Heterocycles 3 - PDF

Fused Five-Membered Rings 4 3 5 2 6 N1 O S 7 H indole benzofuran benzothiophene (benzopyrrole) Five-membered aromatic ring fuse...

Fused Five-Membered Rings 4 3 5 2 6 N1 O S 7 H indole benzofuran benzothiophene (benzopyrrole) Five-membered aromatic ring fused to benzene Planar and aromatic – 10 p electron system One lone pair of e-’s are part of the p cloud Indole  does not act as a base (similar to pyrrole) Considered p excessive  Electrophilic Aromatic Substitution E Substitution primarily at + E+ the C-3 position N N H H + E+ E Substitution primarily at the C-2 position O O E + E+ E + S S S Substitution at both the C-2 & C-3 position Substitution pattern is dependant on resonance contributors and electronegativity of the heteroatom  Importance of Indole CO2H Tryptophan is an essential amino acid NH2 Built into many proteins Found in many protein based N H foods & dietary products Tryptophan (Trp) Precursor to many indole alkaloids [O] Metabolised to CO2H 5-hyroxytryptophan (5-HTP) 5-HTP HO NH2 – crosses the BBB – is sold as a health supplement N H in the US 5-HTP – is a precursor to serotonin  Pharmaceutical Importance OH HO NH2 Me O N H N Indomethacin – Serotonin - neurotransmittor in the CNS anti inflammatory Controls mood, body temp., sleep, O for arthritis anger, metabolism O Cl N N N H N H O O N H Lysergic acid diethylamide (LSD)- Strychnine - pesticide Psychedelic drug, mimics serotonin Monocyclic Rings – 2 Heteroatoms 1,2- & 1,3-Azoles 4 3 5 1 N2 1 N2 1 N2 N S O H pyrazole isothiazole isoxazole pKa = 2.5 pKa = -0.5 pKa = -3.0 4 N3 N3 N3 5 1 2 1 1 N S O H oxazole imidazole thiazole pKa = 7.1 pKa = 2.5 pKa = 0.8 The atom at position 1 contributes 2 e-’s to the aromatic sextet The atom at position 1 takes precedence over the others (O, S, N)  Pyrazole & Imidazole N3 N 1 N2 N 1 N N N N H H H H The N at the 1-position is non-basic as the lone-pair of e-’s form part of the aromatic sextet (pyrrole-like). N-2 & N-3 are basic (pyridine-like). Imidazole is a stronger base than pyrazole due to resonance (in imidazole) & the e- withdrawing effect (in pyrazole). Imidazole has a pKa of almost exactly 7, i.e. it is 50% protonated in neutral water.  -H+ -H+ HN NH HN N N N +H+ +H+ tautomerism pKaH 7.1 pKa 14.5 HN NH N NH N N The 2 N’s share the charge equally They are perfectly symmetrical and unusually stable It is amphoteric in nature (acting as a base, but also a weak acid)  Hydrogen Bonding in Imidazole N N N H N H H N N N H N Imidazole, like water, is good at donating & accepting H-bonds. This property is central to the mode of action of several enzymes which utilise the imidazole ring of a histidine.  Pharmaceutical Importance Cimetidine- Histamine- Histidine- for heartburn vasodilator essential amino acid O & peptic ulcers H N MeHN N N OH S N NH2 N N H2N CN H N N H H O O N N O N N O NH O Dantrolen- H H O N Muscle relaxant used for S strokes, MS, ecstacy intoxication O N O O N O S S OH N Oxacillin- O H Antibiotic for penicillin resistant H2N Sufathiazole- Staphylococcus Aureus antimicrobial  1,2-, 1,3- & 1,4-Diazines 4 N N3 3 1 N2 1 2 1 2 N N N pyridazine pyrimidine pyrazine pKa = 2.3 pKa = 1.3 pKa = 0.65 All are stable, colourless compounds, soluble in water. Both nitrogens are pyridine-like (lone pair e-’s are not delocalized). + H Behave as weak bases. N N N N H  Pyrimidones Pyrimidines are more important because of their involvement in DNA & RNA – the pyrimidones O O NH2 Me NH NH N N O N O N O H H H Uracil (U) Thymine (T) Cytosine (C) Derivatives: – Pyrimidine nucleosides (base + sugar) – Pyrimidine nucleotides (base + sugar + phosphate ester) – RNA, DNA (polynucleotides)  Barbiturates – another pyrimidone Barbituric acid is not biologically active O O NH R1 NH O 5 O NH R2 NH O O Barbituric acid Derivatives differ only in substituents at the 5-position (R1 & R2) Used as hypnotics (can cause sedation right through to total anaesthesia) and anticonvulsants  The N lone pair of e-’s are unavailable for bonding. Barbiturates are  not basic. They do however donate protons and are  weak acids (pKa ~ 7-8) O O O O NH N R1 N R1 N R1 -H R1 + O O O O R2 R2 R2 NH R2 NH NH NH O O O O O R1 N O R2 NH O  Pharmaceutical Importance O NH2 Me O NH N HO N O O N NH2 O H O N3 AZT – Zidovudine Trimethoprim – Antiretroviral (HIV, AIDS) Bacteriostatic antibiotic (UTI) O H N N N N N NH2 O N Minaprine – antidepressant Pyrazinamide – bacteriostatic Monoamine oxidase inhibitor (tuberculosis)