid (LSD)Strychnine Indole Alkaloids Aromatic due to 10  -electrons Benzene part is non-reactive Electrophilic aromatic substitution occurs at the 3-position Mitomycin C

15. Other Five Membered Heterocycles 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. AlCl 3 Electrophilic Aromatic Substitution of Thiophene

17. Some Reactions of Furan 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

19. The Diels-Alder Reaction Otto Diels Kurt Alder Noble Prize in 1950 Diene 4  system dienophile 2  system 4+2  cycloaddition Electron rich Electron poor

20. The configuration of the dienophile is retained Always reacts via the cis-diene Under kinetic control

21. 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 - SO 2 This sulfone is not aromatic & very reactive

22. Five-membered Rings with Two or More Nitrogens Diazoles ImidazolePyrazole Imidazole is more basic than pyridine, but more acidic than pyrrole Imidazole + H + Imidazole - H + NaOH Properties: Very stable cation and anion of imidazole is formed pKa = 14.5 (imidazole) pKa = 16.5 (pyrrole) - H 2 O

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 (i)(ii)(iii) (i)ClCPh 3, NEt 3 (ii) Bu-Li, n-PrONO 2 (iii) HCl (aq), MeOH 30% 2-Nitroimidazole, “azomycin” 5-Nitroimidazoles, “metronidazole” is used to treat anaerobic protozoan infections metronidazoleinactive (i) (i) HNO 3, H 2 SO 4 80% 5 4

25. Triazoles 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 pKa ~ 5 ~ RCOOH

26. Indomethacin Tetrazole derivative Tetrazoles are used in drugs as replacements for CO 2 H Anti-arthritis drug - Non steroidal anti-inflammatory drug – reduces fever, pain, stiffness, delays premature labour & other uses Indomethacin

27. Synthesis of Indomethacin

28. Bioreductive Anti-Tumour Agents I C 50 ≈ 1.0 µM I C 50 ≈ 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 + 2 e - + 2 H + CY P450 reductase Two electron activation DT-diaphorase. + 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 ●, ● 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