Measures of Basicity in Amines: Kb, pKb, Ka, and pKa

1. Amines Chemical / Biological / Neurological Activity

2. 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

3. + – •• •• 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

4. + 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

5. Relationships between acidity and basicity constants Ka Kb = 10-14 pKa + pKb = 14

6. 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?

7. 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….

8. 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?

9. “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?

10. Acid -Base Reactions

11. Acid Base Reactions

12. Basicity of Amines in Aqueous Solution • 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.

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

14. 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 Notice that the difference separating a primary,secondary, and tertiary amine is only 0.3 pK units.

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.

16. 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

17. •• •• 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. + + +

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 3.8 x 10-10 6 x 10-14 ~10-19 Kb

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.

20. X 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

21. – •• •• 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. +

22. Effect is Cumulative • Aniline is 3800 times more basic thanp-nitroaniline. • Aniline is ~1,000,000,000 times more basic than 2,4-dinitroaniline.

23. •• 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)

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

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

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

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

31. Alkaloids: Naturally Occuring Bases Nitrogen Heterocycles

32. Preparation and Reactions of Amines

33. The Gabriel Synthesis of Primary Amines

34. Reductive Amination

35. 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

36. 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

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

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

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

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

42. Amine Oxides Undergo a Cope Elimination Reaction

43. Amines & Neurotransmitters

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

45. Mescaline

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

47. Dopamine, Serotonin, Melatonin

48. Adrenalin

49. Cathecols: epinephrine & mdma http://faculty.washington.edu/chudler/mdma.html Principal sympathomimetic adrenal hormone & a controlled substance