Chapter 17 Amines (胺)
17.1 Amine Nomenclature
17.2 Structures of amines
17.3 Basicity of amines
17.4 Preparation of amines
17.4.1 Preparation of amines
by alkylation of ammonia
17.4.2 The Gabriel synthesis of primary
amines
17.4.3 Preparation of amines by reduction
17.5 Reactions of amines
17.5.1 Alkylation of amines
17.5.2 Acylation of amines
17.5.3 The Hofmann Elimination
17.5.4 Reactions of amines with nitrous acid
(A) Reactions of primary aliphatic
amines with nitrous acid
(B) Reactions of primary arylamines
with nitrous acid
(C) Reactions of secondary amines
with nitrous acid
(D) Reactions of tertiary amines
with nitrous acid
17.5.5 Synthetic transformations of aryl
diazonium salt
(A) Replacement of the diazonium
group by －OH
(B) Replacement of the diazonium group
by －X, －CN
(c) Replacement of the diazonium group
by －H
17.5.6 Azo coupling
17.6 Spectroscopic analysis of amines
17.1 Amine Nomenclature
Organic derivatives of ammonia
H N
R N
Alkylamines
H
H
Ar N
Arylamines
Primary amines （伯胺）:
CH3NH2
P380
CH3
CHCH2NH2
CH3
H
N
H
Aniline
(苯胺)
CH2NH2
Isobutylamine Benzylamine
Methylamine
(异丁胺)
(甲胺） 2-Methylpropylamine (苄胺）
（2-甲基丙胺）
NH2
Cyclohexylamine
(环己胺)
CH3
N H
amines:
CH3CH2
Secondary
(仲胺）
(CH3CH2)2NH
Ethylmethylamine
（甲乙胺）
Diethylamine
N-Methylethylamine
（二乙胺）
(N-甲基乙胺）
Tertiary amines:
（叔胺）
H3C
(CH3)3N
N
CH3
Trimethylamine
N,N-DimethylN,N-Dimethylmethylamine
aniline
（三甲胺）
（N,N-二甲基甲胺）
(N,N-二甲基苯胺)
H3C
N
CH2CH3
N-Ethyl-N-methylcyclohexylamine
(N-甲基-N-乙基环己胺)
Diamines:
H2NCH2CH2NH2
1,2-Ethyldiamine
（1,2-乙二胺）
Ammonium ions
（铵离子）
C16H33N(C4H9)3 Br
Aminium salts
NH3 Cl
（铵盐）
Anilinium chloride Quaternary
（盐酸苯胺）
ammonium
salts
HOCH CH NH
2
2
2
2-Aminoethanol
（2-氨基乙醇）
（季铵盐）
Heterocyclic amine:
(杂环胺)
N
N
N
N
H
Pyridine Pyrrole Quinoline
(吡啶)
(吡咯)
(喹啉)
N
N
H
H
Pyrrolidine
(吡咯烷)
(四氢吡咯)
Indole
(吲哚)
Piperidine
( 哌啶)
17.2 Structures of amines
P383,
12.2
C N
H
sp3-sp3 hybridized
C－N： orbitals overlap
3hybridized -1s
N: 1s22s22px12py12pz1
sp
N－H：
orbitals overlap
3
sp -hybrid Pyramid(棱锥型)
Tertiary amines with 3 different groups:
R'
R'' N
R'''
R'
N R''
R'''
Interconversion of amine enantiomers
Quarternary ammonium salt:
Et
CH3
CH3
N CH
6 5
CH2CH CH2
N
X
Et
C6H5
CH2 CHCH2
X
(R)
(S)
17.3 Basicity of amines
Weak bases
RNH2 + H2O
[ RNH3 ] [ OH ]
Kb =
[ RNH2 ]
P384,
12.3
RNH3 + OH
pKb = - log Kb
Table 1 Basic strength of some amines
Amines
pKb
NH3
4.7
CH3NH2
3.4
(CH3)2NH
3.3
(CH3)3N
4.3
9.4
NH2
O2N
NH2
13
CH3O
NH2
8.7
P385,
Table
12.1
1. All amines are weak bases:
H2O < RNH2 < < OH 2.
NH2
RNH2 > NH3 >
P384,
12.3
Alkylamines are slightly stronger bases
than ammonia; Arylamines are much weaker
bases than ammonia and alkylamines.
p -πconjugation
R NH2
+I
Delocalization of
nitrogen lone-pair
electrons
N
H
Decreasing the
H
electron density
at nitrogen.
NH2
NH2
NH2
NH2
NH2
R NH3 + H2O
R NH2 + H3O
[RNH 2][H3O+]
pKa = -logKa
Ka =
+
[RNH3 ]
pKa + pKb = 14
Weaker base:Smaller pKa for ammonium ion
Stronger base: Larger pKa for ammonium ion
NH3 pKa = 4.63
CH3 NH3 pKa = 10.66
3. R2NH > RNH2 > R3N >NH3
R
Poorer
solvation
N H
R
R
Anilinium ion
NH3Cl
NH2 + HCl
Separation of amines from neutral organic
compounds
P384,
17.4 Preparation of amines
12.3
17.4.1 Preparation of amines by alkylation
of ammonia
NH3 (excess) + R X
R NH3X
NaOH
R
NH2
1.R X
NH2
2. OH
R
R2NH
1. R
X
2. OH
R3N
17.4.2 The Gabriel synthesis of primary
amines
R X
R NH2 Primary alkyl halide, SN2
Potassium salt of
Phthalimide
O
Reagent:
C
C
O
C
C
O
N H
NK
（邻苯二甲酰胺钾盐）
O
O
KOH
C
Ch.P436
C
O
O
NK
R X
C
DMF
C
Imide
（酰亚胺）
O
N R
O
O
C
N R
NaOH, H 2O

C
O
RX:
O
CHCR'
,
X
C
O
C
O
R NH2 +
O
O
CHCOR'
X
ROTs
ArX
,
17.4.3 Preparation of amines by reduction
Reduction of nitriles to amines
CH2C
N + 2 H2
Raney Ni
140¡æ
CH2CH2NH2
(71%)
LiAlH4
Siegmund Gabriel was born
in Berlin,Germany,and
received his Ph.D. in1874
at the University of Berlin,
working with August von
Hofmann. After further
work with Robert Bunsen,
he became Professor of
Chemistry at the Univ. of
Berlin.
Robert Wilhelm
Bunsen
1811-1899
Siegmund Gabriel
(1851-1924)
poohbah.cem.msu.edu/
Portraits/
Gabriel Synthesis.
Gabriel, Ber. 20, 2224(1887).
M. S. Gibson, R. W. Bradshaw, Angew. Chem. Int. Ed.
7, 919 (1968); B. Dietrich et al., J. Am. Chem. Soc. 103,
1282 (1981); O. Mitsunobu, Comp. Org. Syn. 6, 79-85 (1991).
Modified conditions: S. E. Sen, S. L. Roach, Synthesis 1994,
756; M. N. Khan, J. Org. Chem. 61, 8063 (1996).
Stereoselectivity: A. Kubo et al., Tetrahedron Letters 37,
4957 (1996).
Reduction of nitro compounds to arylamines
Ar
HNO3
H H2SO4
Ar NO2
NO2
[ H]
Ar NH2 P389
NH2
H2, cat
1) Fe, HCl
2) OH
Reduction of amides to amines:
O
N CCH3 + LiAlH41) Et2O
N CH2CH3
CH3
CH3
2) H2O
Reductive amination:
R
(R')H
C O + NH3(or R''NH2)
H2, Ni
-H2O
R
CH NH2(R'')
(R')H
H
C O + NH3
R
C NH(R'')
(R')H
Imine
（亚胺）
Ch.P435
H2, Ni
90 atm
40 ~ 70¡æ
(CH3)2C O + H2NCH2CH2OH
H2, Ni, EtOH
95£¥
CH2NH2
(89%)
(CH3)2CNHCH2CH2OH
17.5 Reactions of amines
Unshared electron pair
of nitrogen:
N
Basicity:
+ H X
N
Nucleophilicity:
N
+
C O
17.5.1 Alkylation of amines
RNH2
R'CH2X
RNHCH2R'
R'CH2X
R'CH2X
RN(CH2R')2
RN(CH2R')3X
CH2NH2 + 3 CH3I
(Cyclohexylmethyl)amine
MeOH
heat
CH2N(CH3)3 I
(cyclohexylmethyl)trimethylammonium iodide
(99%)
Methyl
iodide
17.5.2 Acylation of amines
Acylating agents: acyl chlorides, carboxylic
acid anhydrides
Synthesis of Paracetamol （扑热息痛）:
Cl
HO
NO2
1) NaOH, H2O
2)
NH2
H3+O
(CH3CO)2O
HO
HO
NO2
H2, Ni
NHCCH3
O
Decreasing the activity of aryl ring or
Protecting amino groups :
NH2
(CH3CO)2O
NHCOCH3
NHCOCH3
NH2
H2O,OH- ,¡÷
Br2, ¡÷
Br
Br
17.5.3 The Hofmann Elimination
RNH2
C
C
Methylation of an amine by excess CH3I:
CH3CH2CH2CH2CH2CH2NH2
CH3I
excess
CH3CH2CH2CH2CH2CH2N(CH3)3I
Hexylamine
Hexyltrimethylammonium iodide
Quaternary ammonium hydroxides
（氢氧化季铵碱）can be prepared from
Quaternary ammonium halides:
2 RCH2CH2N(CH3)3X + Ag2O + H2O
CH2N(CH3)3 I
Ag2O
H2O, CH3OH
2 RCH2CH2N(CH3)3OH
+ 2AgX
CH2N(CH3)3 OH
Quaternary ammonium hydroxides
heat β- Elimination to form alkenes
and an amine
CH2 N(CH3)3
H
OH
Ch.P448
(六)
160¡æ
CH2 + (CH3)3N + H2O
Methylenecyclohexane
（亚甲基环己烷）
(69%)
HO
H
C C
E2 reaction
C
C
+ N(CH3)3 + H2O
N(CH3)3+
¦Ä
N(CH3)3
E2 Reaction
RCH CH2
Anti relationship
¦Ä
The base attacks the most HO H
Transition state
acidic hydrogen or least
hinder hydrogen.
Regioselectivity of Hofmann elimination:
To give a less substituted alkene.
CH3
CH3CH2CHNH2
1) 3CH3I
2) AgOH
H2C H
CH CH N(CH3)3OH
CH3
H
CH3CH2CH CH2 + CH3CH CHCH3
(5%)
(95%)
¡÷
Hofmann rule is opposed to the Zaitsev rule.
C1–C2
C2–C3
HO
HO
HO
H
CH3CH2
H
H
CH3CH2
-H2O
-N(CH3)3
H
N(CH3)3
H
H
CH3
H H
H
CH3
H
N(CH3)3
H
-H2O
-N(CH3)3
CH3
CH3 H
August Wilhelm von , 1818–1892,
German organic chemist. He was
Professor at the Univ. of Berlin
from 1865 and was a founder
(1868) of the German Chemical
Society. He studied the constitution of aniline and was the first
to prepare rosaniline and its
derivatives, thereby laying the
basis for the aniline dye industry.
He also discovered a reaction for
deriving amines from amides and
developed the Hofmann method
August Wilhelm von of finding the vapor densities, and
from these the molecular weights,
1818–1892
of liquids. He also helped to
popularize the concept of valence
(the word comes from his term
quantivalence
17.5.4 Reactions of amines with
nitrous acid (Nitrosation 亚硝化反应)
(A) Reactions of primary aliphatic amines
with nitrous acid
Nitrosating agent:
NaNO2 + HCl
1/2 H 2SO4
HNO2 + NaCl
1/2 Na2SO4
Primary aliphatic amines Nitrous acid
to yield unstable aliphatic diazonium salt
(重氮盐)
Diazotization (重氮化反应)
Aliphatic diazonium salts decompose to form
carbocations and nitrogen:
CH3CH2CH2NH2
NaNO2, HCl
CH3CH2CH2 N
NCl
CH3CH2CH2 + N2 + HCl
Alkene, alcohol, alkyl halide
(B) Reactions of primary arylamines
with nitrous acid
P390
Primary arylamines form diazonium salt on
nitrosation:
NH2 + NaNO2 + 2 HCl
0 ~ 5¡æ
N
N Cl + H2O + NaCl
Aryl diazoniumsalts are stable below 5℃
(C) Reactions of secondary amines
with nitrous acid
Secondary amines: both aryl amines and
alkyl amines react with nitrous acid to yield
N-nitrosoamines（亚硝胺）
N O
NHCH3 + NaNO2 + 2 HCl
N
CH3
N-nitrosoamines are usually separated from
the reaction mixture as oily yellow liquids
(D) Reactions of tertiary amines
with nitrous acid
R3N
NaNO2, HCl
No reaction
Tertiary aryl amines react with nitrous acid
to form C-nitroso aromatic compounds:
N(CH3)2
NaNO2, HCl
ON
N(CH3)2
Electrophilic aromatic substitution ( )
17.5.5 Synthetic transformations of aryl
diazonium salt
The diazonium group （重氮基）may be
replaced by other atomes or groups: －X,
－OH, －CN and －H.
P391
Aryl diazonium salts can be prepared
from arene:
ArH
ArNO2
ArNH2
ArN
N
(A) Replacement of the diazonium
group by －OH
Aryl diazonium ion is converted to phenols(酚)
(CH3)2CH
1. NaNO2, H2SO4, H2O
(CH3)2CH
NH2
2. H2O, heat
p-Isopropylaniline
OH
p-Isopropylphenol
(73%)
+
N2 :Electron-withdrawing
Hydrolysis
group
Sulfuric acid is usually used instead of
hydrochloric acid
OH
Question: Design a synsthesis of
Br
(B) Replacement of the diazonium
group by －X, －CN
The preparation of aryl iodides
NO2
NO2
NO2
H2SO4, NaNO2
H2O, 0 ~ 5¡æ
NH2
KI
N2+HSO4
+ N2
I (81%)
The preparation of aryl fluorides:
Treating the diazonium salt with fluoboric
acid (HBF4)
CH3
CH3
CH3
1) NaNO2, H+
NH2
2) HBF4
¡÷
N2+BF4
+ N2 + BF3
F
(69%)
The Sandmeyer reaction:
Aryl diazonium salts react with cuprous
chloride, cuprous bromide, cuprous cyanide
£- N2
NH2
-X or -CN
N2+ Br -
HBr, NaNO2
H2O
0 ~ 5¡æ
Cl
Br
+ N2
CuBr
100¡æ
Cl
Cl
(70% overall)
NO2
NH2
HCl, NaNO2
H2O
(r.t)
NO2
N2+Cl
NO2
CN
CuCN
90 ~ 100¡æ
+ N2
(65% overall)
Born inWettingen near Zurich, and lived in the
Zurich area for nearly all of his life. He trained
as a precision instrument-maker, but became
interested in chemistry. Self-educated in
chemistry, he carried out chemical
experiments in his kitchen. In 1881, he became
a lecture assistant to Victor Meyer
(1848-1897). He followed Meyer to
Göttingen in 1886, but soon returned to
Zurich and worked for Arthur Hantzsch
(1857-1935). Sandmeyer joined Geigy as
a research scientist in 1888, and eventually
became a director of the firm. He discovered
the decomposition of aryl diazonium
Chlorides to chloroarenes in the presence of
copper (I) chloride in 1884. He also worked
on the triphenylmethane dyes and the synthesis
of isatin. Many years before, he had suggested
Traugott Sandmeyer to Victor Meyer an impurity in commerical
benzene was responsible for the isatin reaction
(1854-1922).
with sulphuric acid, thereby paving the way
for Meyer's discovery of thiophen.
(C) Replacement of the diazonium
group by －H
Aryl diazonium salts react with
hypophosphorous acid (H3PO2) (次磷酸）
or ethanol to yield the product:
Ar£- N2
CH3
Ar£- H
CH3
CH3
1) Br2
2) OH -, H2O,¡÷
(CH3CO)2O
NH2
P392
NH
COCH3
CH3
H2PO2
H2O
H2SO4, NaNO2
H2O, 0 ~ 5¡æ
N2+
Br r.t
Br
NH2
CH3
Deamination
（脱氨基作用）
Br
(85%)
The value of diazonium salts in synthesis:
1. Substituents that are otherwise accessible
only with difficulty, such as －F, －I,
－CN, －OH, may be introduced onto
a benzene ring.
2. Compounds that have substitution patterns
not directly available by electrophilic
aromatic substitution can be prepared
NH2
Br
NaNO2, H2SO4 Br
NH2
Br2
H2O
Br
Br
H2O
EtOH
Br
Br
1,3,5-Tribromo2,4,6-Tribromoaniline
Aniline
Benzene(74-77%)
(100%)
17.5.6 Azo coupling (偶氮偶合反应)
Aryl diazonium salts are weak electrophiles,
they react with highly reactive aromatic
compounds, to yield azo compounds
N2+Cl
+
OH
N(CH3)2
pH = ~ 8
CH3COO -Na+
0¡æ
H2O
N N
N(CH3)2
O Alkaline solution
Azo dyes （偶氮染料）
Orange II：
N N
OH
SO3 Na
P393
17. 6 Spectroscopic analysis of amines
IR：
N H:
Ch.P437(四)
Streching
3000-3500 cm-1
vibration Primary amine two peaks
-1
3280
cm
Secondary amines
Tertiary amines
C N:
one peak
No peak
Streching Aliphatic 1020-1220 cm-1
vibration amines
Aromatic
-1
1250-1360
cm
amines
N–H
Stretching
vibration
C–N
Stretching
vibration
Infrared spectrum of isobutylamine
CH3
CH3
CH CH2 N H
H
N-H
伸
缩
苯环
伸缩
C-N
伸
缩
N-甲基苯胺的红外光谱
1H
NMR
N-H
C NR2
H
δ：0. 6 ~ 5 ppm
δ：2.2 ~ 2.8 ppm
Problems to Chapter 17
P402
12.21 (a), (d),(e)
12.22 (a), (c),(f)
12.24 酶斯卡灵，一种
高效的致幻剂。从
仙人掌中得来。
12.27(b), (d),
12.29(b), (c)
12.30 (a)
12.31(b), (c)
12.37
12.39
12.41
12.42
12.48
12.51
12.52
Additional Problems to Chapter 17
1. What are the major products you would
expect
from
Hofmann
elimination
of
the
1following amines? Show the reactions.
(a)N-Methylcyclopentylamine
CH3
(c)
CH3CHCHCH2CH2CH3
NH2
2. Predict the product(s) of the following
reactions.Give the major product.
(CH3)3I
N
H
excess
A? Ag2O, H2O B? heat C?
(3) How would you prepare the following
compounds from toluene? A diaonio
(重氮盐)replacement reaction is needed
in some instances.
(a)
NH2
H3C
(4) Ch.P464
(十六), (十七)
(b)
CH3
CH2NH2
O
(c)
I
C
OCH3