Professional Documents
Culture Documents
有機化學 20
有機化學 20
有機化學乙
蔡蘊明 教授
【本著作除另有註明,作者皆為蔡蘊明教授,所有內容皆採用 創用CC 姓
名標示-非商業使用-相同方式分享 3.0 台灣 授權條款釋出】
Chapter 20 Amines
※ Nomenclature
RNH2 primary amine
R2NH secondary amine
R3N tertiary amine
R4N+X− quaternary amine salt
aniline CH3
N-methylaniline
(benzenamine)
p-toluidine
Heterocyclic amines
4 3 4 3
N
5 1 2 5 1 2
N N N
H H H
pyrrole indole
imidazole
(1-azacyclopenta-2,4-diene) (1-azaindene)
N N
pyridine quinoline
N N
H H
piperidine pyrrolidine
※ Physical properties and structures
p
pyramidal
inversion
N N N
fast sp2
enantiomeric TS for inversion
R'' R''
R' R'
N R R N
R''' R'''
separable quaternary ammonium salt
※ Basicity
Kb
RNH2 + H2O RNH3 + OH−
electron donating
NH3 CH3NH2 increases basicity
pKb 4.47 3.36
NH3
N
N N
H
H H
pKa of corresponding piperidine pyrrolidine diethylamine
aminium ion 11.20 11.11 10.98
N
N
N N
H
pyridine pyrimidine pyrrole
5.23 2.70 0.40
Amides
O O
R NH2 R NH2
Basically neutral
Strong amide resonance makes the
lone pair unavailable
O
H H H
O O O
better
R NH2 R NH2 R NH2
◎ Aminium salt and quaternary ammonium salt
R''
R N H
aminium salt
R'
Ag2O, H2O
HCl/H2O HCl/H2O
HO HO NH2 N
H
OH
epinephrine dopamine serotonine
(adrenaline)
Cl
N CH3
NH2
N
N NH2 CH3
CH3
H
N
amphetamine
histamine
chlorpheniramine
(an antihistamine)
H
HO
H N
H
HO O
H
H3CO N
H CH3
HO
N
(-)-qunine morphine
O
O
O HO
R' O O
N
O P O N OH
O OH H
lecithins ractopamine
(卵磷脂)
O
acetylcholine esterase
N N
H3C O HO
acetylcholine choline
(膽鹼)
nerve
impulse
nerve
cell
impulse
※ Preparation
◎ Via substitutions
OH−
NH3 + R X R NH3 X− RNH2
Problem:
multiple alkylations
OH−
RNH2 + R-X R2NH
OH−
R2NH + R-X R3N
OH−
R3N + R-X R4N X−
Some solutions:
O O O
stops at
phthalimide
mono-
pKa = 9 NH2NH2
alkylation
EtOH
O O
H+
NH NHR
RNH2 +
NH
NH2
N
O O H
phthalazine-1,4-dione
◎ Via reduction
From nitro compounds
HNO3 O [H]
Ar H Ar N Ar NH2
H2SO4 O
condition
H2/Ni
or 1) Fe, HCl; 2) OH−
−
or 1) Zn, AcOH; 2) OH
or 1) Sn, HCl; 2) OH−
1) Fe, HCl
NO2 − NH2
2) OH
97%
From cyanide
Raney Ni
C C N CH2CH2NH2
o
H2 140 C, EtOH
or LAH
From oximes
OH
Na, EtOH
N NH2
or
LAH
From amides
CH3COCl O 1) LAH, Et2O
PhCH2NH2
PhCH2NH CH3 2) H2O
PhCH2NHCH2CH3
★ Reductive amination
R H2, Pd R R''
+ R''R'''NH R' N
O or
R' H R'''
H2, Ni
aldehyde or
or NaBH4
ketone or
NaBH3CN at pH ~3
Mechanism:
R R R'' [H] R
O + R''NH2 N R' NHR''
R' R' H
imine
(Schiff base)
R R R'' [H] R
+ R''R'''NH N R' NR''R'''
O
R' R' R''' H
iminium ion
例
O NH3, H2, Ni
CH2NH2
H 90 atm
40-70 oC 89%
(CH3)2NH CH3
O N
NaBH3CN CH3
52-54%
◎ Through rearrangements
◎ Substitution reaction
Amines are good nucleophiles
— better than oxygen compounds
reacts with R-LVG
or O
R Cl
◎ Oxidation of amines
R OOH
R R'
N
1o Aliphatic amines
H2O N O
R NH2 + NaNO2 + 2HCl
R NH
tautomerization
X H
H+ N OH
N O H
R N N R N
R N
a diazonium salt
R+ + N2
arenediazonium salts
more stable
decompose at higher T
2o Aryl amines
H N O
N + NaNO2 + HCl N
Me Me
yellow color
3o Aryl amines
Me NaNO2 Me O
N N N
Me HCl Me
8 oC, H2O 80-90%
◎ Reactions of arenediazonium salts
NH2 N2+Br− Br
HBr, NaNO2 CuBr
+ N2
Cl H2O, 0-10 C o Cl 100 oC Cl
+ N2
Aryl fluorides
H3C 1) HONO, H+ H3C H3C
∆
NH2 2) HBF4 N2+BF4− F
+ N2 + BF3
Phenols
O2N O2N O2 N
H2SO4, NaNO2 H2SO4
NH2
H2O, 0-5 Co N2+HSO4− H2O, 100 oC OH
+ N2
Deamination
CH3
CH3 CH3
Ac2O 1) Br2
−
2) OH Br
HN
NH2 H2O, ∆ NH2
O
H2SO4,
o
0-5 C NaNO2,
H2O
CH3 CH3
H3PO2
H2O, 25 oC
Br Br
N2+HSO4−
N N + Z N N Z
−
X
Z: electron an azo compound
donating group colored (azo dyes):
with highly conjugated
π system
例 SO3−Na+
N
N
OH
orange II
例 0 oC
N2Cl + OH N N OH
NaOH
H2O
p-(phenylazo)phenol
orange color
O
ONa
N2Cl + N N N N
o
0 C
H2O
yellow color
Mechanism:
N N O− N N O
H
N N O−
If too basic:
HO
Ar N N Ar N N OH
H
does not couple
For arylamines: pH 5-7 is preferred
If too acidic: H H
NR2 NR2
CH3 CH3
◎ Reactions with sulfonyl chlorides
O −HCl O
RNH2 + Cl S Ar R N S Ar
O H O
a sulfonamide
O −HCl O
R2NH + Cl S Ar R2N S Ar
O O
O 1) H3O+, ∆ O
R2N S Ar − R2NH + O S Ar
2) OH
O O
The sulfonyl group can be used as a protecting group
O
R3N + Cl S Ar NR
O
※ The sulfa drugs
1936 biologically
O
H2N S NH2 sulfanilamide
O
H2N N N OH
O
N
N N C N HO
OH H H
O OH
folic acid
H OH H O
N C 2.3 Å N S NH2 2.4 Å
H O H O
6.7 Å 6.9 Å
RNH2
O
NH2 1) dil. HCl, ∆
HN
2) OH−
SO2NHR
SO2NHR
※ Ammonium compounds
∆ + AgX
RCH=CH2
Regiochemistry: The Hofmann elimination
CH3CH2CHCH3 150 oC
CH3CH=CHCH3 + CH3CH2CH=CH2
−
NMe3
HO 5 : 95
cf.
CH3CH2CHCH3
CH3CH=CHCH3 + CH3CH2CH=CH2
−
SMe2
EtO 26 : 74 + Me2S
+ EtOH
CH3CH2CHCH3 NaOEt
75 : 25
Br
Reason:
Basic requirement for elimination – anti-periplanar
HO−
H
C C
NR3
Further consideration
δ−
B
B
H
− H
δ
C C C C
LVG LVG
δ−
Develops −
δ
negative charge
on this carbon Alkene like transition state
Carbanion like
Zaitsev orientation
gives more stable compound
*Carbanion stability
1o > 2o > 3o
x H H H preferred
H3CHC C CH2
NMe3
※ Spectroscopy
MS
NH2 NH2
NH2