Heterocycles

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 OOxa SThia NAza
• 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

2
Heterocycles

• Hantzsch Widman Nomenclature (adopted by
  IUPAC)

Ring Size Saturated Partly Saturated Unsaturated
3 -irane - -irene
4 -etane (dihydro) -ete
5 -olane (dihydro) -ole
6 -inane (di or tetrahydro) -ine
7 -epane (di or tetrahydro) -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
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
4
Heterocycles

• Hantzsch Widman Nomenclature (adopted by
  IUPAC)

1,3-Oxazocane
1,3,7-Oxathiazocane
Azocane
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
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
6
Oxygen Containing Heterocycles

• Epoxides in our system

• Role of Vitamin K epoxide?

• Role of Squalene epoxide?

Squalene Epoxide
7
Oxygen Containing Heterocycles

• Reactions of Epoxides

Acid Opening of Epoxides
8
Oxygen Containing Heterocycles

• Reactions of Epoxides

Enzymatic opening of epoxides
Opening of epoxides with amines (lysine mimics)
and alcohols (serine mimics)
9
Oxygen Containing Heterocycles

• Higher Oxides

Oxetane oxolane oxane 1,4-dioxane

• Structure?
• Reactivity?
• Usage?
• Toxicity?

10
Oxygen Containing Heterocycles

• Higher Oxides

Stability of these oxides change drastically on
a-substitution
Lactones

anhydrides
Hemi-acetals

acetals
11
Oxygen Containing Heterocycles

• Examples of Acetals or Hemi-Acetals in Nature

12
Oxygen Containing Heterocycles

• Interconversion of a- and b-forms of sugars
• The phenomenon of mutarotation

13
Oxygen Containing Heterocycles

• Examples of sugars in natural systems
• Deoxynucleic Acids and Ribonucleic
  Acids

Live link http//www.bmrb.wisc.edu/referenc/nomen
clature/
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.
15
Oxygen Containing Heterocycles

• Sugars
• Monosaccharides

D-Glyceraldehye
D-Threose
D-Erythrose
D-Lyxose
D-Ribose
D-Xylose
D-Arabinose
D-Galactose
D-Allose
D-Gulose
D-Glucose
D-Talose
D-Altrose
D-Idose
D-Mannose
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
17
Oxygen Containing Heterocycles

• Derivatized Forms of Monosaccharides

D-Glucosamine
a-D-Glucosamine
D-Glucose
D-Idose
D-Glucuronic Acid
D-Iduronic Acid
a-D-Glucuronic Acid
D-Gluconic Acid
D-Idonic Acid
a-D-Iduronic Acid
18
Oxygen Containing Heterocycles

• Fructose

• Sucrose

19
Oxygen Containing Heterocycles

• Polysaccharides Cellulose and Starch

20
Nitrogen Containing Heterocycles

• 3-Membered Ring

21
Nitrogen Containing Heterocycles

• 3-Membered Ring in our system?

• How do these work?

22
Higher Heterocycles Containing Nitrogen

• Basic Ring Systems

• Acid Base Properties

Ist pKA ? IInd pKA ?

• Stability to Water, Acid and Base

Without substituents ? With substituents ?
23
Higher Heterocycles Containing Nitrogen

• Examples of Drugs 4-membered ring

• Hydrolysis of b-lactams acid/base and
  enzymatic conditions

24
Higher Heterocycles Containing Nitrogen

• Importance of b-lactam ring in activity
  generation of resistance!!

Clavulinic Acid antidote to antibiotic
resistance
25
Higher Heterocycles Containing Nitrogen

• Examples of Drugs 5-membered ring

(anti-hyperlipidemic agent)
(anti-histaminic)
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 ?
27
Higher Heterocycles Containing Nitrogen and
Another Heteroatom

• Stability to Water, Acid and Base

Without substituents ? With substituents ?
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

29
5-Membered Heterocycles

• Metabolism of Aromatic Rings Containing Two
  Heteroatoms

30
Higher Heterocycles Containing Nitrogen and
Another Heteroatom

• Examples of such heterocycles in Drugs

(anti-biotic agent)
(anti-biotic agent)
(pain medication)
31
Heterocycles Containing Sulfur

• Basic Ring Systems

• Examples in Drugs

(Antihistamine)
(Antibiotic)
(Antimalarial)
32
Complex Heterocycles

• Examples in Drugs

(Antibiotic)
(Antihypertensive)
(for pneumonia)
(Antihypertensive)
(Anti-infectious)
(Anti-seizure)
33
6 Membered Rings Containing One Nitrogen

• Examples in Drugs

34
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 ?
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)
36
6 Membered Rings Containing Two Nitrogens

• Special Pyrimidines Barbituric Acid

(Keto form)
pKA 4
Phenytoin (anti-psychotic)
(Enol form)
37
Heterocycles

• More Complex Unsaturated Ring Systems

• 6-membered and higher heterocycles

38
Heterocycles

• More Complex Unsaturated Ring Systems

• 6-membered and higher heterocycles

Azepine diazepine oxazepine
39
7 and 8 Membered Nitrogen Containing Heterocycles
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