1. Amines Biological/Neurological Activity
Chem 227
Spring 2003

2. Measures of Amine Basicity3

3. 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 6

4. Basicity Constant (Kb) and pKb
Kb is the equilibrium constant for the reaction:
R3N + H H OH •• –
• • OH ••
R3N
• • + +
[R3NH+][HO–]
Kb =
[R3N]
and
pKb =
- log Kb 2

5. Ka and pKa of Conjugate Acid
Ka is the equilibrium constant for the dissociation of the conjugate acid of the amine:
R3N
• • + H H+
[R3N][H+]
Ka =
[R3NH+]
and
pKa =
- log Ka 3

6. Relationships between acidity and basicity constants
Ka Kb =
pKa + pKb = 14 3

7. Extract of leaves of Erythroxylon coca
Historical uses: in Coca Cola, as a psycho-therapeutic and as an opthalmic topical anesthetic.
Currently a controlled substance under U.S. Federal Regulations: Title 21 secs & (1987).
Commonly chewed by indigenous tribes in the Andes.
Merck Index, #2450, 11th ed.: Caution: May be habit forming.

8. Acid -Base Chemistry (Physical Properties)
m.p. 98 oC
(very volatile > 90 oC)
Solubility: Water: 1.67 x 10-3 g/mL CHCl3: 1.43 g/mL Ether: 0.29 g/mL

9. “Regular” Cocaine (Physical Properties)
m.p. >195 oC
Solubility:
Water: 2.5 g/mL
CHCl3: 0.08 g/mL
Ether: insoluble

10. Acid -Base Reactions

11. Acid Base Reactions

12. Basicity of Amines in Aqueous Solution
Amine Conj. Acid pKa
NH3 NH4+ 9.3
CH3CH2NH2 CH3CH2NH
CH3CH2NH3+ is a weaker acid than NH4+; therefore, CH3CH2NH2 is a stronger base than NH3. 6

13. Effect of Structure on Basicity
1. Alkylamines are slightly stronger bases than ammonia.
2. Alkylamines differ very little in basicity. 5

14. Basicity of Amines in Aqueous Solution
Amine Conj. Acid pKa
NH3 NH4+ 9.3
CH3CH2NH2 CH3CH2NH
(CH3CH2)2NH (CH3CH2)2NH
(CH3CH2)3N (CH3CH2)3NH+ 10.8
Notice that the difference separating a primary, secondary, and tertiary amine is only 0.3 pK units. 6

15. 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. 5

16. Basicity of Amines in Aqueous Solution
Amine Conj. Acid pKa
NH3 NH4+ 9.3
CH3CH2NH2 CH3CH2NH
(CH3CH2)2NH (CH3CH2)2NH
(CH3CH2)3N (CH3CH2)3NH+ 10.8
C6H5NH2 C6H5NH3+ 4.6 6

17. Decreased basicity of arylamines
NH2 •• H OH •• +
Aniline (reactant) is stabilized by conjugation of nitrogen lone pair with ring p system.
This stabilization is lost on protonation.
NH3 + –
• • OH •• + 2

18. 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 Kb
3.8 x 10-10
6 x 10-14
~10-19 2

19. 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. 5

20. Basicity of ArylaminesX
NH2 X
NH3+
X pKb pKa H CH CF
O2N 7

21. p-Nitroaniline
NH2 O N – ••
• • + O N – ••
• •
NH2 + +
Lone pair on amine nitrogen is conjugated with p-nitro group—more delocalized than in aniline itself. Delocalization lost on protonation. 2

22. 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. 2

23. (resembles an arylamine in basicity)
Heterocyclic Amines N •• N H ••
is more basic than
piperidine
pyridine
Kb = 1.6 x 10-3
Kb = 1.4 x 10-9
(an alkylamine)
(resembles an arylamine in basicity) 9

24. Heterocyclic Amines N N H is more basic than imidazole pyridine•• N H
• •
is more basic than
imidazole
pyridine
Kb = 1 x 10-7
Kb = 1.4 x 10-9 9

25. Imidazole Which nitrogen is protonated in imidazole? N H H+ H+ N H N H
• • H+ H+ N H
• • N H
• • + + 11

26. Imidazole Which nitrogen is protonated in imidazole? N H H+ N H + • •11

27. Imidazole Protonation in the direction shown gives a stabilized ion. N
• • H+ N H
• • + + N H
• • 11

29. Reductive Amination 3

30. Synthesis of Amines via Reductive Amination
In reductive amination, an aldehyde or ketone is subjected to catalytic hydrogenation in the presence of ammonia or an amine. O C R R'
fast NH C R R' +
NH3 +
H2O
The aldehyde or ketone equilibrates with the imine faster than hydrogenation occurs. 12

31. Synthesis of Amines via Reductive Amination
The imine undergoes hydrogenation faster than the aldehyde or ketone. An amine is the product. O C R R'
fast NH C R R' +
NH3 +
H2O
NH2 R R' C H
H2, Ni 12

32. Example: Ammonia gives a primary amine.
H2, Ni O H
NH2 +
NH3
ethanol
(80%) NH
via: 18

33. Example: Primary amines give secondary amines
CH3(CH2)5CH O +
H2N
H2, Ni
ethanol
CH3(CH2)5CH2NH
(65%) 18

34. Example: Primary amines give secondary amines
CH3(CH2)5CH O +
H2N
H2, Ni
ethanol
CH3(CH2)5CH2NH
(65%) N
CH3(CH2)5CH
via: 18

35. Example: Secondary amines give tertiary aminesH
CH3CH2CH2CH O +
H2, Ni, ethanol N
CH2CH2CH2CH3
(93%) 18

37. Amines & Neurotransmitters

38. Barbiturates
Can you draw the enolized form?
Is it aromatic?
Could it possibly be aromatic?

39. Mescaline

40. Inhibits gastric secretions & pepsin output
Tagamet: cimetidine
Histidine receptor antagonist (a precursor to histamine, a vasodilator)
Inhibits gastric secretions & pepsin output

41. Dopamine, Serotonin, Melatonin

42. Adrenalin

43. Cathecols: epinephrine & mdma
Principal sympathomimetic adrenal hormone
& a controlled substance