Amines & Nitriles
By junru wang
Chapter O Amines and Nitriles
¾－C,H,O
－C=O，－CHO，－COOH －
CO-Y
¾－N,－P,－S
¾－Organic compounds
‰蛋白质，多肽
‰氮杂环（生物碱，核酸等）
‰酰胺
‰硝基化合物
‰胺
‰腈
‰重氮化合物
‰偶氮化合物
of nitrogen N
Biological Activity
™Neurotransmitters: dopamine
™Bioregulators: epinephrine肾上腺
素
™Vitamins: niacin(烟酸), B6
™Alkaloids: nicotine, morphine,
cocaine
™Amino acids
O0 Introduction
Alkaloids
™Physiologically active
nitrogen-containing
compounds
™Obtained from plants
™Used as anesthetics,
antidepressants, and
stimulants
™Many are addictive
Morphine: The sure cure for teething babies
抚慰的糖浆
Summary of Amines.
many physiologically active compounds
are amines.
HO
F3C
NH2
O
CH CH2 NH CH3
N
H
Fluoxetine
(Prozac)
a selective serotonin
re-uptake inhibitor
serotonin
Natural
neurotransmitter
血清素
神经递质, 神经传递素
Some Examples:
H
N
H
Amphetamine
(安非他明)
a 1° amine
used as a central nervous system
stimulant in the treatment of certain
conditions, such as narcolepsy and
depression.
Some Examples:
N
H
coniine 毒芹碱
a 2° amine
Poison-Hemlock
(芹叶钩吻)Conium maculatum L.
Some Examples:
CH3
N
Cocaine
a 3° amine
CO2CH3
O
O
Ph
Some Examples:
O
CH3
N
CH3
O
CH3
CH3
acetyl choline(胆碱)
a quaternary amine
salt
classed in the vitamin B complex
and a constituent of many other
biologically important molecules,
such as acetylcholine and lecithin.
O0 Introduction
™Organic derivatives of ammonia
™Many are biologically active.
Amines can be considered
derivatives of ammonia.
amine
derivatives
R
H
H
N
H
ammonia
R
R
H
N
H
1º
R
R
N
R
H
2º
R
R
N
R
3º
R
R
R
N
R
R
quaternary
salt
Classify:
CH3
N
CH3
N
H
CH3
CH3
C NH2
CH3
_
Br
+
CH3CH2 N CH2CH3
CH3
Common Names
Name the alkyl or aryl groups
bonded to nitrogen, then add
suffix -amine.
(CH3CH2)2NCH3
diethylmethylamine
NH
Diphenylamine
NHCH3
cyclopentylmethylamine
Amine as Substituent
™On a molecule with a higher
priority functional group the amine
is named as a substituent.
NH2CH2CH2CH2COOH
γ-aminobutyric acid or
4-aminobutanoic acid
OH
NHCH3
2-methylaminophenol
IUPAC Names
™Name is based on longest carbon chain.
™-e of alkane is replaced with -amine.
™Substituents on nitrogen have N- prefix.
Br
NH2CH2CH2CHCH2CH3
3-bromo-1-pentanamine
N(CH3)2
CH3CH2CHCH2CH2CH3
N,N-dimethyl-3-hexanamine
Aromatic Amines
Amino group is bonded to a
benzene ring. Parent compound is
called aniline.
NH 2
N
CH3
aniline
NH2
CH3
N,N-dimethylaniline
H3C
4-methylaniline
or p-toluidine
Heterocyclic Amines
The nitrogen is assigned the
number 1.
H
N
aziridine
N
N
H
H
Pyrrole
Pyrrolidine
N
N
CH3
Pyridine
2-methylpyridine
NH 2
trans-2-aminocyclohexanol
OH
反式－2－氨基－环己醇
NH 2
(CH 3)2NCH 2CH 2CHO
CH 3CH 2CHCOOH
2-aminobutanoic acid
3-dimethylaminopropanal
3－二甲氨基己醛
CH 3
2－氨基丁酸
NH 2
O 2N
NH 2
p-nitroaniline
or p-methylaniline
(4-nitrobenzenamine)
(4-methylbenzenamine) 3，5－二溴－对N,N-二甲氨基苯胺
Br
N(CH 3)2
3,5-dibromo-N,N-dimethylaniline
(N.N-dimethyl-3,5-dibromobenzenamine)
Br
01 PREPARATION OF AMINES
™Reduction
™Substitution with NH3
™Alkylation of alkylamines
™Rearrangements
™arylamines
Nitrile Reduction (1°)
™Nitrile, -C≡N, is a good SN2
nucleophile.
™Reduction with H2 or LiAlH4 adds CH2NH2.
Br
CN
NaCN
1) LiAlH4
2) H2O
CH2NH2
Examples
N OH
O
CH3CH2CH2
NH2 OH
C CH3
+
H
CH3CH2CH2
C CH3
NH2
H2
Ni
CH3CH2CH2
CH CH3
primary amine
O
CH3
C
CH3
CH3NH2
H+
NCH3
CH3
H3C
O
C H
HN(CH3)2
+
H
C
CH3
NHCH3
1) LiAlH4
2) H2O
CH3
H3C
Na(CH3COO)3BH
CH3COOH
CH3
secondary amine
CH3
N+
C H
CH
N
CH3
C H
H
tertiary amine
Examples
O
CH3
O
C Cl
NH3
C NH2
2) H2O
CH3 CH2 NH2
primary amine
O
O
C Cl
CH3
1) LiAlH4
HN(CH3)2
C N(CH ) 1) LiAlH
4
3 2
2) H2O
CH2
N(CH3)2
tertiary amine
Preparation via Azides
™Primary alkyl halides and some
secondary alkyl halides can undergo SN2
nucleophilic substitution with an azide
ion (N3-) to give an alkyl azide (Topic L6).
™The azide can then be reduced with
LiAlH4 to give a primary amine
Preparation via Azides
™Alkylation of azide ion
RN 3
Benzyl chloride
N
N:
-
An alkyl azide
+
CH2 Cl
R
+
N
:
:
:
-:
:
+
N3
N N N:
Azide ion
(a good nucleophile)
-
-
K N3
(phase-transfer
catalyst)
CH2 N3
Benzyl azide
1 . LiA lH4
2 . H2 O
CH 2 NH 2
Benzylamine
Azide Reduction (1°)
™Azide ion, N3-, is a good nucleophile.
™React azide with unhindered 1° or
2° halide or tosylate (SN2).
™Alkyl azides are explosive! Do not
isolate.
Br
N3
NaN3
1) LiAlH4
2) H2O
NH2
Preparation via Azides
‰alkylation of azide ion
ArCO3 H
Cyclohexene
+
1 . K N3
O
2 . H2 O
1,2-Epoxycyclohexane
OH
N3
-
1 . LiAlH4
2 . H2 O
trans-2-Azidocyclohexanol
OH
NH2
trans-2-Aminocyclohexanol
Substitution with NH3
™Alkylation of ammonia and amines by
SN2
SN 2
N
H
+
CH3 Br
3
CH3 NH 3 + Br Methylammonium
bromide
CH3 Br + NH3
-
+
CH3 NH3 + Br + (CH3 ) 2 NH2 Br
-
+
+
+ (CH3 ) 3 NH Br + (CH3 ) 4 N Br
™unfortunately, such alkylations give
mixtures of products through a series
of proton transfer and nucleophilic
substitution reactions
-
Direct Alkylation (1°)
™Use a large excess (10:1) of
ammonia with a primary alkyl
halide or tosylate.
™Reaction mechanism is SN2.
CH3CH2CH2
Br
NH3
CH3CH2CH2
NH2 + NH4Br
Gabriel Synthesis (1°)
™Use the phthalimide anion as a
form of ammonia that can only
alkylate once.
™React the anion with a good SN2
substrate, then heat with
hydrazine.
O
_
N
O
O
O
R X
N R
O
NH
H2N NH2
heat
NH
O
+ R NH2
Gabriel synthesis of amines
Substitution with NH3
the Hofmann rearrangements.
the Curtius rearrangements
Hofmann Rearrangement of
Amides (1°)
In the presence of a strong base,
primary amides react with
chlorine or bromine to form
amines with one less C.
O
C NH2
_
Br2, OH
H2O
NH2
Synthesis of Arylamines
Nitro groups can be added directly by
electrophilic substitution and then reduced to
the amine
Reduction of Nitro
Compounds (1°)
™-NO2 is reduced to -NH2 by catalytic
hydrogenation, or active metal with acid.
™Commonly used to synthesize anilines.
CH3
Zn, HCl
CH3
NO2
CH3CH2OH
NH2
O2 PROPERTIES OF AMINES
™Structure
™Pyramidal inversion
™Basicity
™Physical properties
R N H
H
sp3
反应性：N:
碱性
亲核试剂
Structure of Amines
Nitrogen is sp3 hybridized with a
lone pair of electrons in an sp3
orbital.
:
:
能垒～6KCaL/mol
N
H3 C
H
CH2 CH3
H
(R)-Ethylmethylamine
:
sp 3 hybrid
CH 3
CH 3 CH 2
(S)-Ethylmethylamine
CH3
N
N
H
C H 2C H 3
unhybridized
2p orbital
Planar transition
state
:
CH3
N
CH3
Pyramidal inversion
(S)-Ethylm ethylam ine
N
sp 3 hybrid
:
H
C H 2C H 3
H
C H 2C H 3
(R )-Ethylm ethylam ine
Chiral Amines
™Amines with chiral carbon: 2-butanamine.
™Quaternary ammonium salts with four different
groups bonded to nitrogen.
™Amines in which the nitrogen is restricted in
rotation so it cannot interconvert.
Chiral Amines
=>
Amines in which the nitrogen is restricted in
rotation so it cannot interconvert
H3 C Ph
Cl
N
R enantiomer
-
Cl
-
Ph CH3
N
S enantiomer
芳香胺
NH2
Aniline
H N
H
H3 C
NH2
4-Methylaniline
(p-Toluidine)
H
+N
H
between sp2 and sp3
Resonance Effects
Any delocalization of the electron
pair weakens the base.
Hybridization Effects
Electrons are held more tightly in
orbitals with more s character, so
those compounds are weaker bases.
A 脂肪胺的碱性强弱
Inductive effect（诱导效应）:
Due to the alkyl group (e-donating group)
3o > 2o > 1o > NH3 BUT
Ease of solvation of protonated amine
（溶剂化效应）:
Due to the formation of H-bond between N-H
and H2O
NH3 > 1o > 2o > 3o
Overall effect:
2o ≥ 1o > 3o >NH3
A 脂肪胺的碱性强弱
气相下： R3N>R2NH>RNH2>NH3
水溶液： R2NH>RNH2>R3N>NH3
(CH3)2NH (CH3)3N
CH3NH2
3.36
3.23
4.26
pKb
C2H5NH2
pKb
3.33
(C2H5)2NH
(C2H5)3N
3.07
3.42
季胺碱的碱性最强： R4N+OH-
溶剂化作用
OH2
H
+
H
N
R
H
R
OH2 >
OH2
H
OH2
H
> R
OH2
R
+
N
R
R
+
N
H
OH2
芳香胺的碱性
B
.
H
H
NH3 >
H
.
.
.
unhybridized
2p orbital of N
H
.
..
.
N
H
NH2 > (
H
H
nitrogen is
sp2 hybridized
) NH > (
2
)3 N
芳香胺的碱性
B
O2 N
N H2
3-Nitroaniline
pKb 11.53
O2 N
N H2
4-Nitroaniline
pKb 13.0
:
:
-
:O
:O :
:
+N
+N
-
:O:
:
:
-
: O:
N H2
N H2
+
Basicity-Aliphatic Amines
™Aliphatic Amines
Amine
Ammonia
Primary Amines
methylamine
ethylamine
cyclohexylamine
Secondary Amines
dimethylamine
diethylamine
Tertiary Amines
trimethylamine
triethylamine
pKb
Structure
pKa
N H3
9.26
4.74
10.64
10.81
10.66
3.36
3.19
3.34
( CH3 ) 2 N H
10.73
( CH3 CH2 ) 2 NH 10.98
3.27
3.02
9.81
10.75
4.19
3.25
CH3 N H2
CH3 CH2 NH 2
C6 H1 1 NH 2
( CH3 ) 3 N
( CH3 CH2 ) 3 N
Basicity-Aromatic Amines
™Aromatic amines
Amine
Structure
aniline
N H2
4-methylaniline
CH 3
4-chloroaniline
Cl
4-nitroaniline
O2 N
N H2
N H2
N H2
pKa
pKb
4.63
9.37
5.08
8.92
4.15
9.85
1.0
13.0
Predict which of the following amines is the more basic.
NH2
(a)
CH2 NH2
or
NH2
NH2
(b)
or
H3 C
O2 N
CH3
O
(c)
(d) H2 NCNH2
or
N
NH
or H2 NCNH2
N
H
(e)
NH or
NH
(f) ( CH3 CH2 CH2 ) 3 N or
N(CH3 ) 2
Amine Salts
™Ionic solids with high melting points
™Soluble in water
™No fishy odor
Solubility and Odor
™Small amines (<6 C) soluble in water.
™All amines accept hydrogen bonds from
water and alcohol.
™Branching increases solubility.
™Most amines smell like rotting fish.
NH2CH2CH2CH2CH2CH2NH2
1,5-pentanediamine or cadaverine
Boiling Points
™N-H less polar than O-H.
™Weaker hydrogen bonding.
™Tertiary amines cannot hydrogen bond.
1-Propylamine, 1-propanol, acetic acid and
butane have about the same molar masses.
Which would you expect to have the (a)
highest boiling point, (b) lowest boiling point,
(c) least solubility in water, and (d) least
chemical reactivity?
NH2
1-propylamine
OH
1-propanol
O
OH
acetic acid
butane
(a) highest boiling point?
NH2
48 °C
1-propylamine
97 °C
OH
1-propanol
O
OH
acetic acid
118 °C
-0.5 °C
butane
(b) lowest boiling point?
NH2
48 °C
1-propylamine
97 °C
1-propanol
O
OH
118 °C
-0.5 °C
butane
acetic acid
OH
O3 REACTIONS OF AMINES
™作为亲核试剂
‰烷基化Alkylation
‰酰基化Acylation
‰磺酰化Sulfonation
™与亚硝酸的作用
™Diazonium salts
™Hofmann消除
1. Alkylation
Alkylation of Amines
™Amines react with 1° alkyl halides
via the SN2 mechanism.
™Mixtures of the mono-, di-, and trialkylated products are obtained.
Useful Alkylations
™Exhaustive alkylation to form
the tetraalkylammonium salt.
NH2
CH3CH2CHCH2CH2CH3
3 CH3I
NaHCO3
_
+
N(CH3)3 I
CH3CH2CHCH2CH2CH3
• Reaction with large excess of NH3 to
form the primary amine.
CH3CH2CH2Br
NH3 (xs)
CH3CH2CH2NH2
+
NH4Br
Alkylation
RNH2 + RX
R2NH
R2NH + RX
R3N
+
R4N X -
R3N + RX
NH2
NRH
+ RX
Such method will give mixture of products.混合物
(CH3)3N
CH3I
(CH3)4 NI
季铵盐
AgOH
(CH3)4+NOH
季胺碱
AgI
Alkylation
NH3 CH3I
NH2
CH3+NH3I-
CH3I
OH-
(CH3)2+NH2I-
(CH3)3+NHI- (CH3)4+NI-
NHCH3
I
H2O
2、Acylation of Amines
（与酰氯或酸酐反生氨解反应）
O
RNH2 +
RNH2 +
RNH2 +
RNH2 +
R'
R'
R'
R'
C
O
OR"
C
O
Cl
C
O
OH
C
O
R'
R'
R'
20胺也可反应
但30胺不发应
R"
R
C
O
N H
C
O
N H
R
R
C
O
C
O
R'
N H
O
R
C
N H
2. Acylation of Amines
by Acid Chlorides
™Amine attacks C=O, chloride ion
leaves.
™Product is amide, neutral, not basic.
™Useful for decreasing activity of
aniline toward electrophilic aromatic
substitution.
O
O
NH2
CH3
C Cl
N
to remove HCl
N C
H
CH3
2、酰基化反应
O
O
RNH2 +
C
Cl
O
O
NH2 +
C
C
Cl
C
H
N R
H
N
3. Sulfonation
3、 Sulfonation
磺酰基化反应（Hinsberg反应）
O
O
S OH
S Cl
C OH
C Cl
O
O
O
O
苯磺酸
SO2Cl
苯磺酰氯
苯甲酸
苯甲酰氯
NaOH
RNH2
SO2NHR
R2NH
SO2NR2 NaOH X
R3N
X
SO2-NRNa+
1，2，3 级胺的分离与鉴别
™
鉴别
10
20
30
苯磺酰氯
NaOH
™
溶于反应液中
10胺
有沉淀生成 20胺
溶液分层
30胺
分离10，20，30胺
1.
2.
3.
4.
与苯磺酰氯在碱性溶液中
蒸馏，叔胺先出来
过滤反应液，将固体水解的仲胺
滤液酸化后酸解的伯胺
4、与亚硝酸的作用
ROH + N2 + H2O
RNH2 + HNO2
NH2
+
N
NaNO2 / HCl
N
o
<5 C
(1)脂肪族胺
RNH2
R+
RN2+
复杂混合物
N2定量放出，R+重排，产物为混合物
HONO
R2NH
R2N
N
O
H+
R2NH HONO
N－亚硝基胺（黄色油状物，不溶于水）
R3N
R3N
不稳定的亚硝酸盐
类盐，R3N.HNO2，室温分解
（2）芳香胺
NH2
0~5 ℃
Ph2NH
HONO
+
N2X- NaX
Ph2N NO
CH3
H2O
CH3
CH3
N
N
CH3
H2O
N NO
NHCH3
2H2O
NO
（棕色油状）
重氮盐
N-亚硝基－N-甲基苯胺
(黄色固体）
强烈致癌
H2O
CH3
对亚硝基－N,N-二甲基苯胺
（绿色叶片状）
（3）重氮盐的反应
A 取代
H2 O
Ar-OH
HBF4
Ar-F Schiemann
reaction
Ar-Cl
Sandmeye
Ar-Br reaction
HCl, CuCl
Ar-N2
+
(-N2 )
HBr, CuBr
KCN, CuCN
KI
H3 PO2
Ar-CN
Ar-I
Ar-H
B 重氮偶联反应
在弱碱、弱酸或中性环境中可与酚芳胺生成偶氮化合物
N2Cl +
N2Cl +
OH
N(CH3)2
0 oc
NaOH
NaOAc
c
0o
N N
N N
OH
N(CH3)2
5 Elimination
5、Hofmann彻底甲基化与Hofmann消除
3CH3I
RCH 2CH 2NH 2
AgOH
RCH 2CH 2+N(CH 3)3I-
RCH 2CH 2+N(CH 3)3OH -
RCH
eg
AgOH
2CH 3I
N
H
+
N
CH3
CH 2 N(CH 3)3 H 2O
I
CH3
+
H2O
OH
N
N
CH3
CH3
CH3
CH3
E2 Mechanism
6. Electrophilic Substitution
of Aniline
™-NH2 is strong activator, o-,p-
directing.
™May trisubstitute with excess
reagent.
™H+ changes -NH2 to -NH3+, a metadirecting deactivator.
™Attempt to nitrate aniline may
explode.
6. Electronoic aromatic sunstitution
NH2
NH2
Br
Br
3Br2
3HBr
Br (白）
（1）卤代反应
NHAc
NHAc
NH2
H+ or OH-
Br2
Ac2O
NH2
无H3HOAc
NH3
Br
Br
H+
+
NH2
NH3
Br
Br
(2)硝化反应
NHAc
NH2
NHAc
HNO3
HOAc
Ac2o
HNO3
Ac2O
H2SO4
NH2
NH3HSO4
NO2 (主）
NO2
NHAc
NO2
NH2
（主）
NH2
NH3HSO4
HNO3
NO2
NaOH
NO2
NO2
(3)磺化反应
NH2
NH3HSO4
NHSO3H
NH2
NH3
SO3H
SO3
180 oc
H2SO4
H2O
Electronoic aromatic sunstitution
Electrophilic Substitution
of Pyridine
™Strongly deactivated by
electronegative N.
™Substitutes in the 3-position.
™Electrons on N react with
electrophile.
N
fuming H 2 SO 4
o
HgSO 4 , 230 C
SO 3 H
N
Nucleophilic Substitution
of Pyridine
™Deactivated toward electrophilic
attack.
™Activated toward nucleophilic attack.
™Nucleophile will replace a good
leaving group in the 2- or 4-position.
_
_
OCH3
N
Cl
+
N
OCH3
Cl
合成应用举例
HO
CH3
COOH
CH3
CH3
Br
Br
Cl
H2N
COOH
CH3
CH3
COOH
(1)
(2)
COOH
(3)
N O2
N O2
COOH
(4)
N H2
OH
CH3
CH3
CH3
1.
Ac2O
Br2
2. OH- ,H2O
Br
NHAc
NH2
NH2
65%
CH3
CH3
H2SO4,NaNO2
H3PO2
H2O, 0~5 oc
Br
N2+
H2O, 25
N2
c
o
Br
85%
Synthesize
Synthesize m-Bromochlorobenzene
m-Bromochlorobenzene
NO2
HNO3
H2SO4
nitration
NO2
Cl2
FeCl3
chlorination
NH2
+
1. Fe, H3O
2. NaOH
Cl reduction
N N
HNO2
H2SO4
Cl
diazotization
Br
HBr
CuBr
Cl Sandmeyer
reaction
Cl
Synthesize
Synthesize p-Aminobenzoic
p-Aminobenzoic Acid
Acid (PABA)
(PABA)
CH3
CH3
+
CH3Cl
AlCl3
HNO3
H2SO4
1. Fe, H3O
2. NaOH
alkylation
nitration
reduction
CH3
NO2
COOH
KMnO4
H2O
PABA
oxidation
NH2
NH2