Transcript Acid -Base Chemistry - Welcome to ChemConnections

Amines
Chemical / Biological / Neurological
Activity
Measures of Basicity
• 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
+
R3N
••
OH
••
Kb =
and pKb =
[R3NH+][HO–]
[R3N]
- log Kb
– ••
H + •• OH
••
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 Kb = 10-14
pKa + pKb = 14
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?
The beverage reportedly produced using the
extract of leaves of Erythroxylon coca:
The compound: cocaine, it is an organic base:
Merck Index, #2450, 11th ed.: Caution: May be habit
forming….
Acid -Base Chemistry
(Physical Properties)
CH3 ..
N
CO2CH3
O2C
"Crack" Cocaine
What structural feature makes
cocaine a base? What simple
compound can you relate it to?
• m.p. 98 oC
• b.p. (very volatile
> 90 oC)
Solubility:
• Water: 1.67 x 10-3
g/mL
• CHCl3: 1.43 g/mL
• Ether: 0.29 g/mL
“Regular” Cocaine
Conjugate Acid of Cocaine
(Physical Properties)
H
Cl
+
CH3
N
CO2 CH3
O2 C
Cocaine Hydrochloride
What accounts for the differences
in solubilities of the base and
conjugate acid?
• m.p. >195 oC
Solubility:
•
Water: 2.5 g/mL
•
CHCl3: 0.08 g/mL
•
Ether: insoluble
Acid -Base Reactions
CH3 ..
N
CH3
N
CO2CH3
+
O2C
+
H
Cl
H Cl
-
CO2 CH3
O2 C
Cocaine Hydrochloride
Acid Base Reactions
CH3
+
N
H Cl
CH3 ..
N
-
CO2CH3
+
O2C
CO2CH3
OH -
O2C
"Crack" Cocaine
Basicity of Amines in Aqueous Solution
•Amine
Conj. Acid
pKa
•NH3
NH4+
9.3
•CH3CH2NH2
CH3CH2NH3+
10.8
CH3CH2NH3+ is a weaker acid than NH4+;
therefore, CH3CH2NH2 is a stronger base
than NH3.
Effect of Structure on Basicity
•1. Alkylamines are slightly stronger bases than
ammonia.
•2. Alkylamines differ very little in basicity.
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
Notice that the difference separating a primary,
secondary, and tertiary amine is only 0.3 pK units.
Effect of Structure on Basicity
•1. Alkylamines are slightly stronger bases than
ammonia.
•2. Alkylamines differ very little in basicity.
•3. Arylamines are much weaker bases than
ammonia.
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 p 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
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.
Basicity of Arylamines
X
•X
•H
•CH3
•CF3
•O2N
NH2
pKb
9.4
8.7
11.5
13.0
NH3+
X
pKa
4.6
5.3
2.5
1.0
p-Nitroaniline
– ••
•• 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.
+
NH2
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.
Heterocyclic Amines
••
N
is more basic than
N
••
H
piperidine
pyridine
Kb = 1.6 x 10-3
Kb = 1.4 x 10-9
(an alkylamine)
(resembles an
arylamine in
basicity)
Heterocyclic Amines
•• N
•• N
is more basic than
H
imidazole
Kb = 1 x 10-7
N
••
pyridine
Kb = 1.4 x 10-9
Imidazole
• Which nitrogen is protonated in imidazole?
•• N
•• N
H
H+
+
H N
H+
•N
•
H
•• N
+ H
N
H
Imidazole
• Which nitrogen is protonated in imidazole?
•• N
H+
+
H N
•N
•
H
•• N
H
Imidazole
•
Protonation in the direction shown gives a
stabilized ion.
•• N
•• N
H
H+
+
H N
•N
•
H
H
N ••
+
N H
Alkaloids: Naturally Occuring Bases
Nitrogen Heterocycles
Preparation and Reactions of Amines
The Gabriel Synthesis of Primary Amines
Reductive Amination
Synthesis of Amines via Reductive Amination
In reductive amination, an aldehyde or ketone
is subjected to catalytic hydrogenation in the
presence of ammonia or an amine.
R
fast
C
R'
R
O + NH3
C
NH +
H2O
R'
•The aldehyde or ketone equilibrates with the
imine faster than hydrogenation occurs.
Synthesis of Amines via Reductive Amination
The imine undergoes hydrogenation faster
than the aldehyde or ketone. An amine is
the product.
R
fast
C
R
O + NH3
R'
C
H
NH +
R'
R
R'
C
H2, Ni
NH2
H2O
Example: Ammonia gives a primary amine.
O + NH3
H2, Ni
H
ethanol
NH2
(80%)
via:
NH
Example: Primary amines give secondary amines
O
CH3(CH2)5CH
+ H2N
H2, Ni
ethanol
CH3(CH2)5CH2NH
(65%)
Example: Primary amines give secondary amines
O
CH3(CH2)5CH
+ H2N
H2, Ni
ethanol
CH3(CH2)5CH2NH
via:
CH3(CH2)5CH
N
(65%)
Example: Secondary amines give tertiary amines
O
CH3CH2CH2CH
+
N
H
H2, Ni, ethanol
N
CH2CH2CH2CH3
(93%)
Amine Oxides Undergo a
Cope Elimination Reaction
Amines & Neurotransmitters
Barbiturates
O
O R' O
NH2CNH2 + CH3CH2OC C COCH2CH3
R
O
R'
H
N
R
O N O
H
•Can you draw the enolized form?
•Is it aromatic?
•Could it possibly be aromatic?
RCH2 CH2NH2
CH2 CH2 NH2
CH3O
CH3O
CH2 CH2NH2
CH3O
Mescaline
RCH2 CH2 NH2
CH2 CH2 NH2
N
N
H
O
CH3 NHCNHCH2 CH2 SCH2
N
CH3
N
H
Tagamet: cimetidine
Histidine receptor antagonist (a precursor to histamine, a
vasodilator)
Inhibits gastric secretions & pepsin output
CH2CH2NH2
CH3O
N
H
CH3O
CH2CH2NH2
HO
O
CH2CH2NHCCH3
CH3O
N
H
N
H
Dopamine, Serotonin, Melatonin
CH3
HOCH2CH2N CH3
CH3
O
CH3
CH3COCH2CH2N CH3
CH3
HO
HO
OH
CHCH2NHCH3
Adrenalin
Cathecols: epinephrine & mdma
http://faculty.washington.edu/chudler/mdma.html
Principal sympathomimetic adrenal hormone
& a controlled substance
http://w w w %2Drci.rutgers.edu/%7Elw h/drugs/
http://w eb.indstate.edu/thcme/mw king/nerves.html#table
http://w w w .sfn.org/briefings/addiction.html
http://faculty.w ashington.edu/chudler/amp.html