台灣大學開放式課程

有機化學乙
蔡蘊明 教授

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Chapter 20 Amines

※ Nomenclature
RNH2 primary amine
R2NH secondary amine
R3N tertiary amine
R4N+X− quaternary amine salt

CH3NH2 methylamine or methanamine

NH2 cyclohexylamine or cyclohexanamine

CH3NHCH2CH3 ethylmethylamine or N-methylethanamine

Et3N triethylamine or N,N-diethylethanamine
H2NCH2CH2OH 2-aminoethanol
amino group
 Arylamines

NH2 NHCH3 NH2

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

Polar, water soluble when small

N H N Hydrogen bonding possible

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

Gas phase basicity:

(CH3)3N > (CH3)2NH > CH3NH2 > NH3
Solution phase:
(CH3)2NH > CH3NH2 > (CH3)3N > NH3
R
R less solvation stabilization
N H
(steric effect)
R
 NH2 NH2

pKb 3.36 9.42

NH2 NH2 NH2 NH2

Lone pair delocalized into the π system

NH3

Lone pair no longer exists

  Basicity of heterocyclic amines

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

R NH3 Lost amide resonance completely

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'

CH3CH2NH3 Cl− ethylaminium chloride

Et4N+ Br− tetraethylammonium bromide

Ag2O, H2O

AgBr + Et4N+ OH− tetraethylammonium hydroxide

strong base as NaOH
◎ Acidity of amines

Pr2NH + n-BuLi Pr2N− Li+ + Butane

pKa ~40 lithium pKa ~50

diisopropylamide
(LDA)
※ Amines used as resolving agents

CO2H HO2C H2N

H OH HO H H
+ Ph
Ph Ph CH3
R S R

(R)-acid(R)-amine salt + (S)-acid(R)-amine salt

diastereomers
separable by fractional recrystallization

HCl/H2O HCl/H2O

(R)-acid + (R)-aminium salt (S)-acid + (R)-aminium salt

(in aqueous solution) (in aqueous solution)
Naturally occurring optically active amines can be used
as resolving agents
例
N
H3CO
H
(−)-brucine
H3CO N
H H 馬錢子鹼
O O
 HO H
NHCH3 HO
HO NH2

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:

 Use excess amine to stop at mono-alkylations

 LAH
R X + NaN3 R N N N RNH2
or
sodium alkyl azide Na/alcohol
azide
  Gabriel synthesis
H+
O O 1o, 2o O
KOH − +
R X
NH N K N R

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

 Hofmann rearrangement (Hofmann degradation)

O H2O
+ Br2 + 4 NaOH R NH2 + 2 NaBr
R NH2 + Na2CO3
+ 2 H2O
Mechanism: more acidic
O O O
+ OH− H
R NH2 R NH Br Br R N
Br
pKa~15
−
OH
O O O
− O
OH C
HO N N Br
HO N R N
R R R
isocyanate R migrates with
retention
O −CO2 H2O
R NH R NH2
O NH
R *Prepare primary amine only
※ Reactions of amines

◎ Substitution reaction
Amines are good nucleophiles
— better than oxygen compounds
reacts with R-LVG
or O

R Cl
◎ Oxidation of amines

R3N + H2O2 R3N O

tertiary or a tertiary amine oxide
amines
O

R OOH

R R'
N

Electron rich, oxidize the ring easily

◎ Reaction with nitrous acid (HNO2)
NaNO2 (aq) + HCl(aq)  HO-N=O(aq) + NaCl(aq)
sodium nitrite (H2SO4) (Na2SO4)

 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

Alkenes, alcohols, alkyl halides

 Not useful for 1o amines
 2o Aliphatic amines
H2O O
Me2NH + NaNO2 + HCl Me2N N
N-nitrosodimethylamine
(yellow color)
strong carcinogen
 1o Aryl amines
−
X
Ar NH2 + NaNO2 + HX Ar N N

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

 The Sandmeyer reaction

CuCl
Ar Cl
+ CuBr
Ar N2 Ar Br
CuCN
Ar CN
例 H3C NH2
HCl, NaNO2
H3C N2+Cl−
CuCl
H3C Cl
+ N2
o
H2O, 0-5 C 15-60 oC

NH2 N2+Br− Br
HBr, NaNO2 CuBr
+ N2
Cl H2O, 0-10 C o Cl 100 oC Cl

O2N NH2 O2N N2+Cl− O2N CN

HCl, NaNO2 CuCN
+ N2
o
H2O, RT 90-100 C
 Aryl iodides
H2SO4, NaNO2 KI
O2N NH2 O2N N2+HSO4− O2 N I
H2O, 0-5 oC

+ 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−

H3PO2 hypophosphorous acid

 Coupling reactions

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

para attack preferred HO

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

does not couple

Ortho coupling also possible

OH OH
−
Cl
N N
N N +

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

Paul Ehrlich Chemotherapy

Gerhard Domagk 1935
NH2
O
H2N N N S NH2
O
prontosil

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

Folic acid is important in cell division

H2N N N OH
CH3 O methotrexate:
N
N N C N HO
H anti-cancer
NH2
O OH
◎ Preparation of sulfa drugs
O O
NH2
HN HOSO2Cl HN
Ac2O
80 oC
−H2O
SO2Cl

RNH2

O
NH2 1) dil. HCl, ∆
HN
2) OH−

SO2NHR
SO2NHR
※ Ammonium compounds

The Hofmann elimination

HO−
H
C C NR3 C C + H2O + R3N

RCH2CH2N(CH3)3 X + Ag2O + H2O RCH2CH2N(CH3)3 OH

∆ + 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

IR: N-H stretching 3300-3550 cm−1 (br)

1H NMR

N-H δ 1-5 depends on concentration

CH3NR2 RCH2NR2 R2CHNR2
δ 2.2 2.4 2.8

MS
NH2 NH2

NH2