Organic chemistry II

Zdenk Friedl

Chapter 24

Heterocyclic compounds

Solomons & Fryhle: Organic

Chemistry 8th Ed., Wiley 2004

Heterocyclic compounds

structure of five and six-membered heterocycles

reaction scheme of five-membered heterocycles
SEAr reactions
reaction scheme of pyridine and pyridine N-oxide
SEAr and SNAr reactions
condensed heterocyclic compounds
bases of nucleic acids, nucleosides and nucleotides
primary and secondary structure of DNA

Most important heteroaromatic compounds

The p-orbital structure of furan and thiophene

a creation of an aromatic (4+2) system

The p-orbital structure of pyrrole

a creation of an aromatic (4+2) system

The p-orbital structure of pyridine

a creation of an aromatic (4+2) system

The reaction scheme of five-membered heterocycles

_
O
_

_
N

_
S
_

H
SEAr

SEAr

Substitution reactions
of five-membered heterocycles
special reagents are essential

N
H

+ Br2

+ HNO3

O
+ CH3CCl

dioxane
0C

acetic
anhyride

benzene
SnCl4

Br
O
2-bromofuran
(90%)

+ HBr

NO2 + H2O

N
H
2-nitropyrrole
(83%)

CH3 + HCl
C
S
O
2-acetylthiophene
(83%)
8

The prosthetic group of hemoglobin HEME

chelating effect of 4 conjugated pyrrole units (porphyrin)

Psychoactive compounds III

alkaloids
CH3COO
O
CH3
N
N

CH3

nicotine

CH3
N

N
N
CH3

caffeine

N
CH3COO

CH3

heroin

10

The reaction scheme of pyridine

SEAr
__
E+

N
_

SNAr

N+

N+

O_

11

SEAr

Electrophilic substitutions on pyridine

reactions proceed very hard to the position 3- ()
Br

Br2
300C

N
3-bromopyridine
(30%)

SO3H

SO3, H2SO4
HgSO4, 220C

N
pyridine-3-sulfonic acid
(70%)

HNO3
NaNO3, 370C

NO2
N
3-nitropyridine
(5%)
12

SNAr

Nucleophilic substitutions on pyridine

reactions proceed moderately in positions 2- and 4- ( and )
Cl

OEt
Na+ -OEt
EtOH

Cl

Cl-

+
N
4-ethoxypyridine
(75%)

NaNH2
NH3

+
N

Cl-

NH2

2-aminopyridine

+
N

Cl

NH2

+ Cl-

NH2
Cl

NH2

13

SEAr

Electrophilic substitutions on quinoline

reactions proceed on less deactivated benzene ring
Br

Br2
H2SO4

+ HBr

Br
5-bromoquinoline 8-bromoquinoline
a 51:49 ratio
NO2
HNO3
N H2SO4, 0C

+ HBr

NO2
5-nitroisoquinoline 8-nitroisoquinoline
a 90:10 ratio
14

TCDD

Dioxins
persistent organic pollutants (POP)

Cl

Cl

Na O

Cl

+
Cl

O Na

Cl

Cl

Cl

Cl

2 NaCl

Cl

Cl

2,3,7,8-tetrachlorodibenzo[b,e]dioxin
LD50 rat (p.o.) 0.045 mg kg-1 (220 x)
KCN

10 mg kg-1

15

Psychoactive compounds IV
alkaloids

(Et)2NOC

CH3
N
COOCH3

CH3

OOC
N
CH3
cocaine

LSD

16

Psychoactive compounds V
actual toxicity of alkaloids

(i.v.) 0.96 mg kg-1 (~ 0.9 x)

(p.o.) 150.0 mg kg-1 (0.07 x)
LD50 rat
(i.v.) 12.0 mg kg-1
KCN (p.o.) 10 mg kg-1
17

The basics of genetics structure of DNA

18

Heterocyclic bases contained in DNA

PURINE and PYRIMIDINE derivatives A G C T

19

Heterocyclic bases contained in RNA

RNA contains bases A G C but T is replaced by Uracil

20

Nucleosides contained in DNA

21

Nucleosides contained in RNA

22

The primary structure of DNA

3,5-DIESTER BONDS

23

Pairing of heterocyclic bases by HYDROGEN ... BONDS

24

Secondary structure of DNA

DOUBLE HELIX

25

3,5- Cyclic adenosine monophosphate

c-AMP

biosynthesis vs. laboratory synthesis

26

Purine skeleton related drugs

Medical applications:
acute leukemia in childern

treatment of gout

herpes viruses

27