Measures of Basicity
Amines
Chemical / Biological / Neurological
Activity
• The basicity of amines may be measured
and compared by using any of these values:
•
1) Kb
•
2) pK b
•
3) Ka of conjugate acid
•
4) pK a of conjugate acid
Basicity Constant (Kb) and pKb
• Kb is the equilibrium constant for the
reaction:
R3N •• + H
+
R3N
••
OH
••
Kb =
H +
– ••
•• OH
••
[R3NH+][HO–]
[R3N]
and pK b = - log K b
Ka and pKa of Conjugate Acid
•
K a is the equilibrium constant for the
dissociation of the conjugate acid of the amine:
+
R3N
R3N •• + H+
H
Ka =
[R3N][H+]
[R3NH+]
and pK a = - log K a
Relationships between acidity and basicity
constants
Ka K b = 10-14
pK a + pK
pK b = 14
Basicity of Amines in Aqueous Solution
•Amine
Conj. Acid
+
•NH3
NH4
•CH3CH2NH2
CH3CH2NH3+
pKa
9.3
10.8
CH3CH2NH3+ is a weaker acid than NH4+;
therefore, CH3CH2NH2 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
pKa
Effect of Structure on Basicity
9.3
•1. Alkylamines are slightly stronger bases than
ammonia.
CH3CH2NH3+
10.8
•2. Alkylamines differ very little in basicity.
•(CH3CH2) 2NH
(CH3CH2)2NH2+
10.9
•(CH3CH2) 3N
(CH3CH2)3NH+
11.1
•3. Arylamines are much weaker bases than
ammonia.
•NH3
NH4
•CH3CH2NH2
+
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+
Decreased basicity of arylamines
••
NH 2 + H
10.8
+
•(CH3CH2) 2NH
(CH3CH2)2NH2
•(CH3CH2) 3N
(CH3CH2)3NH+
11.1
•C6H5NH2
C6H5NH3+
4.6
••
10.9
+
NH 3 +
OH • Aniline (reactant) is
••
stabilized by
conjugation of
nitrogen lone pair
with ring π system.
• This stabilization is
– ••
lost on protonation.
•• OH
••
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
•O2 N
NH3+
X
pKb
9.4
8.7
11.5
13.0
••
N
is more basic than
••
O ••
+
N
pKa
4.6
5.3
2.5
1.0
•O•
–• •• •
••
NH2
– ••
•• O ••
+
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)
(resembles an
arylamine in
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?
(HINT: Resonance is the key.)
•• N
•• N
•
•• N
H+
H
+
N
•• N
H
H
+
N
•• N
H
•• N
•• N
H
+
N H
H
Which of the following amines is more basic?
•
A)
B)
•
C)
D)
H
H+
•• N
+
N
H+
Question
Protonation in the direction shown gives a
stabilized ion.
H
H
H+
H
Imidazole
•• N
H
N ••
+
N H
Preparation of Amines by Reduction
Preparation of Amines by Reduction
Synthesis of Amines via Azides
•Almost any nitrogen-containing compound can
be reduced to an amine, including:
•SN2 reaction, followed by reduction, gives a
primary alkylamine.
• azides
nitriles
nitro-substituted benzene derivatives
amides
CH2CH2Br
NaN
NaN 3
CH2CH2N3
(74%)
1. LiAlH4
2. H2O
Azides may also be
reduced by catalytic
hydrogenation.
CH2CH2NH2
(89%)
Question
• What is the product of the reaction shown?
Question
• Identify compound C formed in the synthetic
sequence below.
Synthesis of Amines via Nitriles
•SN2 reaction, followed by reduction, gives a
primary alkylamine.
CH3CH2CH2CH2Br
•
A)
B)
•
C)
D)
• A) (R)-2-octanamine
• C) (R)-2-octanol
B) (S)-2-octanamine
D) octane
Nitriles may also be
reduced by lithium
aluminum hydride.
NaC
NaC N
CH3CH2CH2CH2CN
(69%)
H2 (100 atm), Ni
CH3CH2CH2CH2CH 2NH2
(56%)
Synthesis of Amines via Nitriles
•SN2 reaction, followed by reduction, gives a
primary alkylamine.
CH3CH2CH2CH2Br
NaC
NaC N
The reduction also
works with cyanohydrins.
Synthesis of Amines via Nitroarenes
Question
• What is the major organic product of the
synthesis shown?
CH3CH2CH2CH2CN
•
•
•
•
(69%)
H2 (100 atm), Ni
CH3CH2CH2CH2CH 2NH2
A)
B)
C)
D)
C 6H5CH2CN
C 6H5CH2CHO
C 6H5CH2CH2NH2
C 6H5CH2NH2
HN O 3
Cl
Nitro groups may also
be reduced with tin (Sn)
+ HCl or by catalytic
hydrogenation.
B)
• C)
D)
1. Fe, HCl
2. NaOH
NH 2
(95%)
Question
Question
• A)
(88-95%)
Cl
(56%)
• Which one of the following is produced when mnitroacetophenone is treated with Sn and HCl
followed by NaOH?
NO 2
Cl
H2SO4
• Starting with benzene, which of the sequences below will
produce p-methylaniline as the major product of the
reaction?
•
A)
•
B)
•
C)
•
D)
1. HNO3, H2 SO4 ; 2. CH3 Cl, AlCl3 ; 3. Fe, HCl; 4.
NaOH
1. HNO3, H2 SO4 ; 2. Fe, HCl; 3. NaOH; 4. CH3Cl,
AlCl3
1. CH3 Cl, AlCl3 ; 2. HNO3, H2 SO4 ; 3. Fe, HCl; 4.
NaOH
1. CH3 Cl, AlCl3 ; 2. HNO3, H2 SO4 ; 3. H2
Synthesis of Amines via Amides
O
COH
O
1. SOCl2
CN (CH3)2
2. (CH3) 2NH
(86-89%)
Only LiAlH4 is an
appropriate reducing
agent for this reaction.
1. LiAlH4
2. H2O
CH2N(CH3) 2
(88%)
The Gabriel Synthesis of Primary Amines
Question
• Identify the product of the synthesis shown.
Preparation and Reactions of Amines
LiAlH4
5. H2 O
•
•
•
•
A)
B)
C)
D)
C 6H5NH2
C 6H5CH=NH
C 6H5CH2NH2
C 6H5C(=O)NH2
Question
Synthesis of Amines via Reductive Amination
• What is the product of the Gabriel
synthesis shown?
Reductive Amination
•
•
•
•
A)
B)
C)
D)
diethyl ether
ethanol
ethyl amine
CH3CH2NHNH2
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 + NH 3
C
NH +
H2O
R'
•The aldehyde or ketone equilibrates with the
imine faster than hydrogenation occurs.
Synthesis of Amines via Reductive Amination
O
The imine undergoes hydrogenation faster
than the aldehyde or ketone. An amine is
the product.
R
C
O + NH 3
R'
C
NaBH3CN or H2, Ni
C
NH +
Example: Secondary amines give tertiary amines
O
CH3CH2CH2CH
+
ethanol
N
H
H2, Ni, ethanol
H2O
CH3(CH2) 5CH2NH
R'
R
R'
CH3(CH2) 5CH + H2N
R
fast
Example: Primary amines give secondary amines
H2, Ni
NH 2
H
Question
• How would you accomplish the conversion of
propanal into N-ethyl-N-methylpropanamine?
•
• A) NH3 , NaBH3 CN; CH3 I; CH3CH2I
• B) CH3 NH2 , NaBH3 CN; CH3 COCl, pyridine; LiAlH4;
H2 O
• C) CrO3 , H2 SO4 ; SOCl2 , pyridine; 2 equiv CH3 NH2 ;
CH3 I
• D) CH3 CH2 NH2 , H2 , Ni; (CH3 CO)2 O, pyridine;
NaBH4
via:
CH3(CH2) 5CH
N
N
CH2CH2CH2CH3
Quarternary Amines Can Undergo an
E2 Elimination Reaction
The Hofmann Elimination
(93%)
Quaternary Ammonium Hydroxides
The Hofmann Elimination
•a quaternary ammonium hydroxide is the reactant
and an alkene is the product
Regioselectivity
are prepared by treating quaternary ammmonium
halides with moist silver oxide
•is an anti elimination
CH2N(CH3) 3 I
–
Ag2O
+ N(CH3)3
H2O, CH3OH
–
HO
+
–
CH2N(CH3) 3 HO
Regioselectivity
H2C
CH3CHCH2CH3
•the leaving group is a trialkylamine
•the regioselectivity is opposite to the Zaitsev rule.
Elimination occurs in the direction that gives
the less-substituted double bond. This is called
the Hofmann rule.
CHCH2CH3 (95%)
heat
+
CH3CH
CHCH3 (5%)
Regioselectivity
H
H
CH3CH2
H
H
H
H
CH3CH2
+ N(CH3)3
largest group is between two H atoms
C
C
H
H
major product
H
CH3
CH3
H
+ N(CH3)3
largest group is between an
H atom and a methyl group
CH3
H
C
C
H
CH3
minor product
Nitrosation of Arylamines
Synthetic Origin of Aryl Diazonium Salts
Nitrosation of Primary Arylamines
Ar
•Gives aryl diazonium ions.
•Aryl diazonium ions are much more stable than
alkyl diazonium ions.
•Most aryl diazonium ions are stable under the
conditions of their formation (0-10°C).
+
RN
N
+
ArN
ArN
N
fast
+
R
+ N2
slow
+
Ar
+ N2
Ar
CN
CuCN,
heat
Cl
CuCl
CuCl or CuBr
CuBr
heat
+
N
Ar
N
H3PO2
Ar
H
Br
Ar
H2O, heat
Ar
OH
Ar
F
HBF4 / heat
KI
Ar
Ar
Synthetic Transformations
of Aryl Diazonium Salts
NO 2
Ar
NH 2
Ar
Transformations of Aryl Diazonium Salts
Ar
H
I
+
N
N
Question
• Identify the product isolated from the
reaction of p-nitroaniline with NaNO2 in
H2SO4 followed by the addition of
potassium iodide (KI).
•
A) nitrobenzene
•
B) p-iodoaniline
•
C) p-iodonitrobenzene
•
D) p-diiodonitrobenzene
Alkaloids
Alkaloids: Naturally Occuring Bases
Amines & Neurotransmitters
Nitrogen Heterocycles
ibogaine
R-CH2CH2 NH2
CH2CH2NH2
HO
CH2CH2 NH2
CH3O
CH2CH2NH2
CH3 O
H3 CO
N
H
CH3O
HO
HO
CH2CH2NH2
CH3
HOCH2CH2N CH3
CH3
O
CH2CH2NHCCH3
CH3O
N
H
OH
CHCH2NHCH3
N
H
H3CO
R-ethylamine
dopamine
mescaline
HO
HO
O
CH3
CH3COCH2CH2N CH3
CH3
Serotonin --------- Melatonin
Acetylcholine
Epinephrine (Adrenaline)
Cathecols: epinephrine & mdma
http://faculty.washington.edu/chudler/mdma.html
Drug Uptake:
Drug Uptake:
Rank from slowest to fastest.
Rank from slowest to fastest.
a) injection; b) ingestion; c) inhalation; d) snorting
a) injection; b) ingestion; c) inhalation; d) snorting
A) a<b<c<d
B) c<a<d<b
A) a<b<c<d
B) c<a<d<b
C) b<d<a<c
D) d<b<c<a
C) b<d<a<c
D) d<b<c<a
Principal sympathomimetic adrenal hormone
& a controlled substance
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
morphine
LSD
ibogaine