More biologically active amines…
RO
O
H3C
O
CH3
N
C OCH
3
H
N
O
H
CH3
R'O
O
N
N
N
O
NCH3
H3C
C
cocaine
caffeine
O
codeine (R = CH3, R' = H)
morphine (R and R' = H)
heroin (R and R' = COCH3)
CH3
H
N
N
CH3
nicotine
CH3CH2O
C
NCH3
CH3CH2
C
C6H5 NCH3
O
O
mepiridine
(Demerol)
CH3
Methadone
More biologically active amines…
H
H
O
(CH3CH2)2N
C
H
N
CH3
N
N
HO
H
H
N
N
quinine
N
O
H
strychnine
lysergic acid diethylamide (LSD)
H
N
CH2CH2CH3
H
coniin (the poison from
hemlock used to kill Socrates)
O
Basicity of amines

Amines are slightly basic. This because they have a
lone pair of electrons to donate to a proton. This
same feature makes them nucleophiles.
RNH2
+
H OH
Kb =

RNH3
+
OH
[RNH3 ] [OH ]
[RNH2]
Typical amines have Kb values = 10-3 to 10-4
Basicity of amines…

However, instead of measuring an amine’s basicity
using the above equilibrium, chemists usually refer
to the acidity of the conjugate acid of the amine.
The weaker the conjugate acid, the stronger the
base strength of the amine.
RNH3

RNH2
+
H
Ka =
[RNH2] [H ]
[RNH3 ]
Typical amines have Ka values (of their conjugate
acids) of 10-10 to 10-11 (pKa values of 10 to 11.)
pKa values of conjugate acids of
amines
CH3NH2
CH3CH2NH2
10.7
10.8
(CH3)2NH
(CH3CH2)2NH
10.7
10.5
(CH3)3N
(CH3CH2)3N
9.8
11.0
All are about the same value.
The same substituent effects
that stabilize carbocations
that are more highly
substituted by alkyl groups
are offset by diminished
stabilization by solvent due to
crowding.
Some amines that are weaker bases
NH2
N
N
H
aniline
pKa = 4.6
pyridine
5.2
pyrrole
0.4
(conj. acid)



Aniline is a weaker base because the lp of electrons
is delocalized by resonance into the aromatic ring.
Pyridine is weaker because it is an imine (C=N).
Pyrrole is much weaker because the lp of electrons is
delocalized with the other p electrons to make 6 p e-.
Therefore, the lp is unavailable to act as a base.
Substituent Effects on Basicity of Aniline
pKa of
conj. acid:
NH2
NH2
4.6
OCH3
5.3
NH2
NO2
1.0
(much weaker base)
2 explanations of weaker basicity of nitroaniline:
NH2
NO2
NH2
O
N
O
NH2
O
N
O
O
NH2
NH3
N
NO2
O
Resonance stabilizes free base, destabilizes its protonated form (see next slide)
Substituent Effects on Basicity of Anilines
O2N
Energy
NH3
NH3
CH3O
Reaction progress (protonation)
NH3
An amine that is a stronger base


There is one type of amine
that is a stronger base:
NH
H2N
C
NH2
guanidine
pKa = 13.6
(conj. acid)
Guanidine is a strong base because its conjugate
acid is stabilized by resonance:
H2N
NH2
NH2
NH2
NH2
C
C
C
C
NH2
H2N
NH2
H2N
NH2
H2N
NH2
A guanidine group is part of the structure of the amino acid arginine.
Amines are Protonated at Physiological pH


Recall the Henderson-Hasselbach equation:
pH = pKa + log
+
[RNH3 ]
Consider the neurotransmitter dopamine, a typical amine (having a pKa of
its conjugate acid = 10.6) in a living cell (buffered at pH = 7.3):
7.3 = 10.6 + log
[RNH2]
+
;
-3.3 = log
-4
5 x 10
=
[RNH2]
+
[RNH3 ]
[RNH2]
+
[RNH3 ]
[RNH3 ]

[RNH2]
+
;
3
2 x 10
=
[RNH3 ]
[RNH2]
That is, the concentration of the protonated amine is 2000x that of the
neutral amine! Typical amines are >99.9% protonated at physiological pH.