Transcript   Hetero-atom is to be counted as 1 or as low... When there is more than one hetero-atom, preference is given...

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
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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
O
Common name : ethylene oxide
Systematic name : Oxa + irane …. Oxirane
O
Common name : furan
Systematic name : Oxa + ole …. Oxole
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2
Heterocycles

Hantzsch – Widman Nomenclature (adopted by IUPAC)
NH Common name : pyrrole
Systematic name : H at 1 position + Aza + ole …. 1H-Azole
H
N
Common name : piperidine
Systematic name : Aza + inane …. 1H-Azinane
N
Common name : pyrimidine
Systematic name : two aza at 1, 3 positions + ine …. [1,3]-diazine
N
MEDC 527 Fall 2008
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Heterocycles

Hantzsch – Widman Nomenclature (adopted by IUPAC)
H
N
O
O
S
NH
[1,3]-Oxazocane
Azocane
[1,3,7]-Oxathiazocane
Ph
Ph
O
O
O
S
NH
S
N
4,5-dihydro-2H,8H[1,3,7]-oxathiazocine
N
CH3
6-Methyl-2-phenyl2H,8H-[1,3,7]-oxathiazocine
MEDC 527 Fall 2008
CH 3
6-Methyl-2-phenyl2H,3H,8H-oxocine
4
Oxygen Containing Heterocycles
3-Membered Ring :: Ethylene Oxide or oxirane

H
H
H
O





H
Structure?
Form at room temperature?
Reactivity?
Usage?
Toxicity?
Oxirane formation in our body

H
R
H
O
R
Oxidizing Enzymes
H
H
H
MEDC 527 Fall 2008
H
5
Oxygen Containing Heterocycles

Epoxides in our system
O
CH3
CH3
O
H3C
3
CH3

Role of Vitamin K epoxide?

Role of Squalene epoxide?
O
Vitamin K epoxide
O
Squalene Epoxide
MEDC 527 Fall 2008
6
Oxygen Containing Heterocycles

Reactions of Epoxides
Acid Opening of Epoxides
R
H
O
H
H
HCl
R
H
H+
O H
H
R
H +
MEDC 527 Fall 2008
OH
H
H
H2O
R
H
OH OH
H
H
7
Oxygen Containing Heterocycles
Reactions of Epoxides

Enzymatic opening of epoxides
R
H
O
Epoxide
Hydrase
H
R
H+
O H
H
H
H2O
R
OH OH
H
H
H
H
Opening of epoxides with amines (lysine mimics) and alcohols (serine mimics)
R
H
H
..
O..
R
H
H
..
O.
.
H
R
H
H
H
H+
O+
H
+
R
H
H
O
H
R’NH2
R'H2N
H
R’ÖH
HO
H
OR'
H
R
O-
+
R'O
R
O-
R
H
NH2R'
+
MEDC 527 Fall 2008
+
R
H
OH
R'HN
HO
R
R
+
H
OH
H
NHR'
8
Oxygen Containing Heterocycles

Higher Oxides
O
O
O
O
Oxetane




oxolane
oxane
O
1,4-dioxane
Structure?
Reactivity?
Usage?
Toxicity?
MEDC 527 Fall 2008
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Oxygen Containing Heterocycles

Higher Oxides
Stability of these oxides change drastically on a-substitution
O
OH
O H+, H O
2
COOH
O
O
Lactones
O
OH
H2O
HO
O OH-, H O O
2
_ O_
O
O
anhydrides
H
O
O
Hemi-acetals
OMe
HO
H3O+
H
O
acetals
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10
Oxygen Containing Heterocycles

Examples of Acetals or Hemi-Acetals in Nature
Same side = 
Opposite side = a
CHO
H
OH
H
OH
H
OH
CH2OH
ribose
HOH2C
O
H
H
OH
H
OH OH
hemiacetal
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Oxygen Containing Heterocycles
Interconversion of a- and -forms of sugars
The phenomenon of mutarotation

CHO
H
OH
HO
H
OH
H
OH
H
HO
H
H
H
HO
H
HO
OH
H
H
OH
H
OH
H
OH
H
OH
H
O
H
OH
H
O
CH2 OH
H
OH
H
D-glucose
O
HO
HO
H
H
H
OH
a-glucose
-glucose
glucose
CH2OH
O
H
H
CH2 OH
CH2 OH
a-glucose
H
CH2OH
OH
H
H
HO
H
OH
glucose
HO
HO
HO
H
CH2 OH
H
CHO
HO
HO
OH
MEDC 527 Fall 2008
H
CH2OH
OH
H
H
H
OH
H
D-glucose
O
HO
HO
CH2OH
O
H
OH
H
OH
H
-glucose
12
H
Oxygen Containing Heterocycles

Examples of sugars in natural systems
Deoxynucleic Acids and Ribonucleic Acids
OH2C
H
H
O
H
OH = RNA
H = DNA
H
N
N
N
Sugar
Adenine
N
HN
H2N
O
NH2
O
NH2
N
Base
O
N
Sugar
N
Guanine
O
CH3
HN
N
N
Sugar
Cytidine
O
N
Sugar
Thymidine
Live link: http://www.bmrb.wisc.edu/referenc/nomenclature/
MEDC 527 Fall 2008
13
Oxygen Containing Heterocycles

Sugars and Diabetes
O
H
H
OH
HO
H
NR
H
NHR
HO
H
..
H2N
H
OH
HO
H
H
HO
OH
H
H
OH
H
OH
H
OH
H
OH
H
OH
H
OH
CH2OH
CH2OH
CH2OH
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.
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Oxygen Containing Heterocycles
Sugars
Monosaccharides

CHO
H
D-Glyceraldehye
OH
CH2OH
D-Erythrose
CHO
D-Threose
CHO
HO
H
H
H
OH
OH
H
OH
CH2OH
CH2OH
D-Xylose
D-Lyxose
CHO
H
H
HO
H
HO
H
OH
H
OH
HO
H
H
OH
H
OH
OH
H
OH
H
OH
CHO
CHO
CHO
OH
HO
H
H
OH
HO
H
HO
H
H
OH
H
HO
H
HO
H
HO
H
OH
CH2OH
D-Galactose
H
CH2OH
CHO
HO
H
OH
CH2OH
D-Talose
H
H
OH
CH2OH
D-Gulose
CHO
OH
CH2OH
CH2OH
D-Arabinose
CHO
CHO
HO
H
D-Ribose
HO
H
H
CH2OH
CHO
CHO
CHO
CHO
H
H
OH
HO
OH
H
OH
H
OH
HO
H
H
OH
H
OH
H
OH
H
OH
OH
H
OH
H
OH
H
OH
H
OH
CH2OH
D-Idose
CH2OH
D-Allose
MEDC 527 Fall 2008
H
CH2OH
D-Altrose
H
OH
HO
H
H
HO
H
CH2OH
D-Glucose
CH2OH
D-Mannose
15
Oxygen Containing Heterocycles

Reducing and Non-reducing Sugars
CHO
H
HO
H
H
CHO
OH
HO
H
H
HO
H
OH
H
OH
H
CH2OH
D-Glucose
HO
OH
CH2OH
D-Mannose
CH2OH
H
OH
CH2OH
OH
HO
H
HO
H
H
H
OH
H
OH
H
OH
H
OH
CH2OH
D-Sorbitol
CH2OH
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
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Oxygen Containing Heterocycles
Derivatized Forms of Monosaccharides

CHO
CH2OH
O
H
HO
H
HO
H
NH2
H
OH
H
H
NH2
HO
H
H
HO
H
OH
H
H
OH
H
CH2OH
H
COOH
O
H
HO
H
HO
H
OH
H
OH
a-D-Glucuronic
HO
H
OH
H
H
OH
H
O_
O
Acid
O
OH
O
_
OSO3
HO
OH
H
H
OH
HO
OH
H
CH2OH
D-Gluconic
O
OH
OH
OH
O_
COO
OH
_
NHSO3
O
O
OH
O
_
OSO3
MEDC 527 Fall 2008
CHO
H
HO
OH
H
H
HO
OH
CH2OH
D-Idonic
Acid
CH2OH
O
O
HO
H
_
CH2OSO3
OH
H
CH2OH
OH
_
COO
O
_
NHSO3
OH
OH
COOH
H
_
CH2OSO3
COO
OH
H
COOH
H
COOH
D-Glucuronic
Acid
H
H
D-Idose
OH
HO
HO
D-Glucose
CHO
H
OH
CH2OH
D-Glucosamine
a-D-Glucosamine
CHO
CHO
H
Acid
H
OH
H
OH
COOH
D-Iduronic
Acid
OH COOH
O
OH
H
H
H
H
H
OH
OH
a-D-Iduronic
_
NHSO3
17
Acid
Oxygen Containing Heterocycles

Fructose
CHO
H
HO
H
CH2OH
OH
OH
OH
HO
O
H
HO
H
H
OH
H
OH
H
OH
H
OH
H
O
H
OH
CH2OH
D-glucose

H
CH2OH
ene-diol
HOH2C
CH2OH
H
O
H HO
OH
CH2OH
OH H
fructose (open-chain form) fructose (furanose form)
Sucrose
CH2OH
H
O HOH2C
O
H
H
HO
H HO
HO
H
O
CH2OH
OH
OH H
H
H
a-D-glucose
-D-fructose
MEDC 527 Fall 2008
18
Oxygen Containing Heterocycles

Polysaccharides – Cellulose and Starch
H
CH2OH
H
OH
O
HO H
H
1
O 4
O
HO
H
H
O
4
OH 1
CH
OH
2
H
H
H
H
*
O
*
n
Cellulose (14--D-glucose polymer)
CH2OH
O
H
O
H
HO
H
H
OH
H
O
HO
H
*
CH2OH
O
H
H
H
OH
H
O
n *
Amylose (14-a-D-glucose polymer)
80% constituent of starch; 20% is amylopectin
MEDC 527 Fall 2008
19
Nitrogen Containing Heterocycles

3-Membered Ring
MEDC 527 Fall 2008
20
Nitrogen Containing Heterocycles

3-Membered Ring in our system?
H3C
O
Cl
N
H2N
Cl
Mechlorethamine
H3C
OCONH2
OMe
N P
N
N
NH
O
Mitomycin C

O
TEPA
How do these work?
MEDC 527 Fall 2008
21
Higher Heterocycles Containing Nitrogen

Basic Ring Systems
H
N
H
N
azetidine

pyrrolidine
(azolidine)
H
N
O
N
H
piperidine
piperazine
morpholine
(perhydroazine) (perhydro-1,4-diazine) (perhydro-1,4-oxazine)
Acid – Base Properties
Ist pKA ?
IInd pKA ?
H2+
N
pKA 9.6
N
H2+

H
N
H
N
H2+
N
N
H
pKA 9.9
H
N
N
H
Stability to Water, Acid and Base
Without substituents ?
With substituents ?
MEDC 527 Fall 2008
22
Higher Heterocycles Containing Nitrogen

Examples of Drugs … 4-membered ring
R
H
N
S
O
N
RCONH
CH3
N
NH
CH3
O
-lactam
COOH
penicillin
cephalosporin
CH3
H3C
HO
N
O
S
N
CH3
CH3
N
O
COOH
CH3
HO
O
NH
meropenem

R'
O
O
COOH
CH3
S
S
NH2
COOH
thienamycin
Hydrolysis of -lactams …… acid/base and enzymatic conditions
R'
R
R'
NH3+
NH
O
R
O
O
MEDC 527 Fall 2008
23
Higher Heterocycles Containing Nitrogen

Importance of -lactam ring in activity …… generation of resistance!!
Clavulinic Acid …… antidote to antibiotic resistance
H
OH
O
..
..
Nu-Enz-Ser-OH
O
..
Nu-Enz-Ser-O
HN
N
O
-lactamase
OH
O
COOH
COOH
Clavulinic acid
Enz
Ser
..
Enz- Nu
..
Nu
HO
O
OH
HO
Ser-O
HN
O
OH
HN
O
COOH
MEDC 527 Fall 2008
COOH
24
Higher Heterocycles Containing Nitrogen

F
Examples of Drugs … 5-membered ring
OH
NH2
O
COOH
N
HO OOC
NH
N
H
NH
H3C
pyrrole
tryptophan
CH3
atorvastatin
(anti-hyperlipidemic agent)
CH3
Cl
H3C
N
N
O
CH3
NH
pyrrolidine
nicotine
clemastine
(anti-histaminic)
MEDC 527 Fall 2008
25
Five-membered Rings Containing Nitrogen and Another Heteroatom

Nitrogen and Oxygen
O
N
N
Oxazole
(1,3-oxazole)
O
N
O
Isoxazole
(1,2-oxazole)
N
N
Imidazole
(1,3-diazole)
NH
Oxazoline
Oxazolidine
(1,3-oxazoline) (1,3-oxazolidine)

HN
O
HN
N
HN
N
H
Pyrazole
(1,2-diazole)
NH
Imidazoline
Imidazolidine
(1,3-diazoline) (1,3-diazolidine)
Acid – Base Properties
Ist pKA ?
IInd pKA ?
Why is imidazole not strongly basic ?
pKA with greater substitution ?
MEDC 527 Fall 2008
26
Higher Heterocycles Containing Nitrogen and Another Heteroatom
Stability to Water, Acid and Base
Without substituents ?
With substituents ?

H
N
H3O+
N
no degradation
H3O+
NH3+
H
N
H3O+
N
H3O+
NH3+
no degradation
H3O+
N
H3O+
N
H
OH2+
O
O
O
N
H
N
NH+
NH3+
+
+
HCHO
NH3+
N
H
N
H
HCHO
OH
O
O
+
NH3+
+
HCHO
OH
HCHO
NH3+
MEDC 527 Fall 2008
27
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
H
H
N
sulfation
N
SO3H
S
bromination
S
Br
O
OH
O
metabolic enzyme
MEDC 527 Fall 2008
28
5-Membered Heterocycles
 Metabolism of Aromatic Rings Containing Two Heteroatoms
Oxidative
metabolism
O
O
Oxidative
metabolism
N
O
H
N
OH
N
O
H
N
OH
NH2
N
H
N
N
H
N
OH
O
N
H
MEDC 527 Fall 2008
H
O
NH2
NH2
NH2
29
Higher Heterocycles Containing Nitrogen and Another Heteroatom

Examples of such heterocycles in Drugs
CF3
N
N
CH3
H3C
O
O
N
S
H2N
N
H
O
O2 N
HO
N
N
H3C
CH3
SO2NH2
Sulfisoxazole
Metronidazole
Celecoxib
(anti-biotic agent)
(anti-biotic agent)
(pain medication)
MEDC 527 Fall 2008
30
Heterocycles Containing Sulfur

Basic Ring Systems
S
Thiophene
(Thiole)
Tetrahydrothiophene
(thiolane)

S
S
Examples in Drugs
N
1,3-thiazole
O
S
OMe
HN
N
COOH
H2N
N
N
N
N
CH 3
methapyrilene
(Antihistamine)
O
CH 3
S
S
N
O
H2N
S
NH2
O
S
ceftizoxime
(Antibiotic)
MEDC 527 Fall 2008
thiazolsulfone
(Antimalarial)
31
Complex Heterocycles
Examples in Drugs

OH
O
H2N
S
H
N
O
O
CH3
S
N
H
N N
sulfamethizole
N
N
N
S
CH3
H3C CH
3
timolol
(Antibiotic)
(Antihypertensive)
F
F
OH
N
N
N
N
N
NH
CH3
N
N
Cl
N
N
N
OH
N
fuconazole
(for pneumonia)
O
O
F
N
(Antihypertensive)
O
H
N
N
losartan
NH
O
O
NHAc
linezolid
(Anti-infectious)
phenytoin
(Anti-seizure)
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32
6 Membered Rings Containing One Nitrogen

Examples in Drugs
O
O
O
H
N
OEt
O
N
MeOOC
S
N
Cl
CH3
COOEt
N
Rosiglitazone
(pyridine + thiazolidine2,4-dione)
Anti-diabetic
H3C
CH3
Meperidine
(piperidine)
relieves pain,
narcotic analgesic
N
H
CHOCH2CH2NH2
Amlodipine
(dihydropyridine)
Ca2+ channel blocker,
Antihypertensive, antianginal
O
F
O
HN
O
N
C2H5
N
H
O
Phenobarbital
(pyrimidine)
controls epilepsy, seizures,
as a sedative to relieve anxiety
COOH
N
HN
Ciprofloxacin
(piperazine)
Antibacterial
(anthrax)
MEDC 527 Fall 2008
O
N
H
CH3
Phenmetrazine
(morpholine)
Appetite suppresant
CNS stimulant
Amphetamine-like
33
6 Membered Rings Containing Two Nitrogens

Diazines
N
N
N
N
1,2-diazine
(pyridazine)

N
1,3-diazine
(pyrimidine)
N
1,4-diazine
(pyrazine)
Acid – Base Properties
Ist pKA ?
IInd pKA ?
Why are these dibasic compounds not strongly basic ?
MEDC 527 Fall 2008
34
6 Membered Rings Containing Two Nitrogens

Pyrimidines
Three derivatives are important for RNA/DNA
O
O
H
H
N
O
N
N
N
O
N
H
H
Uracil

CH3
N
O
NH2
H
Thymine
Cytosine
Forms of Pyrimidines
O
H
O
O
H
N
N
O
OH
N
N
N
H
H
Urea
(neutral)
Imide or Keto form
(acidic)
MEDC 527 Fall 2008
HO
N
Enol form
(acidic)
35
6 Membered Rings Containing Two Nitrogens

Special Pyrimidines … Barbituric Acid
O
H
Ph
N
O
O
H
Me
N
O
N
O
H
H
H
H
N
O
H
N
O
H
N
O
H
H
(Keto form)
pKA = ~4
O
HN
O
C2H5
N
H
Ph
OH
H
H
N
O
Phenobarbital
(pyrimidine)
controls epilepsy, seizures,
as a sedative to relieve anxiety
HO
N
OH
H
(Enol form)
MEDC 527 Fall 2008
HN
O
Ph
N
H
O
Phenytoin
(anti-psychotic)
36
Heterocycles
 More Complex Unsaturated Ring Systems
 6-membered and higher heterocycles
N
N
N
N
N
N
N
Pyridine pyridazine pyrimidine pyrazine
N
O
O
N
N
Quinoline
present in ……
Chloroquine
(antimalarial)
N
N
N
Isoquinoline
Coumarin
Quinazoline
Praziquantel
(anti-worm)
Warfarin
(anticoagulant)
Prazosin
(antihypertensive)
H
N
N
N
Pteridine
Triamterene
(antihypertensive
H
N
O
S
N
N
N
NH
Indole
Isoindole
present in …..
Tryptophan
LSD
(common AA) (hypnotic)
Benzimidazole
Omeprazole
(anti-ulcer)
Benzoxazole
Benzthiazole
Chlorozoxazone
(relieves pain)
Ethoxzolamide
(diuretic)
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37
Heterocycles
 More Complex Unsaturated Ring Systems
 6-membered and higher heterocycles
O O
S
N
N
1,2,4-benzothia
diazin-1,1,-dioxide
present in …..
Chlorothiazide
(antihypertensive )
H
N
N
H
N
S
N
N
H
N
N
3H-1,4-Benzo
diazepine
O
1,3-Dihydro-2H-1,4Phenothiazine
benzodiazepin-2-one
Acridine
Chlordiazepoxide
Diazepam
Chloropromazine
(sedative, hypnotic) (sedative, anxiolytic)
(anxiolytic)
H
N
H
N
Imipramine
(anti-depressants)
O
N
Azepine
Quinocrine
(antibiotic)
5H-dibenz
[b,f]azepine
diazepine
MEDC 527 Fall 2008
N
oxazepine
38
7 and 8 Membered Nitrogen Containing Heterocycles
O
CH3
H
N
N O S
O
CH3
Tolazamide
(hexahydroazepine)
Oral hypoglycemic
N
CH3
HO
H3C
CH3
Pentazocine
(octahydroazepine)
Pain reliever
MEDC 527 Fall 2008
39
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
NO2
nitration
N
N
OH
N
metabolic enzyme
N
MEDC 527 Fall 2008
40