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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. • •. • •. ••. ••.

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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) Kb

  • 2)pKb

  • 3)Ka of conjugate acid

  • 4) pKa of conjugate acid


+

••

••

R3N

H

OH

OH

R3N

H

••

••

••

••

Basicity Constant (Kb) and pKb

  • Kb is the equilibrium constant for the reaction:

+

+

[R3NH+][HO–]

Kb =

[R3N]

and

pKb =

- log Kb


+

R3N

+

R3N

H

H+

••

Ka and pKa of Conjugate Acid

  • Ka is the equilibrium constant for the dissociation of the conjugate acid of the amine:

[R3N][H+]

Ka =

[R3NH+]

and

pKa =

- 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)

  • m.p. 98 oC

  • b.p. (very volatile > 90 oC)

    Solubility:

  • Water: 1.67 x 10-3g/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 Acidof 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


Basicity of Amines in Aqueous Solution

  • AmineConj. AcidpKa

  • NH3NH4+9.3

  • CH3CH2NH2CH3CH2NH3+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

  • AmineConj. AcidpKa

  • NH3NH4+9.3

  • CH3CH2NH2CH3CH2NH3+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 thanammonia.


Basicity of Amines in Aqueous Solution

  • AmineConj. AcidpKa

  • NH3NH4+9.3

  • CH3CH2NH2CH3CH2NH3+10.8

  • (CH3CH2)2NH(CH3CH2)2NH2+11.1

  • (CH3CH2)3N(CH3CH2)3NH+10.8

  • C6H5NH2C6H5NH3+4.6


••

••

H

OH

NH2

••

••

OH

NH3

••

••

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

  • Increasing delocalization makes diphenylamine a weaker base than aniline, and triphenylamine a weaker base than diphenylamine.

C6H5NH2

(C6H5)2NH

(C6H5)3N

3.8 x 10-10

6 x 10-14

~10-19

Kb


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

NH2

X

NH3+

Basicity of Arylamines

  • XpKbpKa

  • H9.44.6

  • CH38.75.3

  • CF311.52.5

  • O2N13.01.0


••

••

O

O

••

••

••

+

+

••

N

NH2

N

NH2

O

O

••

••

••

••

••

••

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

  • Aniline is 3800 times more basic thanp-nitroaniline.

  • Aniline is ~1,000,000,000 times more basic than 2,4-dinitroaniline.


••

N

N

••

H

Heterocyclic Amines

is more basic than

piperidine

pyridine

Kb = 1.6 x 10-3

Kb = 1.4 x 10-9

(an alkylamine)

(resembles anarylamine inbasicity)


N

H

••

N

••

N

••

Heterocyclic Amines

is more basic than

imidazole

pyridine

Kb = 1 x 10-7

Kb = 1.4 x 10-9


N

H

••

N

••

+

H

H

N

H

N

••

N

N

••

H

Imidazole

  • Which nitrogen is protonated in imidazole?

H+

H+

+


N

H

••

N

••

+

H

N

H

••

N

Imidazole

  • Which nitrogen is protonated in imidazole?

H+


N

H

••

N

••

+

H

H

N

H

N

H

N

N

••

Imidazole

  • Protonation in the direction shown gives a stabilized ion.

H+

+

••


Alkaloids: Naturally Occuring Bases

Nitrogen Heterocycles


Preparation and Reactions of Amines


The Gabriel Synthesis of Primary Amines


Reductive Amination


R

R

O

NH

C

C

R'

R'

Synthesis of Amines via Reductive Amination

In reductive amination, an aldehyde or ketoneis subjected to catalytic hydrogenation in thepresence of ammonia or an amine.

  • The aldehyde or ketone equilibrates with theimine faster than hydrogenation occurs.

fast

+

+

NH3

H2O


R

R

O

NH

C

C

R'

R'

R

R'

NH2

C

H

Synthesis of Amines via Reductive Amination

The imine undergoes hydrogenation fasterthan the aldehyde or ketone. An amine is the product.

fast

+

+

NH3

H2O

H2, Ni


H

O

NH2

NH

Example: Ammonia gives a primary amine.

H2, Ni

+

NH3

ethanol

(80%)

via:


O

+

CH3(CH2)5CH

H2N

CH3(CH2)5CH2NH

Example: Primary amines give secondary amines

H2, Ni

ethanol

(65%)


O

+

CH3(CH2)5CH

H2N

CH3(CH2)5CH2NH

CH3(CH2)5CH

N

Example: Primary amines give secondary amines

H2, Ni

ethanol

(65%)

via:


O

CH3CH2CH2CH

N

H

N

CH2CH2CH2CH3

Example: Secondary amines give tertiary amines

+

H2, Ni, ethanol

(93%)


Amine Oxides Undergo a

Cope Elimination Reaction


Amines & Neurotransmitters


Barbiturates

  • Can you draw the enolized form?

  • Is it aromatic?

  • Could it possibly be aromatic?


Mescaline


Tagamet: cimetidine

Histidine receptor antagonist (a precursor to histamine, a vasodilator)

Inhibits gastric secretions & pepsin output


Dopamine, Serotonin, Melatonin


Adrenalin


Cathecols: epinephrine & mdma

http://faculty.washington.edu/chudler/mdma.html

Principal sympathomimetic adrenal hormone

& a controlled substance


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