1. Heterocycles
Nomenclature
Hetero-atom is to be counted as 1 or as low as possible
When there is more than one hetero-atom, preference is given to O, then S, then N, then C. Also N-H presides over –N=. Mnemonic: Old Soldiers Never Cry
When there is more than one hetero-atom, numbering should be as direct as possible from one to the other
Substituents are numbered as low as possible
Acceptable prefixes include O=Oxa; S=Thia; N=Aza
Common suffixes for N- and non-N-heterocycles For partially unsaturated systems, H is(are) are used to indicate the location of saturation
Hantzsch-Widman System of systematic name of heterocyclic compounds
MEDC 527 Fall 2008

2. (di, tetra, or hexahydro)
Heterocycles
Hantzsch – Widman Nomenclature (adopted by IUPAC)
Ring Size
Saturated
Partly Saturated
Unsaturated 3
-irane -
-irene 4
-etane
(dihydro)
-ete 5
-olane
-ole 6
-inane
(di or tetrahydro)
-ine 7
-epane
-epine 8
-ocane
(di, tetra, or hexahydro)
-ocine
Common name : ethylene oxide
Systematic name : Oxa + irane …. Oxirane
Common name : furan
Systematic name : Oxa + ole …. Oxole
MEDC 527 Fall 2008

3. Heterocycles
Hantzsch – Widman Nomenclature (adopted by IUPAC)
Common name : pyrrole
Systematic name : H at 1 position + Aza + ole …. 1H-Azole
Common name : piperidine
Systematic name : Aza + inane …. 1H-Azinane
Common name : pyrimidine
Systematic name : two aza at 1, 3 positions + ine …. [1,3]-diazine
MEDC 527 Fall 2008

4. Heterocycles
Hantzsch – Widman Nomenclature (adopted by IUPAC)
Azocane
[1,3]-Oxazocane
[1,3,7]-Oxathiazocane
4,5-dihydro-2H,8H-
[1,3,7]-oxathiazocine
6-Methyl-2-phenyl-
2H,8H-[1,3,7]-oxathiazocine
6-Methyl-2-phenyl-
2H,3H,8H-oxocine
MEDC 527 Fall 2008

5. Oxygen Containing Heterocycles
3-Membered Ring :: Ethylene Oxide or oxirane
Structure?
Form at room temperature?
Reactivity?
Usage?
Toxicity?
Oxirane formation in our body
Oxidizing Enzymes
MEDC 527 Fall 2008

6. Oxygen Containing Heterocycles
Epoxides in our system
Role of Vitamin K epoxide?
Role of Squalene epoxide?
Squalene Epoxide
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7. Oxygen Containing Heterocycles
Reactions of Epoxides
Acid Opening of Epoxides
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8. Oxygen Containing Heterocycles
Reactions of Epoxides
Enzymatic opening of epoxides
Opening of epoxides with amines (lysine mimics) and alcohols (serine mimics)
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9. Oxygen Containing Heterocycles
Higher Oxides
Oxetane oxolane oxane 1,4-dioxane
Structure?
Reactivity?
Usage?
Toxicity?
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10. Oxygen Containing Heterocycles
Higher Oxides
Stability of these oxides change drastically on a-substitution
Lactones anhydrides
Hemi-acetals acetals
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11. Oxygen Containing Heterocycles
Examples of Acetals or Hemi-Acetals in Nature
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12. Oxygen Containing Heterocycles
Interconversion of a- and b-forms of sugars
The phenomenon of mutarotation
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13. Oxygen Containing Heterocycles
Examples of sugars in natural systems
Deoxynucleic Acids and Ribonucleic Acids
Live link:
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14. Oxygen Containing Heterocycles
Sugars and Diabetes
Glycated Hemoglobin (HbA1c or GHb)
Also called glycosylated hemoglobin. The saccharide equilibrium is the reason for the formation of glycated hemoglobin in diabetic patients. Excess free plasma sugar, and therefore the open-chain aldehyde, reacts with the N-terminal NH2 group of hemoglobin (or lysine side chains) to form glycated adducts, which are detected to confirm and monitor diabetes. The upper limit for a normal individual is 7% HbA1c.
MEDC 527 Fall 2008

15. Oxygen Containing Heterocycles
Sugars
Monosaccharides
D-Glyceraldehye
D-Threose
D-Erythrose
D-Lyxose
D-Xylose
D-Ribose
D-Arabinose
D-Galactose
D-Talose
D-Gulose
D-Idose
D-Allose
D-Altrose
D-Glucose
D-Mannose
MEDC 527 Fall 2008

16. Oxygen Containing Heterocycles
Reducing and Non-reducing Sugars
D-Glucose
D-Mannose
D-Sorbitol
D-Mannitol
Sorbitol is 66% as sweet as glucose. It is poorly absorbed and hence does not lead to high sugar levels in blood. It is not as calorific (~70% as calories as glucose) … used as sugar-free sweetner.
Mannitol is a good osmotic diuretic …. Intravenous drip …. Rapidly filtered by kidneys but not reabsorbed resulting in an osmotic effect of water/Na+ excretion
MEDC 527 Fall 2008

17. Oxygen Containing Heterocycles
Derivatized Forms of Monosaccharides
a-D-Glucosamine
D-Glucosamine
D-Glucose
D-Idose
a-D-Glucuronic Acid
D-Glucuronic Acid
D-Gluconic Acid
D-Idonic Acid
D-Iduronic Acid _
a-D-Iduronic Acid
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18. Oxygen Containing Heterocycles
Fructose
Sucrose
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19. Oxygen Containing Heterocycles
Polysaccharides – Cellulose and Starch
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20. Nitrogen Containing Heterocycles
3-Membered Ring
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21. Nitrogen Containing Heterocycles
3-Membered Ring in our system?
How do these work?
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22. Higher Heterocycles Containing Nitrogen
Basic Ring Systems
Acid – Base Properties
H2+
pKA 9.6
pKA 9.9
Ist pKA ?
IInd pKA ?
Stability to Water, Acid and Base
Without substituents ?
With substituents ?
MEDC 527 Fall 2008

23. Higher Heterocycles Containing Nitrogen
Examples of Drugs … 4-membered ring
Hydrolysis of b-lactams …… acid/base and enzymatic conditions
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24. Higher Heterocycles Containing Nitrogen
Importance of b-lactam ring in activity …… generation of resistance!!
Clavulinic Acid …… antidote to antibiotic resistance
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25. Higher Heterocycles Containing Nitrogen
Examples of Drugs … 5-membered ring
(anti-hyperlipidemic agent)
(anti-histaminic)
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26. Five-membered Rings Containing Nitrogen and Another Heteroatom
Nitrogen and Oxygen
Acid – Base Properties
Ist pKA ?
IInd pKA ?
Why is imidazole not strongly basic ?
pKA with greater substitution ?
MEDC 527 Fall 2008

27. Higher Heterocycles Containing Nitrogen and Another Heteroatom
Stability to Water, Acid and Base
Without substituents ?
With substituents ?
MEDC 527 Fall 2008

28. 5-Membered Aromatic Heterocycles
Metabolism of Aromatic Rings Containing One Heteroatom
5-Membered heterocycles generally react well with electrophiles; better than benzene
Stability to metabolic enzymes is generally lower than their carbocyclic analogs
EAS occurs at the 2-position of 5-membered heterocycles
MEDC 527 Fall 2008

29. 5-Membered Heterocycles
Metabolism of Aromatic Rings Containing Two Heteroatoms
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30. Higher Heterocycles Containing Nitrogen and Another Heteroatom
Examples of such heterocycles in Drugs
(anti-biotic agent)
(anti-biotic agent)
(pain medication)
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31. Heterocycles Containing Sulfur
Basic Ring Systems
Examples in Drugs
(Antihistamine) (Antibiotic) (Antimalarial)
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32. Complex Heterocycles
Examples in Drugs
(Antibiotic) (Antihypertensive)
(for pneumonia) (Antihypertensive)
(Anti-infectious) (Anti-seizure)
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33. 6 Membered Rings Containing One Nitrogen
Examples in Drugs
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34. 6 Membered Rings Containing Two Nitrogens
Diazines
1,2-diazine ,3-diazine ,4-diazine
(pyridazine) (pyrimidine) (pyrazine)
Acid – Base Properties
Ist pKA ?
IInd pKA ?
Why are these dibasic compounds not strongly basic ?
MEDC 527 Fall 2008

35. 6 Membered Rings Containing Two Nitrogens
Pyrimidines
Three derivatives are important for RNA/DNA
Uracil Thymine Cytosine
Forms of Pyrimidines
Urea Imide or Keto form Enol form
(neutral) (acidic) (acidic)
MEDC 527 Fall 2008

36. 6 Membered Rings Containing Two Nitrogens
Special Pyrimidines … Barbituric Acid
(Keto form)
pKA = ~4
Phenytoin
(anti-psychotic)
(Enol form)
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37. Heterocycles More Complex Unsaturated Ring Systems
6-membered and higher heterocycles
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38. Azepine diazepine oxazepine
Heterocycles
More Complex Unsaturated Ring Systems
6-membered and higher heterocycles
Azepine diazepine oxazepine
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39. 7 and 8 Membered Nitrogen Containing Heterocycles
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40. Six Membered Aromatic Heterocycles
Metabolism of Pyridines
Pyridines are less reactive toward electrophiles than benzene
Stability to metabolic enzymes is generally higher than their carbocyclic analogs
EAS occurs at the 3-position of 6-membered heterocycles
MEDC 527 Fall 2008