1. Heterocyclic Compounds
Organic Chemistry
6th Edition
Paula Yurkanis Bruice
Chapter 21
More About Amines
Heterocyclic Compounds

2. Nomenclature of Heterocycles
Cyclic amines (the names in quotes are preferred):
Nitrogen is #1 when numbering the ring

3. Heterocycles with oxygen and sulfur heteroatoms (the names in quotes are preferred):

4. Acid–Base Properties of Amines
Amines are the most common organic bases:

5. Saturated amine heterocycles containing five or more atoms have physical and chemical properties typical of acyclic amines:

6. Amines React as Bases and as Nucleophiles
The lone-pair electron on the nitrogen of an amine causes it to be nucleophilic as well as basic:

7. Reactions of Amines Nucleophilic substitution reactions:
Nucleophilic acyl substitution reactions:

8. Nucleophilic addition–elimination reactions:

9. Conjugate addition reactions:

10. Reactions of Quaternary Ammonium Hydroxides
The Hofmann elimination is an E2 reaction: D
The leaving group of a quaternary ammonium ion has
about the same leaving tendency as a protonated amino
group

11. The hydrogen is removed from the b-carbon bonded to
the most hydrogens:
The least-substituted alkene elimination product is often called the Hofmann product

12. Quaternary ammonium ions, like alkyl fluorides, are
poor leaving groups:

13. Hofmann elimination requires exhaustive methylation of the amine, followed by elimination:
A strong base, such as hydroxide ion, must be used in
the elimination reaction

14. Quaternary ammonium salts are used as phase transfer
catalysts in facilitating the reactions between certain
ionic and organic reactants:

15. Consider the reaction between sodium cyanide and an
alkyl halide:

16. Oxidation of Amines
Mechanism:

17. Tertiary Amine Oxides Undergo a Cope Elimination Reaction
The proton is removed from the b-carbon bonded to the
most hydrogens

18. Synthesis of Amines Because ammonia and amines are good nucleophiles,
they readily undergo SN2 reactions with RX:
It is difficult to control the desired number of alkyl
substituents placed on the nitrogen

19. The Gabriel Synthesis of Primary Amines

20. Other Methods for Synthesizing Amines

21. Reduction of amides with LiAlH4:

22. Aromatic Five-Membered Heterocycles

23. Pyrrole is an extremely weak base:

24. The dipole moment in pyrrolidine (left) is attributed to
the electron-withdrawing property of the nitrogen atom:

26. Pyrrole, furan, and thiophene undergo electrophilic
substitution, preferentially at C-2:

27. Electrophilic aromatic substitution reactions:

28. Structures of the intermediates that can be formed from
the reaction of an electrophile with pyrrole at C-2 and C-3
Three resonance structures: more stable
Two resonance structures: less stable

29. If both positions adjacent to the heteroatom are occupied, electrophilic substitution occurs at C-3:

30. Why? Because of cation stabilization by lone-pair resonance release:

31. The relative reactivities of the five-membered
heterocycles in Friedel–Crafts reaction:

32. The resonance hybrid of pyrrole indicates that there is a
partial positive charge on the nitrogen:
Pyrrole is unstable in strongly acid solution because the
protonated pyrrole polymerizes:

33. Five resonance structures for the anion
Pyrrole is more acidic than pyrrolidine because of stabilization of its conjugated base by resonance
Five resonance structures for the anion
Localized anion

35. Indole, benzofuran, and benzothiophene all contain a five-membered aromatic ring fused to a benzene ring:

36. Aromatic Six-Membered-Ring Heterocycles

37. The pyridinium ion is a stronger acid than a typical ammonium ion
Pyridine reacts like a tertiary amine:

38. Pyridine Is Aromatic
The nitrogen lone pair is not released into the aromatic system because it is perpendicular to the  system.
The nitrogen withdraws electrons by resonance, resulting in an electron-deficient ring system.

39. Pyridine undergoes electrophilic aromatic substitution at

41. The pyridine nitrogen is a meta director:

42. Pyridine is reactive toward nucleophilic aromatic substitution because of the presence of the electronegative nitrogen:

43. Pyridine undergoes nucleophilic aromatic substitution at
C-2 and C-4:

44. If the leaving groups at C-2 and C-4 are different, the
incoming nucleophile will preferentially substitute for
the weaker base:

45. Bromination and Oxidation of
Substituted Pyridine

46. Diazotization of Aminopyridine

47. The a-hydrogens of alkyl substituents can be removed by base to generate anionic nucleophiles:
Pyridine a-hydrogen acidity is similar to that of ketone a-hydrogens

48. Reactions of pyridine-based anionic nucleophiles:

49. Quinoline and isoquinoline are ring-fused pyridine derivatives:

50. Some Biologically Important Heterocycles
Imidazole

53. Purine and Pyrimidine

54. Porphyrin