Measures of Basicity
Amines
Chemical / Biological / Neurological
Activity
• The basicity of amines may be measured by:
•
1) Kb
•
2) pKb
•
3) Ka of conjugate acid
•
4) pKa of conjugate acid
Basicity Constant (Kb) and pKb
• Kb is the equilibrium constant for the
reaction:
R3N •• + H
••
Kb =
and pKb =
Ka and pKa of Conjugate Acid
•
Ka is the equilibrium constant for the
dissociation of the conjugate acid of the amine:
+
R3N
R3N •• + H+
H
Ka =
and pKa =
[R3N][H +]
[R3NH+]
- log Ka
Relationships between acidity and basicity
constants
Ka K b =
10 -14
pKa + pK
pKb = 14
+
R3N
••
OH
H +
– ••
•• OH
••
[R3NH+][HO –]
[R3N]
- log Kb
A natural base from Erythroxylon spp.
• It is very valuable. The leaves are chewed by
indigenous tribes in the Andes to boost their energy.
• It has been used as a psycho-therapeutic, an
opthalmic anesthetic and was purportedly used in a
popular beverage that is at the heart of a $20 billion
corporation.
• However, both its base and conjugate acid are
currently controlled substances under U.S. Federal
Regulations: Title 21 secs. 329.1 & 1308.12 (1987).
• Can you name the beverage and the base?
CO2CH3
O2 C
Merck Index, #2450, 11th ed.: Caution: May be habit
forming….
Conjugate Acid of Cocaine
(Physical Properties)
(Physical Properties)
CH3 ..
N
The compound: cocaine, it is an organic base:
“Regular” Cocaine
Acid -Base Chemistry
The beverage reportedly produced using the
extract of leaves of Erythroxylon coca:
• m.p. 98 oC
• b.p. (very volatile
> 90 oC)
Solubility:
• Water: 1.67 x 10 -3
CH3 + H Cl
N
CO2CH3
O2 C
g/mL
"Crack" Cocaine
• CHCl3: 1.43 g/mL
• Ether: 0.29 g/mL
What structural feature makes
cocaine a base? What simple
compound can you relate it to?
• m.p. >195 oC
Cocaine Hydrochloride
Solubility:
•
Water: 2.5 g/mL
•
CHCl 3: 0.08 g/mL
•
Ether: insoluble
What accounts for the differences
in solubilities of the base and
conjugate acid?
Basicity of Amines in Aqueous Solution
Acid -Base Reactions
CH3 ..
N
Acid Base Reactions
•Amine
CH3
N
CO2CH3
+
O2 C
+
H
Cl
H Cl
-
CO2CH3
O2 C
Cocaine Hydrochloride
CH3
+
N
H Cl
CH3 ..
N
-
CO2CH3
+
O2 C
OH -
CO2CH3
O2 C
Conj. Acid
+
•NH3
NH4
•CH3CH2NH2
CH3CH2NH3+
pKa
9.3
10.8
"Crack" Cocaine
CH3CH2NH3+ is a weaker acid than NH 4+;
therefore, CH 3CH2NH2 is a stronger base
than NH3.
Basicity of Amines in Aqueous Solution
Effect of Structure on Basicity
•1. Alkylamines are slightly stronger bases than
ammonia.
•2. Alkylamines differ very little in basicity.
•Amine
Conj. Acid
9.3
•1. Alkylamines are slightly stronger bases than
ammonia.
CH3CH2NH3+
10.8
•2. Alkylamines differ very little in basicity.
(CH3CH2)2NH2+
11.1
•3. Arylamines are much weaker bases than
ammonia.
•NH3
NH4
•CH3CH2NH2
•(CH3CH2)2NH
•(CH3CH2)3N
pKa
Effect of Structure on Basicity
+
(CH3CH2)3
NH+
10.8
Notice that the difference separating a primary,
secondary, and tertiary amine is only 0.3 pK units.
Basicity of Amines in Aqueous Solution
•Amine
Conj. Acid
pKa
•NH3
NH4+
9.3
•CH3CH2NH2
CH3CH2NH3+
10.8
•(CH3CH2)2NH
(CH3CH2)2NH2+
11.1
•(CH3CH2)3N
(CH3CH2)3NH+
10.8
•C6H5NH2
C6H5NH3+
4.6
Decreased basicity of arylamines
••
••
NH2 + H
+
NH3 +
OH
••
– ••
•• OH
••
• Aniline (reactant) is
stabilized by
conjugation of
nitrogen lone pair
with ring π system.
• This stabilization is
lost on protonation.
Decreased basicity of arylamines
•Increasing delocalization makes diphenylamine a
weaker base than aniline, and triphenylamine a
weaker base than diphenylamine.
Kb
C6H5NH2
(C6H5)2NH
(C6H5)3N
3.8 x 10 -10
6 x 10 -14
~10-19
Basicity of Arylamines
Effect of Substituents on Basicity of Arylamines
•1. Alkyl groups on the ring increase basicity, but
only slightly (less than 1 pK unit).
•2. Electron withdrawing groups, especially ortho
and/or para to amine group, decrease basicity
and can have a large effect.
X
NH2
•X
•H
•CH3
•CF3
•O2N
NH3+
X
pKb
9.4
8.7
11.5
13.0
pKa
4.6
5.3
2.5
1.0
••
N
is more basic than
– ••
•• O ••
••
O ••
+
N
•O•
–• •• •
••
NH2
+
N
•O •
– • •• •
•Lone pair on amine nitrogen is conjugated with
p-nitro group—more delocalized than in aniline
itself. Delocalization lost on protonation.
Heterocyclic Amines
Effect is Cumulative
•Aniline is 3800 times more basic than
p-nitroaniline.
•Aniline is ~1,000,000,000 times more
basic than 2,4-dinitroaniline.
p-Nitroaniline
N
••
H
piperidine
Kb = 1.6 x 10 -3
pyridine
Kb = 1.4 x 10 -9
(an alkylamine)
alkylamine)
(resembles an
arylamine in
basicity)
basicity)
+
NH2
Heterocyclic Amines
•• N
•• N
Imidazole
• Which nitrogen is protonated in imidazole?
is more basic than
N
H
••
imidazole
Kb = 1 x 10 -7
•• N
pyridine
Kb = 1.4 x 10 -9
Imidazole
• Which nitrogen is protonated in imidazole?
•• N
•• N
•
Protonation in the direction shown gives a
stabilized ion.
•• N
H
H+
H
+
N
•• N
H
H+
•• N
H
H
+
N
•• N
H
H
N ••
+
N H
H
H+
H
Imidazole
•• N
+
N
H+
•• N
H
•• N
+
N H
H
The Gabriel Synthesis of Primary Amines
Alkaloids: Naturally Occuring Bases
Nitrogen Heterocycles
Preparation and Reactions of Amines
Reductive Amination
Synthesis of Amines via Reductive Amination
Synthesis of Amines via Reductive Amination
In reductive amination,
amination, an aldehyde or ketone
is subjected to catalytic hydrogenation in the
presence of ammonia or an amine.
The imine undergoes hydrogenation faster
than the aldehyde or ketone.
ketone. An amine is
the product.
R
R
fast
C
R'
R
O + NH3
C
NH +
R'
•The aldehyde or ketone equilibrates with the
imine faster than hydrogenation occurs.
fast
C
H2O
R
O + NH3
R'
R
R'
C
H
C
NH +
R'
H2, Ni
NH2
H2O
Example: Primary amines give secondary amines
Example: Primary amines give secondary amines
Example: Ammonia gives a primary amine.
O
O + NH3
CH3(CH2)5CH
H2, Ni
H
ethanol
NH2
(80%)
via:
O
+ H2N
H2, Ni
CH3(CH2)5CH
ethanol
CH3(CH2)5CH 2NH
H2, Ni
(65%)
ethanol
CH3(CH2)5CH 2NH
NH
via:
Example: Secondary amines give tertiary amines
O
CH3CH2CH2CH
+ H2N
+
N
H
H2, Ni, ethanol
N
CH2CH2CH2CH3
(93%)
CH3(CH2)5CH
N
Amine Oxides Undergo a
Cope Elimination Reaction
(65%)
Barbiturates
Amines & Neurotransmitters
RCH2CH2NH2
O
O R' O
NH2CNH2 + CH3CH2OC C COCH2CH3
R
O
R'
H
N
R
O N O
H
CH2CH2NH2
CH3O
CH3O
Mescaline
•Can you draw the enolized form?
•Is it aromatic?
•Could it possibly be aromatic?
RCH2 CH2 NH2
CH2CH2NH2
CH3O
CH2 CH2 NH2
N
N
H
CH3O
N
H
O
CH3 NHCNHCH2 CH2 SCH2
CH2CH2NH2
N
CH3
CH2CH2NH2
CH3O
N
H
Tagamet: cimetidine
Histidine receptor antagonist (a precursor to histamine, a
vasodilator)
Inhibits gastric secretions & pepsin output
HO
CH3
HOCH2CH2N CH3
CH3
O
CH2CH2NHCCH3
CH3O
N
H
HO
HO
N
H
Dopamine, Serotonin, Melatonin
O
CH3
CH3COCH2CH2N CH3
CH3
OH
CHCH2NHCH3
Adrenalin
http://www%2Drci.rutgers.edu/%7Elwh/drugs/
http://web.indstate.edu/thcme/mwking/nerves.html#table
http://www.sfn.org/briefings/addiction.html
http://faculty.washington.edu/chudler/amp.html
Cathecols: epinephrine & mdma
http://faculty.washington.edu/chudler/mdma.html
Principal sympathomimetic adrenal hormone
& a controlled substance