Heterocycles

Ring compounds with elements other than carbon in the ring. The most common elements to appear in heterocyclic compounds are oxygen, nitrogen and sulfur. The aliphatic heterocycles are similar to the open chain analogues, ethers, amines and sulfides. The aromatic heterocycles are similar to other aromatic compounds.

Heterocyclic Nomenclature Replacement nomenclature (IUPAC recommended 1957) Oxygen Sulfur Nitrogen oxa thia aza

Lowest number assigned to the hetero atom with the highest precedence: O > S > N

S thiacyclobutane

NH

1-oxa-3-azacyclopentane

Hantzsch-Widman (1888) Suffixes ring with nitrogen Ring members unsatd satd 3 4 5 6 7 -irine ete ole ine -iridine etidine olidine perhydro__ine ring without nitrogen unsatd satd irene ete ole in irine etane olane ane epane

epine perhydro__epine epin

You must know the * names

O
* oxirane ethylene oxide oxacyclopropane

S
* thiirane ethylene sulfide thiacyclopropane

N H
* aziridine ethylene imine azacyclopropane

N N
diazirane

N 1-azirine

N O

oxaziridine oxazacyclopropane

O
oxetane oxacyclobutane

S
thietane thiacyclobutane

NH
azetidine azacyclobutane

N
azete azacyclobutadiene

N
1-azetine 1-azacyclobutene

O
* furan oxole oxacyclopentandiene

S
* thiophene thiole thiacyclopentandiene

N H * pyrrole

O O
1,3-dioxolane 1,3-dioxacyclopentane

O
* tetrahydrofuran

N H
* pyrrolidine azacyclopentane

N N H N N H
imidazole

N N H N

pyrazole

1,2,4-triazole

N O
oxazole

N O N S
thiazole

isooxazole

O
4-hydropyran

O
4-pyrone

2-pyrone

O O
* 1,4-dioxane

H N N H
* piperidine

N H
piperazine

N N N N
pyrimidine

N N
pyrazine

pyridazine

O N
* pyridine

N H
* morpholine

5 6 7 8

4 3

6 7

N
1

N2
8 1

* quinoline

* isoquinoline

N H
* indole

Aromatic heterocycles

N H pyrrole

O furan

S thiophene

Aromatic! EAS very, very reactive resonance stabilization energy ~ 22-28 Kcal/mole sp2 N H 6 pi electrons no unshared pair on Nitrogen very weak base Kb = 10-14

N H

strong acids N H pyrrole CH3CO2-NO2+

polymer!

(CH3CO)2O, 5oC SO3 pyridine, 90o C6H5-N2+Cl-

N H

NO2

N H

SO3H

N H

N N

CHCl3, KOH N H pyrrole N H H2O O CH=O

HCN, HCl (CH3CO)2O 250o

N H Br Br N H

C CH3 Br Br

Br2, EtOH 0o

CH3CO2NO2 O furan pyridine:SO3 O C6H5N2+ O (CH3CO)2O, BF3 O N SO3H O NO2

C CH3

1. HCN, HCl O furan Br2 dioxane HgCl2 CH3CO2Na O HgCl CH3COCl O O Br 2. H2O O CH=O

I2 O

C CH3

less reactive, can use acids S H2SO4 S CH3CO2NO2 (CH3CO)2O Br2, benzene I2, HgO S I S NO2 SO3H

Br

Br

Why EAS 2-position?

2-

H N H H Y N H H

H Y N H

H Y

3-

N H

N H

H2, Ni N H 250o N H Kb = 10-3 2o amine H2, Ni O 50o O THF

Kb = 10-14

Pyridine N N N 6 pi electrons, sp2, flat aromatic, resonance stabilization energy ~ 23 Kcal/mole Kb = 2.3 X 10-9
4 3 2 5

N
1

CH3 N

-picoline

Pyridine Reactions:

important solvent & base (~ 3o amine)

1) EAS (much less reactive than benzene ~ nitro)

KNO3, H2SO4, 370
o

NO2
3% yield

N H2SO4, SO3, HgSO4 220o, 24 hours

N SO3 N H Br2, 300o N Friedel-Crafts no reaction Br + N Br Br

Deactivated to EAS due to electronegativity of Nitrogen Directs beta due to destabilization of alpha and gamma H H Y N H N Y H Y Y N H Y H Y

N N N

N Y

H Y

H Y

Pyridine, reactions 2) Nucleophilic aromatic substitution

NaNH2 N N NH2

phenyl lithium N

H2O N

NH3, 200o N Cl NH3, 200o N N N Br N NH2 NH2 H N Z Z

Br N

NH3, 200o

NR

activated to nucl. arom. subts. directs alpha & gamma

Pyridine, reactions 3) As base Kb = 2.3 X 10-9

HBr N N H CH3I N N CH3 4o salt I Br

Pyridine, reactions 4) reduction

H2, Pt N HCl, 25o, 3 atm. N H piperidine Kb = 2 X 10-3 aliphatic 2o amine

Polynuclear Heteroaromatics
EAS
6 7 8 5 4 3 2 6 7

EAS
5 4 3

N
1

N
8 1

NAS

quinoline
4 5 6 7 3 2

NAS isoquinoline

EAS

N H

indole

Skraup synthesis of quinoline

NH2 +
aniline

NO2 H2C OH HC OH H2C OH

glycerol

+
nitrobenzene

H2SO4

+ H2O N

The nitrobenzene is not only the solvent, but is also one of the reactants.

H2C OH HC OH H2C OH

H+ -H2O

HC O CH + CH2
acrolein

NH2
H+

O H C CH2 CH2 N H OH H C CH2 CH2 N H

H
-H2O

OH
EAS

N H NO2

N H NH2 + N