Reactions and Synthesis of Heterocyclic Amines and Other Aromatic ...

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atoms in addition to carbon. N, O, S are the most common heteroatoms. Heterocyclic compounds are common in organic chemistry, and many have important.
S p ecial Topic A

Aromatic Heterocyclic Compounds: Reactions and Synthesis 芳香杂环化合物的合成与反应

ORGANIC CHEMISTRY

Special Topic

A.1 Classification

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Cyclic organic compounds

Carbocycles 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. Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Antibiotic: Penicillin

O C6H5CH2 C

NH

H

S

H

CH3 CH3

N O

CO2H H

Penicillin G Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Antiulcer agent: Cimetidine

O CH3HN C NHCH2CH2 S CH2 CH3

N N

Cimentidine

H

甲氰咪胍(抗溃疡药) Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Sedative: Phenobarbital

H N

O H

O CH2CH3

N O

Phenobarbital Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Nonnutritive sweetener: Saccharin

O H N O S O

Saccharin Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Natural products: Heme CH3

CH CH2 N

CH3 N

Fe

HO2CCH2CH2

CH3 N

N

CH CH2 CH3

HO2CCH2CH2

Heme Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Natural products: Chlorophyll CH3 CH2

CH2CH3 N

CH N CH3

CH3

Mg

N O CO2CH3

N CH3 H

H

H O O

CH3

H

CH3

H

Chlorophyll a

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Some heterocycles we’ve encountered O O Epoxide (A cyclic ether)

O

Lactone (A cyclic ester)

O THF (A cyclic ether)

N O H Lactam (A cyclic amide)

N Pyridine (A cyclic amine) Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

4

Special Topic

3 2

5

O1

N H Pyrrole

Furan 呋喃 4 5

O1

Oxazole

噻吩

N

2

N

Thiophene

吡咯

N3

噁唑

S

4

咪唑

吡啶

N3

N

2

5

N H Imidazole

Pyridine

S1

Thiazole 噻唑

N

Pyrimidine 嘧啶

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

CH 3

CH 3 N 3-Methylpyridine

N CH 3 1,3-Dimethylpyrrole

O

N N N H H H Tetrahydrofuran Pyrrolidine Piperidine 2,3-Dihydropyrrole 四氢呋喃 四氢吡咯 六氢吡啶 2,3-二氢吡咯 (哌啶 ) Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

4

5

6

Special Topic

5

9

3 6

8

2 7

N1 H

7

Indole 吲哚

4

10

N

3 9 8

N1

Quinoline 喹啉

2

N

N N H Purine 嘌呤

H N

N S

Carbazole

Benzothioazole

咔唑

苯并噻唑 Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

A.2 Five-Membered Unsaturated Heterocycles

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

A.2.1 Structures of Pyrrole, Furan, and Thiophene

O Furan

S

N H Pyrrole

Thiophene

Lone pair in p orbital

N H sp2 hybridized

Six pi electrons

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

A.2.2 Preparation Ni Catalyst

+

C5H10O5

H3O

CHO 280

Pentose mixture

O Furfural

+ CO O Furan

NH3, H2O O

Al2O3, 400

N H

S 600

S Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

O O CH3C CH C OEt NH2

Special Topic

O O CH3C CH2 C OEt CH3CO2H

O C OEt

CH3

EtO C O

O CH3 O NaOH CH3C CH2NH3 Cl + CH3CCH3 25°C

N H

N H

CH3

CH3

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

A.2.3 Reactions of Furan, Pyrrole and Thiophene

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Protonation H+

H N H

N H

N H

H

N H

N H

H

n H N H

H

H

H

N H

H N H

H

H

N H

H

N H H+

n+2 Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Electrophilic Substitution Reactivity N H

>

>

O

>>

S

Nitration Acetic + HNO3 N H

+ H2O

anhydride

N H

Acetic + HNO3 S

anhydride

S

NO2 83%

+ H2O NO2

O (CH3CO)2O + HNO3

CH3 C ONO2 + CH3CO2H Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

NO2+

NO2

NO2 N H

N H

H

N H

NO2 N H

H

H

H NO2

N H

NO2+ N H

H N H

NO2

NO2

NO2

H N H

H N H Not formed

Electrophilic substitution takes place primary at position 2 Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Sulfonation 100 + N H

N

N H

SO3

N H

SO3

HCl N H

SO3H

+ H2SO4(cond.) S

25 S

SO3H

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Halogenation SOCl2(1 mol) Et2O, 0

Cl

N H

Br

Br N H

Br2 Et2O, 0

Br

N H

Br

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Cl2 40 O

O

+ Cl Cl

O

Cl

Br2 Dioxane, 0

Br

O

Br2 AcOH S

Br

S

I2, HgO C6H6, 0

S

I

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Friedel-Crafts Reactions Benzene S

+ CH3COCl

+ (CH3CO)2O

C CH3

S 83%

O

BF3 O 75 ~ 92%

O

+ (CH3CO)2O N H

SnCl4

C CH3 O

150 ~ 200 N H

C CH3 O

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Coulping Reaction N H

+ C6H5 N N X

N H

N N C6H5

Orientation on Electrophilic Substitution

G (o, p)

minor

G (o, p)

major Z

Z

G (m) major Z

major minor

G (m) Z

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

A.3 Six-Membered Unsaturated Heterocycles

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

O

O

N Pyridine 吡啶

Pyran-2H α-Pyran α-吡喃

Pyran-4H γ-Pyran γ-吡喃 O

O

O

1,2-Pyrone α-吡喃酮

O 1,4-Pyrone γ-吡喃酮 Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

A.3.1 Structure of Pyridine

Lone pair in sp2 orbital 3 4

2 N1

Pyridine

N 2

sp hybridized

Six pi electrons Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

A.3.2 Reactions of Pyridine

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Electrophilic Substitution Br

Br2 200 ~ 220

N

+ N 26%

N 37%

NO2

H2SO4 ,HNO3 N

330

N

HgSO4, 220

15% SO3H

20%SO3-H2SO4 N

Br

Br

N

70%

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Highly unreactive because of positive charge

+

+ H (or E+)

N

N H Pyridinium ion

E+ N H

E

E

E

H

H

H

N

N

N

H

H

H

E

H+ N H

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

H

E+

N

E+

H

E

H

E 2+

E

N

N

N

H

H

H

Especially unstable because N has a sextet And two positive charge

H 2+

N H

E

E H

N H

H

E N H

H

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Nucleophilic Substitution NaNH2 N

+ Br

NH3

Br

N

Cl

NH2

OCH2CH3 NaOCH2CH3

N

C2H5OH

NH2 N

Br

+ Cl N

NH2 N

Br

N

+ Br NH2

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

C6H5 Li N

110°C, toluene

+ C6H5 N Li

N Li

H N Li

H

C6H5

C6H5

+ Li C6H5

N

KOH , O2 N

320°C

N

OH

N

O

H Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

+ NaNH2 N

Special Topic

100 PhN(CH3)2

H2O N

NHNa

N

NH2

Chichibabin reaction

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

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

N

N

N

N

R

R

R

R

OH

K2Fe(CN)6

+ OH N CH3

X

H2O N CH3

H

N

O

CH3 Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

H + NaBH4

H2O

N

N

RX

NaBH4 H H2O

H H

H H

H

H

R

R H

H

N

Na2S2O4 N

H2O

RX O

N R H

H

C NH2 Na S O , OH , H O 2 2 4 2 N R X NAD+

K2Fe(CN)6

O C NH2

N R

NADH

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Oxidation N N

CO2H

HNO3

CH3

N CO2H

KMnO4 N

N

CO2H

30% H2O2-AcOH Pyridine N-oxide N

N

N-氧化吡啶

O Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Reaction of Pyridine N-Oxide NO2

NO2 PCl2

HNO3 N

H2SO4 100

CHCl3

N

O

+ POCl3 N

O OCH3

OCH3

NO2

PCl2

CH3ONa N

N

O

O

CHCl3

+ POCl3 N

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Reduction

H2, Pt, 25 , 3 atm or Na / EtOH

N

-9

Kb = 2.3* 10

N H Piperidine 哌啶 -3 Kb = 2* 10

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

Reaction of Alkylpyridine Side Chains O N CH3

N

+ C6H5 C C6H5 CH3 CH2CH3 NaNH2

CH2

N

NaNH2

C6H5 N

CH2 C OH C6H5

CH2CH3 CH3I

CH2CH3 CH2CH3 N

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

CH3

CH CHPh PhCHO

N

ZnCl2

N NH OH

+ PhCHO I

N CH3

CH3

25 I

N

CH CHPh

CH3

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

A.3.3 Synthesis of Pyridine O O O 2 CH3C CH2 C OEt + NH3 + HCH H

H

EtO2C CH3

CO2Et N H

CH3

HNO3 H2SO4

Et2NH

EtO2C CH3

CO2Et N

CH3

Hantzsch synthesis Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

A.4 Fused-Ring Heterocycles 苯并杂环化合物

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

N

N

Quinoline 喹啉

Isoquinoline 异喹啉

N H

Indole 吲哚

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

A.4.1 Fischer Indole Synthesis

NHNH2 + O C

CH3 HOAc CH3

CH3 NHN C CH3

ZnCl2 180

N H

CH3

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

A.4.2 Skraup Synthesis + NH2

CH2CHCH2

H2SO4

OH OHOH

C6H5NO2

O + CH2 CH C CH3 NH2 + CH3O

NH2

CH3O

N

N

CH3

ZnCl2 or FeCl3

CH2CHCH2

H2SO4

OH OHOH

m-CH3OC6H5NO2

N

Department of Chemistry, Xiamen University

ORGANIC CHEMISTRY

Special Topic

A.4.3 Electrophilic substitution Br Br2

+

H2SO4

N

N

N Br

NO2 HNO3 N

N

H2SO4, 0

+

N NO2

Br

Br2 N H

Dioxane, 0

N H

Department of Chemistry, Xiamen University