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

(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

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

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

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

Oxygen Containing Heterocycles Epoxides in our system Role of Vitamin K epoxide? Role of Squalene epoxide? Squalene Epoxide MEDC 527 Fall 2008

Oxygen Containing Heterocycles Reactions of Epoxides Acid Opening of Epoxides MEDC 527 Fall 2008

Oxygen Containing Heterocycles Reactions of Epoxides Enzymatic opening of epoxides Opening of epoxides with amines (lysine mimics) and alcohols (serine mimics) MEDC 527 Fall 2008

Oxygen Containing Heterocycles Higher Oxides Oxetane oxolane oxane 1,4-dioxane Structure? Reactivity? Usage? Toxicity? MEDC 527 Fall 2008

Oxygen Containing Heterocycles Higher Oxides Stability of these oxides change drastically on a-substitution Lactones anhydrides Hemi-acetals acetals MEDC 527 Fall 2008

Oxygen Containing Heterocycles Examples of Acetals or Hemi-Acetals in Nature MEDC 527 Fall 2008

Oxygen Containing Heterocycles Interconversion of a- and b-forms of sugars The phenomenon of mutarotation MEDC 527 Fall 2008

Oxygen Containing Heterocycles Examples of sugars in natural systems Deoxynucleic Acids and Ribonucleic Acids Live link: http://www.bmrb.wisc.edu/referenc/nomenclature/ MEDC 527 Fall 2008

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

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

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

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 MEDC 527 Fall 2008

Oxygen Containing Heterocycles Fructose Sucrose MEDC 527 Fall 2008

Oxygen Containing Heterocycles Polysaccharides – Cellulose and Starch MEDC 527 Fall 2008

Nitrogen Containing Heterocycles 3-Membered Ring MEDC 527 Fall 2008

Nitrogen Containing Heterocycles 3-Membered Ring in our system? How do these work? MEDC 527 Fall 2008

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

Higher Heterocycles Containing Nitrogen Examples of Drugs … 4-membered ring Hydrolysis of b-lactams …… acid/base and enzymatic conditions MEDC 527 Fall 2008

Higher Heterocycles Containing Nitrogen Importance of b-lactam ring in activity …… generation of resistance!! Clavulinic Acid …… antidote to antibiotic resistance MEDC 527 Fall 2008

Higher Heterocycles Containing Nitrogen Examples of Drugs … 5-membered ring (anti-hyperlipidemic agent) (anti-histaminic) MEDC 527 Fall 2008

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

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

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

5-Membered Heterocycles Metabolism of Aromatic Rings Containing Two Heteroatoms MEDC 527 Fall 2008

Higher Heterocycles Containing Nitrogen and Another Heteroatom Examples of such heterocycles in Drugs (anti-biotic agent) (anti-biotic agent) (pain medication) MEDC 527 Fall 2008

Heterocycles Containing Sulfur Basic Ring Systems Examples in Drugs (Antihistamine) (Antibiotic) (Antimalarial) MEDC 527 Fall 2008

Complex Heterocycles Examples in Drugs (Antibiotic) (Antihypertensive) (for pneumonia) (Antihypertensive) (Anti-infectious) (Anti-seizure) MEDC 527 Fall 2008

6 Membered Rings Containing One Nitrogen Examples in Drugs MEDC 527 Fall 2008

6 Membered Rings Containing Two Nitrogens Diazines 1,2-diazine 1,3-diazine 1,4-diazine (pyridazine) (pyrimidine) (pyrazine) Acid – Base Properties Ist pKA ? IInd pKA ? Why are these dibasic compounds not strongly basic ? MEDC 527 Fall 2008

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

6 Membered Rings Containing Two Nitrogens Special Pyrimidines … Barbituric Acid (Keto form) pKA = ~4 Phenytoin (anti-psychotic) (Enol form) MEDC 527 Fall 2008

Heterocycles More Complex Unsaturated Ring Systems 6-membered and higher heterocycles MEDC 527 Fall 2008

Azepine diazepine oxazepine Heterocycles More Complex Unsaturated Ring Systems 6-membered and higher heterocycles Azepine diazepine oxazepine MEDC 527 Fall 2008

7 and 8 Membered Nitrogen Containing Heterocycles MEDC 527 Fall 2008

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