Reactions and Synthesis of Heterocyclic Amines and...
Transcript of Reactions and Synthesis of Heterocyclic Amines and...
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