Amines Chemical / Biological / Neurological Activity : Amines Chemical / Biological / Neurological Activity
Measures of Basicity : 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 : Basicity Constant (Kb) and pKb Kb is the equilibrium constant for the reaction: + + Kb = [R3NH+][HO–] [R3N] pKb = - log Kb and
Ka and pKa of Conjugate Acid : Ka and pKa of Conjugate Acid Ka = [R3N][H+] [R3NH+] pKa = - log Ka and Ka is the equilibrium constant for the dissociation of the conjugate acid of the amine:
Relationships between acidity and basicity constants : Relationships between acidity and basicity constants pKa + pKb = 14 Ka Kb = 10-14
A natural base from Erythroxylon spp. : 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 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) : Acid -Base Chemistry (Physical Properties) 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) : “Regular” Cocaine Conjugate Acid of Cocaine (Physical Properties) m.p. >195 oC
Solubility:
Water: 2.5 g/mL
CHCl3: 0.08 g/mL
Ether: insoluble What accounts for the differences in solubilities of the base and conjugate acid?
Acid -Base Reactions : Acid -Base Reactions
Acid Base Reactions : Acid Base Reactions
Basicity of Amines in Aqueous Solution : Amine Conj. Acid pKa
NH3 NH4+ 9.3
CH3CH2NH2 CH3CH2NH3+ 10.8 Basicity of Amines in Aqueous Solution CH3CH2NH3+ is a weaker acid than NH4+; therefore, CH3CH2NH2 is a stronger base than NH3.
Effect of Structure on Basicity : 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 Basicity of Amines in Aqueous Solution Notice that the difference separating a primary, secondary, and tertiary amine is only 0.3 pK units.
Effect of Structure on Basicity : 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 Basicity of Amines in Aqueous Solution
Decreased basicity of arylamines : + + + Aniline (reactant) is stabilized by conjugation of nitrogen lone pair with ring p system.
This stabilization is lost on protonation. Decreased basicity of arylamines
Decreased basicity of arylamines : Decreased basicity of arylamines C6H5NH2 (C6H5)2NH (C6H5)3N Kb 3.8 x 10-10 6 x 10-14 ~10-19 Increasing delocalization makes diphenylamine a weaker base than aniline, and triphenylamine a weaker base than diphenylamine.
Effect of Substituents on 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.
Basicity of Arylamines : 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
p-Nitroaniline : p-Nitroaniline + Lone pair on amine nitrogen is conjugated with p-nitro group—more delocalized than in aniline itself. Delocalization lost on protonation.
Effect is Cumulative : 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 : Heterocyclic Amines piperidine pyridine is more basic than Kb = 1.6 x 10-3 Kb = 1.4 x 10-9 (an alkylamine) (resembles an arylamine in basicity)
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Heterocyclic Amines : Heterocyclic Amines imidazole pyridine is more basic than Kb = 1 x 10-7 Kb = 1.4 x 10-9
Imidazole : Imidazole Which nitrogen is protonated in imidazole? H+ H+ +
Imidazole : Imidazole Which nitrogen is protonated in imidazole? H+
Imidazole : Imidazole Protonation in the direction shown gives a stabilized ion. H+ + • •
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Slide31 : Alkaloids: Naturally Occuring Bases
Nitrogen Heterocycles
Preparation and Reactions of Amines : Preparation and Reactions of Amines
Slide33 : The Gabriel Synthesis of Primary Amines
Reductive Amination : Reductive Amination
Synthesis of Amines via Reductive Amination : The aldehyde or ketone equilibrates with the imine faster than hydrogenation occurs. Synthesis of Amines via Reductive Amination + NH3 fast + H2O In reductive amination, an aldehyde or ketone is subjected to catalytic hydrogenation in the presence of ammonia or an amine.
Synthesis of Amines via Reductive Amination : Synthesis of Amines via Reductive Amination H2, Ni + NH3 fast + H2O The imine undergoes hydrogenation faster than the aldehyde or ketone. An amine is the product.
Example: Ammonia gives a primary amine. : Example: Ammonia gives a primary amine. + NH3 H2, Ni ethanol (80%) via:
Example: Primary amines give secondary amines : Example: Primary amines give secondary amines H2, Ni ethanol (65%)
Example: Primary amines give secondary amines : Example: Primary amines give secondary amines H2, Ni ethanol (65%) via:
Example: Secondary amines give tertiary amines : Example: Secondary amines give tertiary amines H2, Ni, ethanol (93%) +
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Slide42 : Amine Oxides Undergo a
Cope Elimination Reaction
Slide43 : Amines & Neurotransmitters
Slide44 : Barbiturates Can you draw the enolized form?
Is it aromatic?
Could it possibly be aromatic?
Slide45 : Mescaline
Slide46 : Tagamet: cimetidine
Histidine receptor antagonist (a precursor to histamine, a vasodilator)
Inhibits gastric secretions & pepsin output
Slide47 : Dopamine, Serotonin, Melatonin
Slide48 : Adrenalin
Slide49 : Cathecols: epinephrine & mdma
http://faculty.washington.edu/chudler/mdma.html
Principal sympathomimetic adrenal hormone
& a controlled substance
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