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