1. Chapter 18 Amines and Heterocycles

2. Amines and Heterocycles
Amines are organic derivatives of ammonia
Amines contain a nitrogen atom with a lone pair of electrons
Amines are basic and nucleophilic
Amines occur widely in both plants and animals

3. 18.1 Naming Amines
Amines can be either aklyl-substituted (alkyamines) or aryl-substituted (arylamines)
Amines are classified depending on the number of organic substituents attached to nitrogen:
Primary (RNH2)
One organic substituent such as methylamine (CH3NH2)
Secondary (R2NH)
Two organic substituents such as dimethylamine [(CH3)2NH]
Tertiary (R3N)
Three organic substituents such as trimethylamine [(CH3)3N]

4. Naming Amines Quaternary ammonium salts
Nitrogen containing compounds with four groups attached to the nitrogen atom
Compound carry a formal positive charge

5. Naming Amines
Primary amines are named in the IUPAC system in several ways
For simple amines the
suffix –amine is added
to the name of the alkyl
substituent
The suffix –amine can by
used in place of the final
–e in the name of the
parent compound

6. Naming Amines
Complex amines with more than one functional group are named by considering the –NH2 as an amino substituent on the parent molecule

7. Naming Amines
Symmetrical secondary and tertiary amines are named by adding the prefix di- or tri- to the alkyl group

8. Naming Amines
Unsymmetrically substituted secondary and tertiary amines are named as N-substituted primary amines
Largest alkyl group is chosen as the parent name
Other alkyl groups are considered N-substituents on the parent
N because they are attached to nitrogen

9. Naming Amines Heterocyclic amines
Compounds in which the nitrogen atom occurs as part of a ring
Each different heterocyclic ring system has its own parent name
The heterocyclic nitrogen atom is always numbered as position 1

10. 18.2 Properties of Amines
Nitrogen atom in alkylamines is sp3-hybridized
Three substituents occupy the three corners of a tetrahedron and the lone pair of electrons occupies the fourth corner
Bond angles are close to 109°

11. Properties of Amines
Nitrogen with three different substituents is chiral
Chiral amines cannot be resolved because the two enantiomeric forms rapidly interconvert by a pyramidal inversion
Inversion occurs by momentary rehybridization of nitrogen atom to planar, sp2 geometry, to give planar intermediate
Rehybridization of planar intermediate to tetrahedral, sp3 geometry
Barrier to inversion is about 25 kJ/mol

12. Properties of Amines
Alkylamines are starting materials for insecticides and pharmaceuticals
Labetalol is a b-blocker used for the treatment of high blood pressure
Prepared by SN2 reaction of an epoxide with a primary amine

13. Properties of Amines
Amines with fewer than five carbons are generally water-soluble
Amines form hydrogen bonds and are highly associated
H-bonding results in higher boiling points than alkanes of similar molecular weights
Amines possess characteristic odors

14. 18.3 Basicity of Amines
Chemistry of amines dominated by the lone pair of electrons on nitrogen
Lone pair makes amines both basic and nucleophilic

15. Basicity of Amines
Amines are much stronger bases than alcohols and ethers
Base strength measured by basicity constant, Kb

16. Basicity of Amines Kb values are not often used
Basicity of the amine is commonly measured by determining the acidity of its conjugate acid

17. Basicity of Amines Weaker base: Smaller pKa for ammonium ion
Stronger base: Larger pKa for ammonium ion

18. Basicity of Amines Amides (RCONH2) are nonbasic
Amides do not undergo substantial protonation when treated with acids
Amides are poor nucleophiles
Nitrogen lone-pair electrons are stabilized through orbital overlap with the carbonyl group

19. Basicity of Amines Primary and secondary amines are very weak acids
N-H proton can be removed by a sufficiently strong base
Diisopropylamine (pKa ≈ 40) reacts with butyllithium to yield lithium diisopropylamide (LDA)

20. 18.4 Basicity of Arylamines
Aryl amines are generally less basic than alkylamines
Nitrogen lone-pair electrons are delocalized by interaction with the aromatic ring p electron system and less available for bonding to H+

21. Basicity of Arylamines
Arylamines have a larger positive DG° for protonation and are therefore less basic than alkylamines, primarily because of resonance stabilization of the ground state
Nitrogen lone-pair electron density is delocalized in the amine but the charge is localized in the corresponding ammonium ion

22. Basicity of Arylamines
Electron-donating substituents which increase the reactivity for an aromatic ring toward electrophilic substitution also increase the basicity of the aryl amine
Electron-withdrawing substituents which decrease ring reactivity toward electrophilic substitution also decrease arylamine basicity

23. 18.5 Biological Amines and the Henderson-Hasselbalch Equation
Amines exist essentially 100% in their protonated conjugate acid forms at physiological pH of 7.3
Use Henderson-Hasselbalch equation to determine relative concentrations of amines and their conjugate acids

24. Biological Amines and the Henderson-Hasselbalch Equation
For a M solution of methylamine at pH = 7.3
pKa of methylammonium ion = 10.64

25. Biological Amines and the Henderson-Hasselbalch Equation
Cellular amines are written in their protonated forms
Amino acids shown in their ammonium carboxylate form to reflect their structures at physiological pH

26. 18.6 Synthesis of Amines
Reduction of Nitriles, Amides and Nitro Compounds
Nitriles and amides are reduced by LiAlH4 into amines
SN2 displacement with CN-
followed by LiAlH4 reduction
of the nitrile converts a
primary alkyl halide into a
primary alkylamine having
one more carbon
Amide reduction with LiAlH4
converts carboxylic acids and
their derivatives into amines
with the same number of
carbon atoms

27. Synthesis of Amines
Aryamines are usually prepared by nitration of an aromatic starting material

28. Synthesis of Amines SN2 Reaction of Alkyl Halides
Ammonia and other amines are good nucleophiles in SN2 reactions
Aklylamines are synthesized most simply by SN2 alkylation of ammonia or an alkylamine with an alkyl halide

29. Synthesis of Amines
Alkylations of ammonia and alkylamines often yield mixtures of products

30. Synthesis of Amines Reductive Amination of Aldehydes and Ketones
Amines can be synthesized in a single step from aldehydes or ketones with ammonia in the presence of a reducing agent
Synthesis called a reductive amination

31. Synthesis of Amines Mechanism of reductive amination
Imine intermediate is
formed by nucleophilic
addition reaction
C=N bond of imine
is then reduced

32. Synthesis of Amines
Ammonia, primary amines, and secondary amines can all be used in reductive amination yielding primary, secondary, and tertiary amines, respectively

33. Synthesis of Amines Reductive aminations occur in biological pathways
Biosynthesis of amino acid proline
Glutamate 5-semialdehyde undergoes internal imine formation to give 1-pyrrolinium-5-carboxylate
1-pyrrolinium-5-carboxylate is reduced by nucleophilic addition of hydride ion by NADH

34. Worked Example 18.1 Using a Reductive Amination Reaction
How might you prepare N-methyl-2-phenylethylamine using a reductive amination reaction?

35. Worked Example 18.1 Using a Reductive Amination Reaction
Strategy
Look at the target molecule, and identify the groups attached to nitrogen
One of the groups must be derived from the aldehyde or ketone component and the other must be derived from the amine component
In the case of N-methyl-2-phenylethylamine there are two combinations that can lead to the product:
Phenylacetaldehyde plus methylamine
Formaldehyde plus 2-phenylethylamine
In general, it’s usually better to choose the combination with the simple amine component – methylamine in this case – and to use an excess of that amine as reactant

36. Worked Example 18.1 Using a Reductive Amination Reaction
Solution

37. 18.7 Reactions of Amines Alkylation and Acylation
Primary and secondary (not tertiary) amines can be acylated by reaction with acid chlorides or acid anhydrides to yield amides

38. Reactions of Amines Hofmann Elimation
Amines can be converted into alkenes by an elimination reaction
NH2- is a poor leaving group and must be converted into a better leaving group
Hofmann elimination
Amine is methylated with excess iodomethane to produce a quaternary ammonium salt
Quaternary ammonium salt undergoes elimination upon heating with silver oxide

39. Reactions of Amines
Silver oxide exchanges hydroxide ion for iodide ion in the quaternary salt
Elimination is E2
Major product is the less highly substituted alkene
Base abstracts hydrogen from least hindered position due to the sterically bulky trialkylamine leaving group

40. Reactions of Amines
Biological eliminations analogous to the Hofmann elimination occur frequently
In the biosynthesis of nucleic acids adenylosuccinate undergoes elimination of a positively charged nitrogen to give fumarate plus adenosine monophosphate

41. Reactions of Amines Electrophilic Aromatic Substitution
Amino substituents are strongly activating, ortho- and para-directing groups in electrophilic aromatic substitution
Often give polysubstituted products

42. Reactions of Amines
Amido- substituted (-NHCOR) benzenes are less strongly activated because the nitrogen lone-pair electrons are delocalized by neighboring carbonyl group

43. Reactions of Amines
Sulfa drugs are prepared by chlorosulfonation of acetanilide
Reaction of p-(N-acetylamino)benzenesulfonyl chloride with ammonia gives a sulfonamide
Amide can be hydrolyzed in presence of sulfonamide group

44. 18.8 Heterocyclic Amines Pyrrole and Imidazole
Heterocyclic amines are common in biological systems

45. Heterocyclic Amines
Most heterocycles have the same chemistry as their open-chain counterparts
Many unsaturated ring heterocycles exhibit unique chemistry
Pyrrole is an aromatic heterocycle prepared by reacting furan with ammonia over alumina

46. Heterocyclic Amines
Each carbon of pyrrole contributes one p electron and the sp2-hybridized nitrogen contributes two from its lone pair

47. Heterocyclic Amines
Nitrogen atom in pyrrole is less electron-rich, less basic, and less nucleophilic than nitrogen atom in an aliphatic amine
Carbon atoms or pyrrole are more electron-rich and more nucleophilic than typical double-bond carbons

48. Heterocyclic Amines
Chemistry of pyrrole is similar to activated benzene rings
Heterocycles are more reactive toward electrophiles than benzene rings and often require low temperatures
Halogenation, nitration, sulfonation, and Friedel-Crafts acylation can all be accomplished with aromatic heterocycles

49. Heterocyclic Amines
Electrophilic substitution normally occurs at C2 next to the nitrogen atom
Substitution at C2 gives more stable intermediate with three resonance forms

50. Heterocyclic Amines
Imidazole (a constituent of histidine) and thiazole (on which the structure of thiamin is based) are common five-membered heterocyclic amines
Only the lone-pair electrons of nitrogen atoms that are not participating in the aromatic p system are basic

51. Heterocyclic Amines Pyridine and Pyrimidine
The five carbon atoms and the sp2-hybridized nitrogen atom of pyridine contribute one p electron to the aromatic sextet
The lone-pair electrons of nitrogen atom occupy an sp2 orbital in the plane of the ring
Pyridine is less basic that alkylamines because the lone-pair electrons are in an sp2 orbital and are held more closely to the positively charged nucleus and thus less available for bonding

52. Heterocyclic Amines
Pyridine does not readily undergo electrophilic aromatic substitution reactions
Substitutions occur only slowly and usually at the C-3 of the ring
Low reactivity of pyridine due to two factors:
Electrophile complexes in and acid-base reaction with the ring nitrogen placing a positive charge on the ring and deactivating it toward electrophilic aromatic substitution
Electron density of the ring is decreased by the inductively withdrawing electronegative nitrogen atom
Pyridine has substantial dipole moment (m = 2.26 D)

53. Heterocyclic Amines Pyrimidine is a constituent of nucleic acids
Pyrimidine is substantially less basic than pyridine due to the inductive effect of the second nitrogen atom

54. 18.9 Fused-Ring Heterocycles
Quinoline, isoquinoline, indole, and purine are common fuse-ring heterocycles
Quinoline alkaloid quinine is an antimalarial drug
The amino acid tryptophan is an indole derivative
The purine adenine is a constituent of nucleic acids

55. Fused-Ring Heterocycles
Quinoline and isoquinoline both undergo electrophilic substitutions less easily than benzene
Reaction occurs on the benzene ring

56. Fused-Ring Heterocycles
Indole has a nonbasic-pyrrole-like nitrogen and undergoes electrophilic substitution more easily than benzene
Substitution occurs at C3 of electron-rich pyrrole ring

57. Fused-Ring Heterocycles
Purine has three basic, pyridine-like nitrogens with lone-pair electrons in sp2 orbitals in the plane of the ring
The remaining purine nitrogen is non-basic and pyrrole-like with its lone-pair electrons part of the aromatic p system

58. 18.10 Spectroscopy of Amines
Infrared Spectroscopy
Primary amines show a pair of bands at about 3350 and 3450 cm-1
Secondary amines show a single band at 3350 cm-1

59. Spectroscopy of Amines
Nuclear Magnetic Resonance Spectroscopy
Amine N-H absorptions can appear over a wide range and are best identified by adding a small amount of D2O to the sample tube
N-H is exchanged for N-D and the N-H signal disappears from the 1H NMR spectrum

60. Spectroscopy of Amines
Hydrogens on the carbon next to nitrogen are deshielded because of the electron-withdrawing effect of the nitrogen
Absorb at lower field than alkane hydrogens
N-methyl groups are distinctive and absorb as a sharp three-hydrogen singlet at 2.2 to 2.6 d

61. Spectroscopy of Amines
Carbons next to amine nitrogens are slightly deshielded in the 13C NMR spectrum and absorb about 20 ppm downfield from where they would otherwise absorb in an alkane of similar structure

62. Spectroscopy of Amines
Mass Spectrometry
Nitrogen rule of mass spectrometry
A compound with an odd number of nitrogen atoms has an odd-numbered molecular weight
Nitrogen is trivalent thus requiring an odd number of hydrogen atoms
Alkylamines undergo characteristic a cleavage
C-C bond nearest the nitrogen atom is broken

63. Spectroscopy of Amines
Mass spectrum of N-ethylpropylamine has peaks at m/z = 58 and m/z = 72 corresponding to the two possible modes of a cleavage