1. Heterocyclic Compounds
Organic Chemistry
4th Edition
Paula Yurkanis Bruice
Chapter 21
More About Amines.
Heterocyclic Compounds
Irene Lee
Case Western Reserve University
Cleveland, OH
©2004, Prentice Hall

2. Amines An amine is a base as well as a nucleophile
Some amines are heterocyclic compounds
(or heterocycles)
Most drugs, vitamins, and many other natural products
are heterocycles
A natural product is a compound synthesized by a plant
or an animal

3. Alkaloids are natural products that contain one or more nitrogen heteroatoms

4. More About Nomenclature of Heterocycles
Cyclic amines
azacylclopropane
aziridine
azacyclobutane
azetidine
3-methylazacyclopentane
3-methylpyrrolidine
2-methylazacyclohexane
2-methylpiperidine
N-ethylazacyclopentane
N-ethylpyrrolidine

5. Heterocycles with oxygen and sulfur heteroatoms
oxacyclopropane
oxirane
ethylene oxide
thiacyclopropane
thiirane
oxacyclobutane
oxetane
oxacyclopentane
tetrahydrofuran
tetrahydropyran
1,4-dioxane

6. The lone-pair electrons on nitrogen allows an amine to
turn “inside out” rapidly at room temperature

7. Amines are the most common organic bases
Saturated heterocycles containing five or more atoms
have physical and chemical properties typical of their
acyclic analogs

8. Reactions of Amines nucleophilic substitution reactions
nucleophilic acyl substitution reactions

9. nucleophilic addition–elimination reactions
conjugate addition reactions

10. Relative Reactivity of Amine
most reactive
least reactive
RCH2F > RCH2OH ~ RCH2OCH3 > RCH2NH2
HF H2O RCH2OH NH3
pKa = 3.2
pKa = 15.7
pKa = 15.5
pKa = 36
The leaving group of a protonated amine cannot
dissociate to form a carbocation or be replaced by a
halide ion

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

12. The hydrogen is removed from the b-carbon bonded to
the most hydrogens
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
oxd
oxd
oxd
a hydroxylamine
a nitroso
compound

17. Cope Elimination Reaction
Amine Oxides Undergo a
Cope Elimination Reaction

18. The Gabriel Synthesis of Primary Amines

19. Other Methods for Synthesizing Amines

21. Reduction of Nitro Compounds

22. Reductive Amination Secondary and tertiary amines can be prepared from
imines and enamines by reducing the imines or enamines

23. Aromatic Five-Membered Heterocycles

24. Pyrrole is an extremely weak base

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

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

30. The relative reactivities of the five-membered-ring
heterocycles in Friedel–Crafts reaction

31. 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
Pyrrole’s acidity is increased due to its conjugated base
being stabilized by resonance

33. indole
benzofuran
benzothiophene

34. Aromatic Six-Membered-Ring Heterocycles

35. The pyridinium ion is a stronger acid than a typical
ammonium ion

36. Pyridine Is a Tertiary Amine

37. Pyridine undergoes electrophilic aromatic substitution at

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

39. Bromination and Oxidation of
Substituted Pyridine

40. Diazotization of Aminopyridine

42. The a-hydrogens of alkyl substituents can be removed by
base to generate nucleophiles

43. Quinoline and isoquinoline are known as benzopyridines

44. Some Biologically Important Heterocycles
Imidazole

47. Porphyrin