Special Topic A

Aromatic Heterocyclic Compounds: Reactions and

Synthesis

Aromatic Heterocyclic Compounds: Reactions and

Synthesis

芳香杂环化合物的合成与反应

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

A.1 Classification

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

Cyclic organic compoundsCarbocycles

Heterocycles

Carbocyclic rings contain only carbon atoms.Heterocyclic rings contain one or more different atoms in addition to carbon.N, O, S are the most common heteroatoms.Heterocyclic compounds are common in organic chemistry, and many have important biological properties.

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

Antibiotic: PenicillinAntibiotic: Penicillin

S

NO

H

HCO2H

NH

H

CH3CH3

CC6H5CH2

O

Penicillin G

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

Antiulcer agent: CimetidineAntiulcer agent: Cimetidine

N

N CH3

H

CH2SNHCH2CH2CO

CH3HN

Cimentidine甲氰咪胍(抗溃疡药)

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

Sedative: PhenobarbitalSedative: Phenobarbital

N

NCH2CH3

O

O

OH

H

Phenobarbital

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

Nonnutritive sweetener: SaccharinNonnutritive sweetener: Saccharin

SN

HO

O

O

Saccharin

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

Natural products: HemeNatural products: Heme

N N

N

N

CHCH3

CH3

CH

CH3

CH3

HO2CCH2CH2

HO2CCH2CH2

CH2

CH2

Fe

Heme

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

Natural products: ChlorophyllNatural products: Chlorophyll

N N

N

N

CH2CH3CH3

CH3CH

CH3

H

Mg

CH2

CH3 H O

O HCH3 CH3 H

OCO2CH3

H

Chlorophyll a

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

Some heterocycles we’ve encounteredSome heterocycles we’ve encountered

OO O N

HO

O N

Epoxide Lactone Lactam

THF Pyridine

(A cyclic ether) (A cyclic ester) (A cyclic amide)

(A cyclic ether) (A cyclic amine)

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

NH

O S

Furan Pyrrole Thiophene

NH

NN

O

N

S

Oxazole Imidazole Thiazole Pyrimidine

N

N

N

Pyridine呋喃 吡咯 噻吩 吡啶

噁唑 咪唑 噻唑 嘧啶

1

2

34

5

1

2

34

55

4 3

21

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

N

CH3

NCH3

CH3

3-Methylpyridine 1,3-Dimethylpyrrole

O NH

Tetrahydrofuran Piperidine

NH

Pyrrolidine四氢呋喃 四氢吡咯 六氢吡啶

(哌啶)

NH

2,3-Dihydropyrrole2,3-二氢吡咯

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

NH

N

N

NNH

N

HN

S

N

Indole Quinoline Purine

Carbazole Benzothioazole

吲哚 喹啉 嘌呤

咔唑 苯并噻唑

12

345

67

8

9

98

7

65 4

3

21

10

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

A.2 Five-MemberedUnsaturated Heterocycles

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

A.2.1 Structures of Pyrrole, Furan, and Thiophene

A.2.1 Structures of Pyrrole, Furan, and Thiophene

NH

O S

Furan Pyrrole Thiophene

NH

sp2 hybridized

Lone pair in p orbital

Six pi electrons

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

A.2.2 PreparationA.2.2 Preparation

O NH

NH3, H2O

Al2O3, 400�

C5H10O5H3O+ Ni Catalyst

280�+ CO

O CHO O

Pentose mixture Furfural Furan

600�

S

S

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

CH3C CHO

CNH2

OOEt

CH3C CH2

OCO

OEt

CH3CO2HNH

C CH3

CH3 C

EtOO

OEtO

CH3C CH2NH3 ClO

+ CH3CCH3

O

NH

CH3

CH3NaOH

25°C

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

A.2.3 Reactions of Furan, Pyrrole and Thiophene

A.2.3 Reactions of Furan, Pyrrole and Thiophene

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

ProtonationProtonation

NH

NH

H

H NH

H

H NH

H

H

NH

H

H

NH

NH H N

H

H

H

NH

NH n + 2

n

H+

H+

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

Electrophilic SubstitutionElectrophilic Substitution

NH

O S> > >>Reactivity

(CH3CO)2O + HNO3 C ONO2

OCH3 + CH3CO2H

NH

NH

+ HNO3 NO2

Aceticanhydride

83%

+ H2O

S S+ HNO3 NO2

Aceticanhydride

+ H2O

Nitration

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

NH

NH

NO2

H NH

NO2

H NH

NO2

H

NH

NO2

NO2+

H

NH N

HNH

NH

NO2 NO2

HH

NO2

Not formed

NO2+

H

Electrophilic substitution takes place primary at position 2

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

NH

NSO3

+100�

NH

SO3 NH

NH

SO3H

S+ H2SO4(cond.)

25�

S SO3H

HCl

Sulfonation

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

NH

Et2O, 0�

SOCl2(1 mol)

NH

Cl

Et2O, 0� NH

Br

Br

Br

BrBr2

Halogenation

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

O

�40�

Cl2

O Cl

Br2

Dioxane, 0� O Br

+O ClCl

S

S I

Br2

C6H6, 0�

S BrAcOH

I2, HgO

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

S S+ CH3COCl

Benzene

C CH3

O83%

O O+ (CH3CO)2O

C CH3

O75 ~ 92%

SnCl4

BF3

NH

NH

+ (CH3CO)2OC CH3

O

150 ~ 200�

Friedel-Crafts Reactions

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

NH

NH

C6H5 N N X+N N C6H5

Coulping Reaction

Z

GZ

G

(m)

(o, p)major

minor

Z

G (o, p)

ZG (m)

Orientation on Electrophilic Substitution

major

minormajor

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

A.3 Six-Membered Unsaturated Heterocycles

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

NPyridine吡啶

O

O O O

O

O

Pyran-4H Pyran-2H

1,2-Pyrone 1,4-Pyroneα-吡喃酮 γ-吡喃酮

γ-Pyran α-Pyranγ-吡喃 α-吡喃

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

A.3.1 Structure of PyridineA.3.1 Structure of Pyridine

NN

Pyridine

Six pi electronssp2 hybridized

Lone pair in sp2 orbital

1

23

4

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

A.3.2 Reactions of PyridineA.3.2 Reactions of Pyridine

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

Electrophilic SubstitutionElectrophilic Substitution

N

,HNO3

N

NO2

330�

N

20%SO3-H2SO4

220�HgSO4, N

SO3H

70%

H2SO4

N N200 ~ 220�

Br

37%

Br2+

N

Br

26%

Br

15%

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

N+(or E+)

H+

NH Pyridinium ion

Highly unreactive becauseof positive charge

N

E

N

E

H HN

E

HN

E+

N

EH+

HH H H

H

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

N

E+ N

EH

N

EH

N

EH

NE

HN

E

HN

E

H

E+

H

H H H

HHH

2+

2+

Especially unstable because N has a sextetAnd two positive charge

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

Nucleophilic SubstitutionNucleophilic Substitution

N Br N NH2

N

Cl

N

OCH2CH3

+ Br

+ Cl

NaNH2

NH3

NaOCH2CH3

C2H5OH

N Br NBr

NH2

N NH2

NH2 + Br

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

N NLi

+N C6H5

H

Li

N C6H5Li

Li+H

C6H5 LiC6H5

110°C, toluene

N C6H5

N 320°CKOH , O2

N OH N OH

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

N+ NaNH2

100�

N NHNa N NH2PhN(CH3)2

H2O

Chichibabin reaction

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

Nucleophilic Addition to Pyridinium IonsNucleophilic Addition to Pyridinium IonsPyridinium ions are especially susceptible to nucleophilic attack at the 2 or 4 position.

NR

NR

NR

NR

NCH3

X

+ OH

NCH3

H2OOH

H

K2Fe(CN)6

NCH3

O

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

NR X

+ NaBH4H2O

NR

H

H

NaBH4H2O

NR

H

H

H

H

HH

NR X

H2O

Na2S2O4

NR

H H

NR X

Na2S2O4 , OH , H2O

NR

H HC NH2

O

C NH2

O

K2Fe(CN)6

NAD+ NADH

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

OxidationOxidation

N

CO2H

N

NCH3

N N

CO2H

CO2H

HNO3

KMnO4

N

30% H2O2-AcOH

NO

Pyridine N-oxide

N-氧化吡啶

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

Reaction of Pyridine N-OxideReaction of Pyridine N-Oxide

NO

100� NO

NO2

N

NO2

NO

NO2

NO

OCH3

N

OCH3

+ POCl3

+ POCl3

HNO3

H2SO4

PCl2

CHCl3

CH3ONa PCl2

CHCl3

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

ReductionReduction

N

H2, Pt, 25�, 3 atm

or Na / EtOH NH

Piperidine哌啶

Kb = 2* 10-3Kb = 2.3* 10-9

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

Reaction of Alkylpyridine Side Chains Reaction of Alkylpyridine Side Chains

N CH3

+ C6H5 C C6H5

O NaNH2

N CH2 CC6H5

C6H5

OH

N

CH3 CH2CH3NaNH2

N

CH2CH2CH3

CH3I

N

CH2CH3CH2CH3

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

N

CH3

PhCHO

ZnCl2N

CH CHPh

N CH3

CH3I

PhCHO+NH

25� N CHCH3

CHPhOH

I

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

A.3.3 Synthesis of Pyridine

CH3C CH2

OCO

OEt2 + NH3 HCHO

+Et2NH

NH

HHCO2Et

CH3

EtO2C

CH3

HNO3

H2SO4 N

CO2Et

CH3

EtO2C

CH3

Hantzsch synthesis

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

A.4 Fused-Ring Heterocycles

苯并杂环化合物

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

NN N

HQuinoline Isoquinoline Indole喹啉 异喹啉 吲哚

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

A.4.1 Fischer Indole Synthesis

NHNH2 CCH3

CH3O+ NHN C

CH3

CH3

HOAc

ZnCl2

180� NH

CH3

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

A.4.2 Skraup Synthesis

NH2

CH2CHCH2

OH OHOH+

H2SO4

C6H5NO2 N

NH2

+ CH2 CH C CH3

O ZnCl2

or FeCl3 N

CH3

NH2CH3O+

CH2CHCH2

OH OHOH m-CH3OC6H5NO2

H2SO4

CH3O N

ORGANIC CHEMISTRY

Department of Chemistry, Xiamen University

Special Topic

A.4.3 Electrophilic substitution

N

Br2

H2SO4 N N+

Br

Br

HNO3

H2SO4, 0�N N N+

NO2

NO2

NH

Br2

Dioxane, 0� NH

Br