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AminesAmines Chemical / Biological / Neurological Chemical / Biological / Neurological
ActivityActivity
Measures of Basicity
• The basicity of amines may be measured and compared by using any of these values:
• 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
•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+ 10.9
•(CH3CH2)3N (CH3CH2)3NH+ 11.1
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+ 10.9
•(CH3CH2)3N (CH3CH2)3NH+ 11.1
•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? (HINT: Resonance is the key.)
HH++
NN HHNN ••••HH++
Imidazole
NN HHNN•••• ••••
• Protonation in the direction shown gives a stabilized ion.
HH++
NN HHNNHH++ ••••
NN HHNNHH••••
++
Question
Which of the following amines is more basic?
• A) B)
• C) D)
Preparation of Amines by Reduction
•Almost any nitrogen-containing compound canbe reduced to an amine, including:
• azidesnitrilesnitro-substituted benzene derivativesamides
Preparation of Amines by Reduction
•SN2 reaction, followed by reduction, gives a
primary alkylamine.
Synthesis of Amines via Azides
CHCH22CHCH22BrBr
CHCH22CHCH22NN33
NaNaNN33
(74%)(74%)
CHCH22CHCH22NNHH22
(89%)(89%)
1. LiAlH1. LiAlH44
2. H2. H22OO
Azides may also bereduced by catalytichydrogenation.
Question
• What is the product of the reaction shown?
• A) B)
• C) D)
• Identify compound C formed in the synthetic sequence below.
• A) (R)-2-octanamine B) (S)-2-octanamine• C) (R)-2-octanol D) octane
Question
•SN2 reaction, followed by reduction, gives a
primary alkylamine.
Synthesis of Amines via Nitriles
CHCH33CHCH22CHCH22CHCH22BrBrNaNaCCNN
(69%)(69%)
CHCH33CHCH22CHCH22CHCH22CCNN
CHCH33CHCH22CHCH22CHCH22CCHH22NNHH22
(56%)(56%)
HH22 (100 atm), Ni (100 atm), Ni
Nitriles may also bereduced by lithiumaluminum hydride.
•SN2 reaction, followed by reduction, gives a
primary alkylamine.
Synthesis of Amines via Nitriles
CHCH33CHCH22CHCH22CHCH22BrBrNaNaCCNN
(69%)(69%)
CHCH33CHCH22CHCH22CHCH22CCNN
CHCH33CHCH22CHCH22CHCH22CCHH22NNHH22
(56%)(56%)
HH22 (100 atm), Ni (100 atm), Ni
The reduction alsoThe reduction alsoworks with cyanohydrins.works with cyanohydrins.
Question
• What is the major organic product of the synthesis shown?
• A) C6H5CH2CN
• B) C6H5CH2CHO
• C) C6H5CH2CH2NH2
• D) C6H5CH2NH2
Synthesis of Amines via Nitroarenes
HHNNOO33
(88-95%)(88-95%)
ClCl
ClCl NNOO22HH22SOSO44
(95%)(95%)
1. Fe, HCl1. Fe, HCl
2. NaOH2. NaOH
ClCl NNHH22
Nitro groups may alsobe reduced with tin (Sn)+ HCl or by catalytichydrogenation.
Question• Which one of the following is produced when m-
nitroacetophenone is treated with Sn and HCl followed by NaOH?
• A) B)
• C) D)
Question• Starting with benzene, which of the sequences below will
produce p-methylaniline as the major product of the reaction?
• A) 1. HNO3, H2SO4; 2. CH3Cl, AlCl3; 3. Fe, HCl; 4.
NaOH
• B) 1. HNO3, H2SO4; 2. Fe, HCl; 3. NaOH; 4. CH3Cl,
AlCl3
• C) 1. CH3Cl, AlCl3; 2. HNO3, H2SO4; 3. Fe, HCl; 4.
NaOH
• D) 1. CH3Cl, AlCl3; 2. HNO3, H2SO4; 3. H2
Synthesis of Amines via Amides
(86-89%)(86-89%)
COHCOH
OO1. SOCl1. SOCl22
2. (CH2. (CH33))22NNHH
CCNN(CH(CH33))22
OO
(88%)(88%)
1. LiAlH1. LiAlH44
2. H2. H22OO
CHCH22NN(CH(CH33))22
Only LiAlH4 is an
appropriate reducingagent for this reaction.
Question• Identify the product of the synthesis shown.
• A) C6H5NH2
• B) C6H5CH=NH
• C) C6H5CH2NH2
• D) C6H5C(=O)NH2
LiAlH45. H2O
Preparation and Reactions of Amines
The Gabriel Synthesis of Primary Amines
Question
• What is the product of the Gabriel synthesis shown?
• A) diethyl ether
• B) ethanol
• C) ethyl amine
• D) CH3CH2NHNH2
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: Primary amines give secondary amines
HH22, Ni, Ni ethanolethanol
CHCH33(CH(CH22))55CHCH22NNHH
++ HH22NN
CHCH33(CH(CH22))55CHCH
OO
NaBHNaBH33CN CN oror
via:via: NN
CHCH33(CH(CH22))55CHCH
Example: Secondary amines give tertiary amines
HH22, Ni, ethanol, Ni, ethanol
(93%)(93%)
++CHCH33CHCH22CHCH22CHCH
OO
NN
HH
NN
CHCH22CHCH22CHCH22CHCH33
Question• How would you accomplish the conversion of propanal into
N-ethyl-N-methylpropanamine? •
• A) NH3, NaBH3CN; CH3I; CH3CH2I
• B) CH3NH2, NaBH3CN; CH3COCl, pyridine; LiAlH4; H2O
• C) CrO3, H2SO4; SOCl2, pyridine; 2 equiv CH3NH2; CH3I
• D) CH3CH2NH2, H2, Ni; (CH3CO)2O, pyridine; NaBH4
Quarternary Amines Can Undergo an E2 Elimination Reaction
The Hofmann Elimination
The Hofmann EliminationThe Hofmann Elimination
•a quaternary ammonium hydroxide is the reactantand an alkene is the product
•is an anti elimination
•the leaving group is a trialkylamine
•the regioselectivity is opposite to the Zaitsev rule.
Quaternary Ammonium Hydroxides
AgAg22OO HH22O, CHO, CH33OHOH
CHCH22NN(CH(CH33))33
++HOHO
––
are prepared by treating quaternary ammmoniumare prepared by treating quaternary ammmoniumhalides with moist silver oxidehalides with moist silver oxide
CHCH22NN(CH(CH33))33
II––
Regioselectivity
heatheat
Elimination occurs in the direction that gives Elimination occurs in the direction that gives the less-substituted double bond. This is called the less-substituted double bond. This is called the the Hofmann rule.Hofmann rule.
NN(CH(CH33))33++
HOHO––
CHCH33CHCHCHCH22CHCH33HH22CC CHCHCHCH22CHCH33
CHCH33CHCH CHCHCHCH33
++
(95%)(95%)
(5%)(5%)
Regioselectivity
NN(CH(CH33))33++
HH
HH
HH HH
CHCH33CHCH22
largest group is between two H atomslargest group is between two H atoms
CC
HHCC
HHHH
CHCH33CHCH22
major productmajor product
Regioselectivity
NN(CH(CH33))33++
HH
HH
HH
CHCH33
largest group is between anlargest group is between anH atom and a methyl groupH atom and a methyl group
CC
HHCC
CHCH33 HH
CHCH33
minor productminor product
CHCH33
Nitrosation of Arylamines
Nitrosation of Primary Arylamines
•Gives aryl diazonium ions.
•Aryl diazonium ions are much more stable thanalkyl diazonium ions.
•Most aryl diazonium ions are stable under the conditions of their formation (0-10°C).
ArArNN NN++
RRNN NN++ fastfast
slowslow
RR++ ++ NN22
ArAr++ ++ NN22
Synthetic Origin of Aryl Diazonium Salts
ArAr HH
ArAr NNOO22
ArAr NNHH22
ArAr NN NN++
Synthetic Transformationsof Aryl Diazonium Salts
Transformations of Aryl Diazonium Salts
ArAr NN NN++
ArAr HH
ArAr OOHH
ArAr II
ArAr FF
ArAr BrBrArAr ClCl
ArAr CNCN
HH22OO, heat, heat
KKII
HBFHBF4 4 / heat/ heat
CuCuCl Cl oror CuCuBrBr
heatheatCuCN,CuCN,
heatheat
HH33POPO22
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 BasesNitrogen Heterocycles
ibogaine
Amines & Neurotransmitters
R-ethylaminedopaminemescaline
R
-
C
H
2
C
H
2
N
H
2
C
H
2
C
H
2
N
H
2
O
H
O
H
C
H
2
C
H
2
N
H
2
C
H
3
O
H
3
C
O
H
3
C
O
CH2CH2NH2
NH
CH3O
CH3O
NH
HO
CH2CH2NH2
NH
CH3O
CH2CH2NHCCH3
O
Serotonin --------- Melatonin
HOCH2CH2N CH3CH3
CH3
CH3COCH2CH2N CH3CH3
CH3O
CHCH2NHCH3
HO
HOOH
AcetylcholineEpinephrine (Adrenaline)
Cathecols: epinephrine & mdmahttp://faculty.washington.edu/chudler/mdma.html
Principal sympathomimetic adrenal hormone & a controlled substance
Drug Uptake:Rank from slowest to fastest.a) injection; b) ingestion; c) inhalation; d) snorting
A) a<b<c<d B) c<a<d<b
C) b<d<a<c D) d<b<c<a
Drug Uptake:Rank from slowest to fastest.a) injection; b) ingestion; c) inhalation; d) snorting
A) a<b<c<d B) c<a<d<b
C) b<d<a<c D) d<b<c<a
http://web.indstate.edu/thcme/mwking/nerves.html#tablehttp://www.sfn.org/briefings/addiction.html
http://faculty.washington.edu/chudler/amp.html
http://www%2Drci.rutgers.edu/%7Elwh/drugs/
morphine LSD
ibogaine
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