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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
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 k b and pk b

+

••

••

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


K a and pk a of conjugate acid

+

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
Relationships between acidity and basicity constants

Ka Kb = 10-14

pKa + pKb = 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 of(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 acid of cocaine physical properties
“Regular” Cocaine of 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?




Basicity of amines in aqueous solution
Basicity of Amines in Aqueous Solution of

  • Amine Conj. Acid pKa

  • NH3 NH4+ 9.3

  • CH3CH2NH2 CH3CH2NH3+ 10.8

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 of

  • 1. Alkylamines are slightly stronger bases than ammonia.

  • 2. Alkylamines differ very little in basicity.


Basicity of amines in aqueous solution1
Basicity of Amines in Aqueous Solution of

  • Amine Conj. Acid pKa

  • NH3 NH4+ 9.3

  • CH3CH2NH2 CH3CH2NH3+ 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 basicity1
Effect of Structure on Basicity of

  • 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 solution2
Basicity of Amines in Aqueous Solution of

  • 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


Decreased basicity of arylamines

•• of

••

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 arylamines1
Decreased basicity of arylamines of

  • 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
Effect of Substituents on Basicity of Arylamines of

  • 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 of

NH2

X

NH3+

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


P nitroaniline

of

••

••

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
Effect is Cumulative of

  • Aniline is 3800 times more basic thanp-nitroaniline.

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


Heterocyclic amines

•• of

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)


Heterocyclic amines1

N of

H

••

N

••

N

••

Heterocyclic Amines

is more basic than

imidazole

pyridine

Kb = 1 x 10-7

Kb = 1.4 x 10-9


Imidazole

N of

H

••

N

••

+

H

H

N

H

N

••

N

N

••

H

Imidazole

  • Which nitrogen is protonated in imidazole?

H+

H+

+


Imidazole1

N of

H

••

N

••

+

H

N

H

••

N

Imidazole

  • Which nitrogen is protonated in imidazole?

H+


Imidazole2

N of

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 of

Nitrogen Heterocycles





Synthesis of amines via reductive amination

R of

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


Synthesis of amines via reductive amination1

R of

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


Example ammonia gives a primary amine

H of

O

NH2

NH

Example: Ammonia gives a primary amine.

H2, Ni

+

NH3

ethanol

(80%)

via:


Example primary amines give secondary amines

O of

+

CH3(CH2)5CH

H2N

CH3(CH2)5CH2NH

Example: Primary amines give secondary amines

H2, Ni

ethanol

(65%)


Example primary amines give secondary amines1

O of

+

CH3(CH2)5CH

H2N

CH3(CH2)5CH2NH

CH3(CH2)5CH

N

Example: Primary amines give secondary amines

H2, Ni

ethanol

(65%)

via:


Example secondary amines give tertiary amines

O of

CH3CH2CH2CH

N

H

N

CH2CH2CH2CH3

Example: Secondary amines give tertiary amines

+

H2, Ni, ethanol

(93%)


Amine Oxides Undergo a of

Cope Elimination Reaction



Barbiturates of

  • Can you draw the enolized form?

  • Is it aromatic?

  • Could it possibly be aromatic?



Tagamet: cimetidine of

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

Inhibits gastric secretions & pepsin output




Cathecols: epinephrine & mdma of

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

Principal sympathomimetic adrenal hormone

& a controlled substance


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