Organic Lecture Series
Amines
Epinephrine (adrenaline)
Chapter 23
1
Organic Lecture Series
Structure & Classification
• Amines are classified as
– 1°, 2°, or , 3° amines: amines in
which 1, 2, or 3 hydrogens of NH3 are
replaced by alkyl or aryl groups
2
o
o
2
Organic Lecture Series
Structure & Classification
• Amines are further divided into aliphatic,
aromatic, and heterocyclic amines:
– aliphatic amine: an amine in which nitrogen
is bonded only to alkyl groups
– aromatic amine: an amine in which nitrogen
is bonded to one or more aryl groups
N- H
CH 2 - N- CH3
:
NH 2
CH 3
:
:
CH 3
Aniline
N-Methylaniline
Benzyldimethylamine
(a 1° aromatic amine) (a 2° aromatic amine) (a 3° aliphatic amine)
3
Organic Lecture Series
Structure & Classification
– heterocyclic amine: an amine in which
nitrogen is one of the atoms of a ring
N
N
H
H
Pyrrolidine Piperid ine
(h eterocyclic alip hatic amines)
N
N
H
Pyrrole
Pyridine
(h eterocyclic aromatic amin es)
4
Organic Lecture Series
Structure & Classification
CH3
H
H
(a)
N
H
(S)-Con iine
N
(b)
N
CH3
COOCH3
(c)
O
N
(S)-N icotine
C6 H5
Cocain e O
Coniine is a poisonous alkaloid found in poison hemlock and the
Yellow Pitcher Plant, and contributes to hemlock's fetid smell. It is
a neurotoxin which disrupts the peripheral nervous system.
Caffeine
5
Organic Lecture Series
Nomenclature
• Aliphatic amines: replace the suffix -e of
the parent alkane by -amine
NH2
H2 N
NH 2
2-Propanamine
(S)-1-Phen ylethanamine
NH2
1,6-Hexanediamine
6
Organic Lecture Series
Nomenclature
• The IUPAC system retains the name
aniline:
NH 2
NH 2
NH 2
NH 2
OCH 3
NO2
CH3
Aniline 4-Nitroaniline 4-Methylaniline 3-Methoxyaniline
(p-Nitroaniline) (p-Toluidine)
(m-Anisidine)
7
Organic Lecture Series
Nomenclature
• Among the various functional groups
discussed in the text, -NH2 is one of the
lowest in order of precedence
H2 N
OH
2-A min oeth anol
OH
NH2
(S )-2-Amin o-3-methyl1-bu tanol
H2 N
COOH
4-A minoben zoic acid
8
Organic Lecture Series
Nomenclature
• Common names for most aliphatic
amines are derived by listing the alkyl
groups bonded to nitrogen in one word
ending with the suffix -amine
H
CH3 NH 2
NH2
N
Et 3 N
Meth ylamine tert -Butylamine D icyclopen tylamine Triethylamin e
9
Organic Lecture Series
Nomenclature
• When four groups are bonded to nitrogen,
the compound is named as a salt of the
corresponding amine
Cl
+
Me4 N Cl
-
-
+
NCH2 ( CH2 ) 1 2 CH3
Tetramethy Tetrad ecylpyrid inium ch loride
ammonium
(Cetylp yridin ium chloride)
chloride
-
Ph CH2 NMe3 OH
Benzyltrimeth ylammoniu m
hydroxid e
10
Organic Lecture Series
Physical Properties
• Amines are polar compounds, and both 1°
and 2° amines form intermolecular
hydrogen bonds
– N-H- - -N hydrogen bonds are weaker than OH- - -O hydrogen bonds because the
difference in electronegativity between N and
H (3.0 - 2.1 =0.9) is less than that between O
and H (3.5 - 2.1 = 1.4)
CH 3 CH 3
MW (g/mol)
bp (°C)
30.1
-88.6
CH 3 NH 2
31.1
-6.3
CH 3 OH
32.0
65.0
11
Organic Lecture Series
Basicity
• All amines are weak bases, and
aqueous solutions of amines are
basic
H
CH3 -N + H-O-H
H
Methylamine
H
+ - O-H
CH3 -N-H
H
Methylammoniu m h yd roxide
12
Organic Lecture Series
Basicity
– it is common to discuss their basicity by
reference to the acid ionization constant of the
conjugate acid:
CH3 NH2 + H3 O+
CH3 NH3 + + H2 O
+
Ka =
[ CH3 NH2 ] [H3 O ]
+
[CH3 NH3 ]
= 2.29 x 10-1 1
pK a = 10.64
13
Organic Lecture Series
Basicity
– using values of pKa, comparisons of the
acidities of amine conjugate acids with
other acids can be made:
+
-
CH3 NH3 + CH3 COO
pK a 10.64
(w eak er
acid )
pK eq = -5.88
Ke q = 7.6 x 105
:
CH3 NH2 + CH3 COOH
pK a 4.76
(s tronger
acid)
R—NH2 + H+
RNH3+
conjugate acid
14
Organic Lecture Series
Basicity-Aliphatic Amines
Amine
pKa
NH 3
9.26
4.74
10.64
10.81
10.66
3.36
3.19
3.34
(CH3 ) 2 NH
10.73
(CH3 CH2 ) 2 NH 10.98
3.27
3.02
9.81
10.75
4.19
3.25
CH3 NH2
CH3 CH2 NH2
C6 H1 1 NH 2
(CH3 ) 3 N
(CH3 CH2 ) 3 N
:
Ammonia
Primary Amines
methylamine
ethylamine
cyclohexylamine
Secondary A mines
dimethylamine
diethylamine
Tertiary Amines
trimethylamine
triethylamine
pKb
Structure
R—NH2 + H+
RNH3+
conjugate acid
Basicity-Aromatic Amines
Amine
Structure
15
Organic Lecture Series
pK a of Conju gate A cid
Aromatic A min es
An iline
4-Methylanilin e
NH2
NH2
CH3
4-Ch loroaniline
Cl
4-N itroanilin e
O2 N
4.63
NH2
NH2
5.08
4.15
1.0
Heterocyclic Aromatic A min es
Pyrid ine
N
5.25
N
Imidazole
Note the effect of
Ar-X on the
acidity:
The stronger the
e- withdrawing
effect, the weaker
the base &
stronger the conj
acid.
6.95
N
H
16
Organic Lecture Series
Basicity-Aromatic Amines
– aromatic amines are considerably weaker
bases than aliphatic amines
+
NH2 + H2 O
-
pK a = 10.66
NH3 OH
Cyclohexylammonium
hydroxid e
Cycloh exylamine
+
NH2 + H2 O
-
NH3 OH
pK a = 4.63
A niliniu m h yd roxide
A niline
17
Basicity-Aromatic Amines
Organic Lecture Series
• Aromatic amines are weaker bases than
aliphatic amines because of two factors
– resonance stabilization of the free base, which is
lost on protonation
H
N H
H .
H+ H
N
.
H .
H
H + H
N
un hybridized 2p orb ital of N
H
..
.
.
H + H
N
.
N
H
H
H
nitrogen is sp 2 h yb rid ized
18
Organic Lecture Series
Basicity-Aromatic Amines
– the greater electron-withdrawing inductive
effect of the sp2-hybridized carbon of an
aromatic amine compared with the sp3hybridized carbon of an aliphatic amine also
decreases basicity
• Electron-releasing, such as alkyl groups,
increase the basicity of aromatic amines
• Electron-withdrawing groups, such as
halogens, the nitro group, and a carbonyl
group decrease the basicity of aromatic
amines by a combination of resonance
and inductive effects
19
Organic Lecture Series
Basicity-Aromatic Amines
4-nitroaniline is a weaker base than 3-nitroaniline
O2 N
NH2
O2 N
NH2
4-N itroaniline
pK a 1.0
3-N itroanilin e
pK a 2.47
de localiz ation of th e n itrog en
lon e p air on to th e oxyg en atom s
of th e n itro grou p
-
O
+N
-
O
NH2
O
+N
-O
NH2 +
20
Organic Lecture Series
Basicity-Aromatic Amines
• Heterocyclic aromatic amines are weaker
bases than heterocyclic aliphatic amines
N
N
H
Piperidine
p Ka 10.75
N
Pyridin e
pK a 5.25
N
H
Imid azole
pK a 6.95
21
Basicity-Aromatic Amines
Organic Lecture Series
– in pyridine, the unshared pair of electrons on
N is not part of the aromatic sextet
.
H
.
H
H
.
.
H
.
.
N
H
:
an sp 2 h yb rid orbital; th e electron
p air in this orbital is n ot a
p art of the aromatic s extet
nitrogen is sp 2 h yb rid ized
– pyridine is a weaker base than heterocyclic
aliphatic amines because the free electron
pair on N lies in an sp2 hybrid orbital (33% s
character) and is held more tightly to the
nucleus than the free electron pair on N in an
sp3 hybrid orbital (25% s character)
22
Organic Lecture Series
Reaction with Acids
• All amines, whether soluble or insoluble in
water, react quantitatively with strong
acids to form water-soluble salts
OH
HO
OH
NH2
+ HCl
HO
(R)-N orepinep hrine
(on ly s ligh tly s olu ble in w ater)
H2 O
+
-
NH3 Cl
HO
HO
(R)-N orepinep hrine h yd roch loride
(a w ater-s olu ble salt)
23
Preparation
Organic Lecture Series
• A summary of synthetic methods:
– nucleophilic ring opening of epoxides by
ammonia and amines (11.9B)
– addition of nitrogen nucleophiles to aldehydes
and ketones to form imines (Section 16.8)
– reduction of imines to amines (16.8A)
– reduction of amides by LiAlH4 (18.10B)
– reduction of nitriles to a 1° amine (18.10C)
– nitration of arenes followed by reduction of the
NO2 group to 1° amines (22.1B)
24
Organic Lecture Series
Preparation
• Alkylation of ammonia and amines by SN2
CH3 Br + N H3
SN 2
CH3 NH 3 + Br Methylammonium
bromide
– unfortunately, such alkylations give mixtures
of products through a series of proton transfer
and nucleophilic substitution reactions
CH3 Br + NH3
-
+
CH3 NH3 + Br + (CH3 ) 2 NH2 Br
-
+
+
+ (CH3 ) 3 NH Br + (CH3 ) 4 N Br
These arise from N-polyalkylation
-
25
Organic Lecture Series
Preparation via Azides
• Alkylation of azide ion, N3N
N: -
Azide ion
(a good nucleophile)
+
Ph CH2 Cl
Benzyl ch loride
K N3
-
RN 3
R
N
+
N
:
+
N
:
-:
:
-
:
N3
N: -
An alkyl azide
1 . LiAlH4
Ph CH2 N3
2 . H2 O
Ben zyl azid e
Ph CH2 NH2
Benzylamin e
26
Organic Lecture Series
Preparation via Azides
– alkylation of azide ion
ArCO3 H
Cyclohexen e
+
1 . K N3 -
O
2 . H2 O
1,2-Epoxycyclohexane
(chiral)
OH
N3
trans-2-Azid ocyclohexan ol
(racemic)
1 . LiAlH4
2 . H2 O
OH
NH2
t rans-2-Aminocyclohexan ol
(racemic)
27
Organic Lecture Series
Reaction with HNO2
• Nitrous acid, a weak acid, is most
commonly prepared by treating NaNO2
with aqueous H2SO4 or HCl
HNO2 + H2 O
H3 O+ + NO2 -
pK a = 3.37
• In its reactions with amines, nitrous acid
– participates in proton-transfer reactions
– is a source of the nitrosyl cation, NO+, a weak
electrophile
28
Organic Lecture Series
Reaction with HNO2
• NO+ is formed in the following way:
H O
N O + H+
(1)
+
H O N O
(2)
H
H O +
H
+
N O
+
N O
The nitrosyl cation
– Focus upon reactions of HNO2 with 1°
aliphatic and aromatic amines
29
Organic Lecture Series
RNH2 with HNO2
• 1° aliphatic amines give a mixture of
unrearranged and rearranged substitution
and elimination products, all of which are
produced by way of a diazonium ion and
its loss of N2 to give a carbocation.
• Diazonium ion: an RN2+ or ArN2+ ion
30
Organic Lecture Series
1° RNH2 with HNO2
• Formation of a diazonium ion
Step 1: reaction of a 1° amine with the nitrosyl cation
R-N-N=O :
An N-nitrosamine
: :
:
:
:
:
:
:
keto-enol
tautomerism
H
+
R-NH2 + : N O :
A 1° aliphatic
amine
:
R-N=N-O-H
A diazotic acid
Step 2: protonation followed by loss of water
+
: :
:
:
R-N=N-O-H
H
••
R-N
A diazotic acid
••
N
R
A diazoniu m ion
+
N
•
+
N
•
•
+
N
-H2 O
•
•
R
H
+
O-H
••
N
A carbocation
31
NOT responsible for mechanism
Organic Lecture Series
1° RNH2 with HNO2
• Aliphatic diazonium ions are unstable and lose
N2 to give a carbocation which may
1. lose a proton to give an alkene
2. react with a nucleophile to give a substitution product
3. rearrange and then react by 1 and/or 2
Cl
(5.2%)
OH
NH 2
NaNO2 , H Cl
o
0-5 C
OH
+
(25%)
(13.2%)
NOT useful for org synthesis (25.9%)
+
(10.6%)
32
Organic Lecture Series
1° ArNH2 with HNO2
• The -N2+ group of an arenediazonium salt
can be replaced in a regioselective
manner by these groups
H2 O
HBF4
Ar-NH2
HNO2
0-5°C
Know these
Ar-N2
+ (-N )
2
Ar-OH
Sch ieman n
reaction
Ar-F
HCl, CuCl
Ar-Cl
HBr, CuBr
Ar-Br
San dmeyer
reaction
KCN, CuCN Ar-CN
KI
Ar-I
H3 PO2
Ar-H
33
Organic Lecture Series
Local Anesthetics
34
Organic
Lecture Series
Medicinal
Chemistry
Cocaine
Topical anesthetic (local)
CNS stimulant
35
Organic
Lecture Series
Medicinal
Chemistry
2
3
3
2
3
2
Alkanolamines
(Ethanolamines)
Procaine
36
Organic
Lecture Series
Medicinal
Chemistry
Synthesis of Procaine
37
Organic
Lecture Series
Medicinal
Chemistry
Synthesis of Procaine
O
+
CH2CH3
HN
CH2CH3
38
Organic
Lecture Series
Medicinal
Chemistry
Synthesis of Procaine
2
2
H 2 Ni
2
2
Procaine
(novocaine)
39
Organic
Lecture Series
Medicinal
Chemistry
40