Solomons & Fryhle: Organic Chemistry 8th Ed., Wiley 2004

Organic chemistry IIZdeněk Friedl

Chapter 24

Heterocyclic compounds

2

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

3

Most important heteroaromatic compounds

4

The p-orbital structure of furan and thiophenea creation of an aromatic (4+2)π system

5

The p-orbital structure of pyrrolea creation of an aromatic (4+2)π system

6

The p-orbital structure of pyridinea creation of an aromatic (4+2)π system

7

The reaction scheme of five-membered heterocycles

N

H

S__

___

SEAr

B

O

H

8

O

N

S

H

+ Br2

+ HNO3

+ CH3CClO

dioxane0°C

aceticanhyride

benzeneSnCl4

O Br

NH

NO2

S CO

CH3

+ HBr

+ H2O

+ HCl

2-bromofuran(90%)

2-nitropyrrole(83%)

2-acetylthiophene(83%)

SEAr Substitution reactionsof five-membered heterocycles

special reagents are essential

9

The prosthetic group of hemoglobin – HEMEchelating effect of 4 conjugated pyrrole units (porphyrin)

10

nicotine caffeine heroin

Psychoactive compounds IIIalkaloids

N

N

CH3

N

N

N

N

O

O

CH3

CH3

CH3

CH3COO

CH3COO

NCH3

O

11

The reaction scheme of pyridine

N N

O

N

O

+ +_

_

_

_SEAr

SNAr

E+

12

N

Br2300°C

SO3, H2SO4HgSO4, 220°C

HNO3NaNO3, 370°C

N

Br

N

NO2

N

SO3H

3-bromopyridine(30%)

pyridine-3-sulfonic acid(70%)

3-nitropyridine(5%)

SEAr Electrophilic substitutions on pyridinereactions proceed very hard to the position 3- (β)

13

SNAr Nucleophilic substitutions on pyridine reactions proceed moderately in positions 2- and 4- (α and γ)

N

Cl

N Cl

Na+ -OEtEtOH

NaNH2NH3

N

OEt

+ Cl-

N NH2

+ Cl-

4-ethoxypyridine(75%)

2-aminopyridine

N Cl+ NH2

N ClNH2

N NH2+ Cl-

14

SEAr Electrophilic substitutions on quinolinereactions proceed on less deactivated benzene ring

N

Br2H2SO4

N N+ + HBr

Br

Br5-bromoquinoline 8-bromoquinoline

a 51:49 ratio

NHNO3

H2SO4, 0°C N N+ + HBr

NO2

NO25-nitroisoquinoline 8-nitroisoquinoline

a 90:10 ratio

15

TCDDTCDD Dioxinspersistent organic pollutants (POP)

Cl

Cl

Cl

O

O

Cl

Cl

Cl

O

O

Cl

Cl

Cl

ClNa

Na+ 2 NaCl

2,3,7,8-tetrachlorodibenzo[b,e]dioxin

LD50 rat (p.o.) 0.045 mg kg-1 (220 x)

KCN 10 mg kg-1

16

cocaine LSD

Psychoactive compounds IValkaloids

NCOOCH3

OOC

CH3

N

N(Et)2NOC

H

CH3

CH3

17

(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

Psychoactive compounds Vactual toxicity of alkaloids

18

The basics of genetics – structure of DNA

19

Heterocyclic bases contained in DNAPURINE and PYRIMIDINE derivatives A G C T

20

Heterocyclic bases contained in RNARNA contains bases A G C but T is replaced by Uracil

21

Nucleosides contained in DNA

22

Nucleosides contained in RNA

23

The primary structure of DNA 3‘,5‘-DIESTER BONDS

24

Pairing of heterocyclic bases by HYDROGEN ... BONDS

25

Secondary structure of DNA DOUBLE HELIX

26

3’,5’- Cyclic adenosine monophosphate c-AMPbiosynthesis vs. laboratory synthesis

27

Purine skeleton related drugs

Medical applications:

acute leukemia in childern treatment of gout herpes viruses