(23) session 23 heterocyclic compounds (self-study!)
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Heterocyclic compunds
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(23) session 23 heterocyclic compounds (self-study!)
- 1. 5/2/2012 1 Session 23 Organic Chemistry, UNAM School of Medicine1 Heterocyclic CompoundsHeterocyclic CompoundsHeterocyclic CompoundsHeterocyclic Compounds Dr L.H.A. Prins (Ph.D.) Dept. of Pharmacy UNAM Learning Outcomes 2 By the end of this session, the student should be able to: Understand the importance of heterocyclic compounds Recognise & name selected heterocyclic compounds Describe the structure of heterocyclic compounds Describe some chemical properties of heterocyclic compounds Organic Chemistry, UNAM School of Medicine
- 2. 5/2/2012 2 Definitions??Definitions??Definitions??Definitions?? 3 Heterocycles = Ring compounds with elements other than C in the ring - Most common elements to appear in heterocyclic compounds: oxygen (O), nitrogen (N) & sulphur (S) -Aliphatic heterocycles are similar to the open chain analogues (ethers, amines & sulphides) - Unsaturated heterocycles have unique & interesting properties Organic Chemistry, UNAM School of Medicine Importance??Importance??Importance??Importance?? 4 Two thirds of all organic compounds are aromatic heterocycles. Most pharmaceuticals are heterocycles. Quinine & sildenafil: Examples of heterocycles used as pharmaceuticals Organic Chemistry, UNAM School of Medicine Quinine Pfizer: Viagra® Treatment of malaria for 400 years Erectile dysfunction Sildenafil
- 3. 5/2/2012 3 Importance??Importance??Importance??Importance?? 5 Organic Chemistry, UNAM School of Medicine N N Me N NHMe N NC H H Ovarian & lung cancer GSK - TopotecanPfizer - Irinotecan Treating stomach & intestinal ulcers Cimetidine Definitions??Definitions??Definitions??Definitions?? 6 Natural product = Compound synthesised by a plant or an animal Alkaloids = Natural products that contain one or more N heteroatoms Organic Chemistry, UNAM School of Medicine
- 4. 5/2/2012 4 Nomenclature ofNomenclature ofNomenclature ofNomenclature of heterocyclesheterocyclesheterocyclesheterocycles 7 Saturated cyclic amine - named as a cycloalkane, using the prefix “aza” to denote the N atom - Heterocyclic rings are numbered so that the heteroatom has lowest possible # - Some common names are acceptable according to IUPAC Examples: Organic Chemistry, UNAM School of Medicine Nomenclature ofNomenclature ofNomenclature ofNomenclature of heterocyclesheterocyclesheterocyclesheterocycles 8 Saturated heterocycles: - Heterocycles with O & S heteroatoms are named similarly - Prefix for O is “oxa” - Prefix for S is “thia” • Examples: Organic Chemistry, UNAM School of Medicine
- 5. 5/2/2012 5 Nomenclature ofNomenclature ofNomenclature ofNomenclature of heterocyclesheterocyclesheterocyclesheterocycles 9 Saturated heterocycles: - Lowest # assigned to heteroatom with the highest precedence: O > S > N • Example: Organic Chemistry, UNAM School of Medicine Nomenclature ofNomenclature ofNomenclature ofNomenclature of heterocyclesheterocyclesheterocyclesheterocycles 10 Heterocyclic names you should know: Organic Chemistry, UNAM School of Medicine
- 6. 5/2/2012 6 Nomenclature ofNomenclature ofNomenclature ofNomenclature of heterocyclesheterocyclesheterocyclesheterocycles 11 Heterocyclic names you should know: Organic Chemistry, UNAM School of Medicine Nomenclature ofNomenclature ofNomenclature ofNomenclature of heterocyclesheterocyclesheterocyclesheterocycles 12 Heterocyclic names you should know: Organic Chemistry, UNAM School of Medicine
- 7. 5/2/2012 7 Nomenclature ofNomenclature ofNomenclature ofNomenclature of heterocyclesheterocyclesheterocyclesheterocycles 13 Heterocyclic names you should know: Organic Chemistry, UNAM School of Medicine Nomenclature ofNomenclature ofNomenclature ofNomenclature of heterocyclesheterocyclesheterocyclesheterocycles 14 Heterocyclic names you should know: Organic Chemistry, UNAM School of Medicine
- 8. 5/2/2012 8 6666----memberedmemberedmemberedmembered heterocyclesheterocyclesheterocyclesheterocycles: Pyridine: Pyridine: Pyridine: Pyridine 15 Organic Chemistry, UNAM School of Medicine N N H pyridine piperidine In pyridine the CH of benzene is replaced by a N atom (& a pair of electrons) Hybridisation = sp2 with similar resonance stabilisation as benzene Lone pair of electrons not involved in aromaticity Pyridine is a weak base Pyridine is ππππ electron deficient Electrophilic aromatic substitution is difficult Nucleophilic aromatic substitution is easy 6666----memberedmemberedmemberedmembered heterocyclesheterocyclesheterocyclesheterocycles: Pyridine: Pyridine: Pyridine: Pyridine 16 Organic Chemistry, UNAM School of Medicine Pyridine (pKa = 5 .25) is a weaker base than alkylamines Reason: Lone-pair e- on pyridine N are in an sp2 orbital, while those on alkylamine N are in an sp3 orbital Because s orbitals have maximum e- density at the nucleus but p orbitals have a node at the nucleus, e- in an orbital with more s character are held more closely to the + charged nucleus & are less available for bonding (∴∴∴∴ less basic) sp2 hybridised N atom (33% s character) in pyridine is less basic than sp3 hybridised N in analkylamine (25% s character )
- 9. 5/2/2012 9 5555----memberedmemberedmemberedmembered heterocyclesheterocyclesheterocyclesheterocycles:::: PyrrolePyrrolePyrrolePyrrole 17 Organic Chemistry, UNAM School of Medicine Pyrrole is aromatic: 6 ππππ electrons Lone pair tied up in aromatic ring Pyrrole is ππππ electron excessive Electrophilic aromatic substitution is easy Nucleophilic aromatic substitution is difficult 5555----memberedmemberedmemberedmembered heterocyclesheterocyclesheterocyclesheterocycles:::: PyrrolePyrrolePyrrolePyrrole 18 Organic Chemistry, UNAM School of Medicine N atom in pyrrole is less e- rich, less basic & less nucleophilic than N in an aliphatic amine C atoms of pyrrole are more e- rich & more nucleophilic than typical = bond C’s ∴∴∴∴ Pyrrole ring – very reactive toward electrophiles
- 10. 5/2/2012 10 5555----memberedmemberedmemberedmembered heterocyclesheterocyclesheterocyclesheterocycles:::: PyrrolePyrrolePyrrolePyrrole 19 Organic Chemistry, UNAM School of Medicine Electrostatic potential maps – pyrrole N is e- poor (less red) compared with N in its saturated counterpart pyrrolidine Pyrrole C atoms are e- rich (more red ) compared with C’s in 1,3- cyclopentadiene 5555----memberedmemberedmemberedmembered heterocyclesheterocyclesheterocyclesheterocycles with 2 or morewith 2 or morewith 2 or morewith 2 or more NitrogensNitrogensNitrogensNitrogens 20 Organic Chemistry, UNAM School of Medicine Diazoles ImidazolePyrazole Triazoles N N N H N N N H N NN H N NN H 1,2,3-Triazole 1,2,4-Triazole pKa = 10.3 pKa = 14.5 (imidazole) pKa = 16.5 (pyrrole) Imidazole is more basic than pyridine, but more acidic than pyrrole Weakly basic like pyridine, but more acidic than imidazole
- 11. 5/2/2012 11 5555----memberedmemberedmemberedmembered heterocyclesheterocyclesheterocyclesheterocycles with 2 or morewith 2 or morewith 2 or morewith 2 or more NitrogensNitrogensNitrogensNitrogens 21 Organic Chemistry, UNAM School of Medicine Tetrazoles N N NN H R N N NN H R N N NN H R N N NN R N N NN R _ _ etc pKa ~ 5 ~ RCOOH PolycyclicPolycyclicPolycyclicPolycyclic heterocyclesheterocyclesheterocyclesheterocycles:::: IndoleIndoleIndoleIndole 22 Organic Chemistry, UNAM School of Medicine Indole is aromatic: 10 ππππ electrons Has a non-basic, pyrrole-like N & undergoes electrophilic substitution more easily than benzene Benzene part is non-reactive Electrophilic aromatic substitution occurs at C3 of the e- rich pyrrole ring N H Indole
- 12. 5/2/2012 12 PolycyclicPolycyclicPolycyclicPolycyclic heterocyclesheterocyclesheterocyclesheterocycles:::: IndoleIndoleIndoleIndole 23 Organic Chemistry, UNAM School of Medicine Quinoline & isoquinoline are aromatic: 10 ππππ electrons Have basic, pyridine-like N atoms Undergo electrophilic substitutions, although less easily than benzene Reaction occurs on the benzene ring rather than on the pyridine ring Quiz: Heterocycles Review of General Chemistry, UNAM School of Medicine24 Which N atom in the hallucinogenic indole alkaloid, N,N- dimethyltryptamine is more basic? Explain.
- 13. 5/2/2012 13 Thank you 25 END Organic Chemistry, UNAM School of Medicine Review of General Chemistry, UNAM School of Medicine26 Quiz answer: The side-chain N atom of N,N-dimethyltryptamine is more basic than the ring N atom because its lone pair electrons is more available for donation to a Lewis acid. The aromatic N lone pair electrons is part of the ring π electron system.
- 14. 5/2/2012 14 Review of General Chemistry, UNAM School of Medicine27 Additional reading on aromaticity: Organic Chemistry, John McMurry (7th Ed) Sections 15.3 – 15.5 Page 523 - 530