amines chemical / biological / neurological activity
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Amines Chemical / Biological / Neurological Activity. Measures of Basicity. The basicity of amines may be measured by: 1) K b 2)p K b 3) K a of conjugate acid 4) p K a of conjugate acid. +. –. ••. ••. R 3 N. H. OH. OH. R 3 N. H. • •. • •. ••. ••. - PowerPoint PPT PresentationTRANSCRIPT
AminesAmines Chemical / Biological / Neurological Chemical / Biological / Neurological
ActivityActivity
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:
RR33NN •••• ++ HH OHOH••••
••••RR33NN
++HH
––•••• OHOH••••
••••++
KKbb = =[R[R33NHNH++][HO][HO––]]
[R[R33N]N]
ppKKbb = = - log - log KKbbandand
Ka and pKa of Conjugate Acid
KKaa = =[R[R33N][HN][H++]]
[R[R33NHNH++]]
ppKKaa = = - log - log KKaaandand
RR33NN ••••RR33NN++
HH ++ HH++
• Ka is the equilibrium constant for the dissociation of the conjugate acid of the amine:
Relationships between acidity and basicity constants
ppKKaa + p + pKKbb = 14 = 14
KKa a KKbb = 10 = 10-14-14
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)
NCO2CH3
O2C
CH3..
"Crack" Cocaine
• 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
What structural feature makes cocaine a base? What simple compound can you relate it to?
“Regular” Cocaine Conjugate Acid of Cocaine
(Physical Properties)
CH3 NCO2CH3
O2C
H Cl -
Cocaine Hydrochloride
+ • m.p. >195 oC
Solubility:• Water: 2.5 g/mL • CHCl3: 0.08
g/mL • Ether:
insolubleWhat accounts for the differences in solubilities of the base and conjugate acid?
Acid -Base Reactions
NCO2CH3
O2C
CH3
+ H Cl
..
CH3N
CO2CH3
O2C
H Cl -
Cocaine Hydrochloride
+
Acid Base Reactions
CH3 NCO2CH3
O2C
H Cl -+
+ OH -
..
"Crack" Cocaine
CH3N
CO2CH3
O2C
•Amine Conj. Acid pKa
•NH3 NH4+ 9.3
•CH3CH2NH2 CH3CH2NH3+ 10.8
Basicity of Amines in Aqueous Solution
CHCH33CHCH22NHNH33++ is a weaker acid than NH is a weaker acid than NH44
++;;therefore, CHtherefore, CH33CHCH22NHNH22 is a stronger base is a stronger base than NHthan NH33..
Effect of Structure on Basicity
•1. Alkylamines are slightly stronger bases than ammonia.
•2. Alkylamines differ very little in basicity.
•Amine Conj. Acid pKa
•NH3 NH4+ 9.3
•CH3CH2NH2 CH3CH2NH3+ 10.8
•(CH3CH2)2NH (CH3CH2)2NH2+ 11.1
•(CH3CH2)3N (CH3CH2)3NH+ 10.8
Basicity of Amines in Aqueous Solution
Notice that the difference separating a primary,Notice that the difference separating a primary,secondary, and tertiary amine is only 0.3 pK units.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 thanammonia.
•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
Basicity of Amines in Aqueous Solution
++ HH OHOH••••
••••
NNHH22••••
++
NNHH33
++ ––•••• OHOH••••
••••
• Aniline (reactant) is stabilized by conjugation of nitrogen lone pair with ring system.
• This stabilization is lost on protonation.
Decreased basicity of arylamines
Decreased basicity of arylamines
CC66HH55NHNH22 (C(C66HH55))22NHNH (C(C66HH55))33NN
KKbb 3.8 x 103.8 x 10-10-10 6 x 106 x 10-14-14 ~10~10-19-19
•Increasing delocalization makes diphenylamine a weaker base than aniline, and triphenylamine a weaker base than diphenylamine.
Effect of Substituents on Basicity of Arylamines
•1. Alkyl groups on the ring increase basicity, butonly slightly (less than 1 pK unit).
•2. Electron withdrawing groups, especially orthoand/or para to amine group, decrease basicityand can have a large effect.
•X pKb pKa
•H 9.4 4.6•CH3 8.7 5.3•CF3 11.5 2.5•O2N 13.0 1.0
Basicity of Arylamines
XX NHNH22
XX NHNH33++
p-Nitroaniline
NHNH22
OO
NN
OO
–– ••••••••••••
••••
++••••
••••
OO
NN
OO
–– ••••••••••••
•••• ••••••••––
NHNH22
++
++
•Lone pair on amine nitrogen is conjugated with p-nitro group—more delocalized than in aniline itself. Delocalization lost on protonation.
Effect is Cumulative
•Aniline is 3800 times more basic thanp-nitroaniline.•Aniline is ~1,000,000,000 times more basic than 2,4-dinitroaniline.
Heterocyclic Amines
NN
HH
••••
NN••••
piperidinepiperidine pyridinepyridine
is more basic thanis more basic than
KKbb = 1.6 x 10 = 1.6 x 10-3-3 KKbb = 1.4 x 10 = 1.4 x 10-9-9
(an alkylamine)(an alkylamine) (resembles an(resembles anarylamine inarylamine in
basicity)basicity)
Heterocyclic Amines
NN••••
imidazoleimidazole pyridinepyridine
is more basic thanis more basic than
KKbb = 1 x 10 = 1 x 10-7-7 KKbb = 1.4 x 10 = 1.4 x 10-9-9
NN HHNN•••• ••••
Imidazole
NN HHNN•••• ••••
• Which nitrogen is protonated in imidazole?
HH++ HH++
NN HHNN ••••HH++
NN HHNN••••HH
++
Imidazole
NN HHNN•••• ••••
• Which nitrogen is protonated in imidazole?
HH++
NN HHNN ••••HH++
Imidazole
NN HHNN•••• ••••
• Protonation in the direction shown gives a stabilized ion.
HH++
NN HHNNHH++ ••••
NN HHNNHH••••
++
Alkaloids: Naturally Occuring BasesNitrogen Heterocycles
Preparation and Reactions of Amines
The Gabriel Synthesis of Primary Amines
Reductive Amination
•The aldehyde or ketone equilibrates with theimine faster than hydrogenation occurs.
Synthesis of Amines via Reductive Amination
OOCC
RR
R'R'
++ NNHH33
fastfast
NNHHCC
RR
R'R'
++ HH22OO
In reductive amination, an aldehyde or ketoneIn reductive amination, an aldehyde or ketoneis subjected to catalytic hydrogenation in theis subjected to catalytic hydrogenation in thepresence of ammonia or an amine.presence of ammonia or an amine.
Synthesis of Amines via Reductive Amination
HH22, Ni, Ni
OOCC
RR
R'R'
++ NNHH33
fastfast
NNHHCC
RR
R'R'
++ HH22OO
NNHH22
RR
R'R' CC
HH
The imine undergoes hydrogenation fasterThe imine undergoes hydrogenation fasterthan the aldehyde or ketone. An amine is than the aldehyde or ketone. An amine is the product.the product.
Example: Ammonia gives a primary amine.
OO ++ NNHH33
HH
NNHH22
HH22, Ni, Ni
ethanolethanol
(80%)(80%)
via:via:
NNHH
Example: Primary amines give secondary amines
HH22, Ni, Ni ethanolethanol
(65%)(65%)
CHCH33(CH(CH22))55CHCH22NNHH
++ HH22NN
CHCH33(CH(CH22))55CHCH
OO
Example: Primary amines give secondary amines
HH22, Ni, Ni ethanolethanol
(65%)(65%)
via:via:
CHCH33(CH(CH22))55CHCH22NNHH
++ HH22NN
CHCH33(CH(CH22))55CHCH
OO
NN
CHCH33(CH(CH22))55CHCH
Example: Secondary amines give tertiary amines
HH22, Ni, ethanol, Ni, ethanol
(93%)(93%)
++CHCH33CHCH22CHCH22CHCH
OO
NN
HH
NN
CHCH22CHCH22CHCH22CHCH33
Amine Oxides Undergo a Cope Elimination Reaction
Amines & Neurotransmitters
NH2CNH2
OCH3CH2OC C COCH2CH3
O OR'
R
N
N
H
HO
R'RO
O
+
Barbiturates
•Can you draw the enolized form?•Is it aromatic? •Could it possibly be aromatic?
RCH2CH2NH2
CH2CH2NH2
CH2CH2NH2
CH3O
CH3O
CH3O
Mescaline
RCH2CH2NH2
CH2CH2NH2
N NH
N
N
CH3H
CH3NHCNHCH2CH2SCH2
O
Tagamet: cimetidineHistidine receptor antagonist (a precursor to histamine, a
vasodilator)Inhibits gastric secretions & pepsin output
CH2CH2NH2
NH
CH3O
CH3O
NH
HOCH2CH2NH2
NH
CH3OCH2CH2NHCCH3
O
Dopamine, Serotonin, Melatonin
HOCH2CH2N CH3CH3
CH3CH3COCH2CH2N CH3
CH3
CH3O
CHCH2NHCH3
HO
HOOH
Adrenalin
Cathecols: epinephrine & mdmahttp://faculty.washington.edu/chudler/mdma.html
Principal sympathomimetic adrenal hormone & a controlled substance
http://web.indstate.edu/thcme/mwking/nerves.html#tablehttp://www.sfn.org/briefings/addiction.htmlhttp://faculty.washington.edu/chudler/amp.html
http://www%2Drci.rutgers.edu/%7Elwh/drugs/