22.6 Reactions of Amines: A Review and a Preview

1. 22.6Reactions of Amines:A Review and a Preview

2. Preparation of Amines • Two questions to answer: • 1) How is the C—N bond to be formed? • 2) How do we obtain the correct oxidation state of nitrogen (and carbon)?

3. Methods for C—N Bond Formation • Nucleophilic substitution by azide ion (N3–) (Section 8.1, 8.13) • Nitration of arenes (Section 12.3) • Nucleophilic ring opening of epoxides by ammonia (Section 16.12) • Nucleophilic addition of amines to aldehydes and ketones (Sections 17.10, 17.11) • Nucleophilic substitution by ammonia on a-halo acids (Section 19.16) • Nucleophilic acyl substitution (Sections 20.4, 20.6, and 20.12)

4. 22.7Preparation of Aminesby Alkylation of Ammonia

5. via: + – •• •• + + R R X X H3N H3N •• •• •• •• •• •• H H then: + + + R H + N H3N H R H3N N •• •• H H Alkylation of Ammonia Desired reaction is: + 2 NH3 + R—X R—NH2 NH4X

6. – + X R4N Alkylation of Ammonia But the method doesn't work well in practice.Usually gives a mixture of primary, secondary,and tertiary amines, plus the quaternary salt. RX RX NH3 RNH2 R2NH RX RX R3N

7. + CH3(CH2)6CH2NHCH2(CH2)6CH3 (43%) Example NH3 CH3(CH2)6CH2Br CH3(CH2)6CH2NH2 • As octylamine is formed, it competes with ammonia for the remaining 1-bromooctane. Reaction of octylamine with 1-bromooctane gives N,N-dioctylamine. (45%)

8. 22.8The Gabriel Synthesis of Primary Alkylamines

9. Gabriel Synthesis • gives primary amines without formation ofsecondary, etc. amines as byproducts • uses an SN2 reaction on an alkyl halide to formthe C—N bond • the nitrogen-containing nucleophileis N-potassiophthalimide

10. O – + K N •• •• O Gabriel Synthesis • gives primary amines without formation ofsecondary, etc. amines as byproducts • uses an SN2 reaction on an alkyl halide to formthe C—N bond • the nitrogen-containing nucleophileis N-potassiophthalimide

11. O – + K N NH •• •• O N-Potassiophthalimide • the pKa of phthalimide is 8.3 • N-potassiophthalimide is easily prepared bythe reaction of phthalimide with KOH O KOH •• O

12. O •• R X N R •• •• •• O – •• + X •• •• •• N-Potassiophthalimide as a nucleophile O SN2 – + N •• •• O

13. O + H2O N R •• O CO2H H2N R CO2H Cleavage of Alkylated Phthalimide • imide hydrolysis is nucleophilic acyl substitution acid or base +

14. O O H2NNH2 NH N R •• NH O O H2N R Cleavage of Alkylated Phthalimide • hydrazinolysis is an alternative method of releasing the amine from its phthalimide derivative +

15. O – + K N •• •• O O (74%) N CH2C6H5 •• O Example + C6H5CH2Cl DMF

16. O NH NH O O N CH2C6H5 •• O Example (97%) + C6H5CH2NH2 H2NNH2

17. 22.9Preparation of Amines by Reduction

18. Preparation of Amines by Reduction • almost any nitrogen-containing compound canbe reduced to an amine, including: • azidesnitrilesnitro-substituted benzene derivatives amides

19. CH2CH2Br CH2CH2N3 1. LiAlH4 2. H2O CH2CH2NH2 (89%) Synthesis of Amines via Azides • SN2 reaction, followed by reduction, gives a primary alkylamine. NaN3 (74%) azides may also bereduced by catalytichydrogenation

20. H2 (100 atm), Ni CH3CH2CH2CH2CH2NH2 (56%) Synthesis of Amines via Nitriles • SN2 reaction, followed by reduction, gives a primary alkylamine. NaCN CH3CH2CH2CH2Br CH3CH2CH2CH2CN (69%) nitriles may also bereduced by lithiumaluminum hydride

21. H2 (100 atm), Ni CH3CH2CH2CH2CH2NH2 (56%) Synthesis of Amines via Nitriles • SN2 reaction, followed by reduction, gives a primary alkylamine. NaCN CH3CH2CH2CH2Br CH3CH2CH2CH2CN (69%) the reduction alsoworks with cyanohydrins

22. NO2 Cl 1. Fe, HCl 2. NaOH NH2 Cl (95%) Synthesis of Amines via Nitroarenes HNO3 Cl H2SO4 nitro groups may alsobe reduced with tin (Sn)+ HCl or by catalytichydrogenation (88-95%)

23. O O COH CN(CH3)2 1. LiAlH4 2. H2O CH2N(CH3)2 (88%) Synthesis of Amines via Amides 1. SOCl2 2. (CH3)2NH (86-89%) only LiAlH4 is anappropriate reducingagent for this reaction

24. 22.10Reductive Amination

25. 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

26. R R O NH C C R' R' R H2, Ni 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

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

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

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

30. + N N CHCH2CH2CH3 HO CHCH2CH2CH3 N CH CHCH2CH3 Example: Secondary amines give tertiary amines possible intermediates include:

31. 22.11Reactions of Amines:A Review and a Preview

32. N as a base: H X •• as a nucleophile: N C O •• Reactions of Amines Reactions of amines almost always involve thenitrogen lone pair.

33. Reactions of Amines Reactions already discussed • basicity (Section 22.4) • reaction with aldehydes and ketones (Sections17.10, 17.11) • reaction with acyl chlorides (Section 20.4),anhydrides (Section 20.6), and esters (Section 20.12)

34. 22.12Reactions of Amines with Alkyl Halides

35. + •• + N N R X R •• •• •• H H + + N R H •• Reaction with Alkyl Halides Amines act as nucleophiles toward alkyl halides. – •• + X •• •• ••

36. NH2 ClCH2 NHCH2 Example: excess amine + (4 mol) (1 mol) NaHCO3 90°C (85-87%)

37. CH2NH2 – CH2N (CH3)3 I Example: excess alkyl halide + 3CH3I methanol heat + (99%)

38. 22.13The Hofmann Elimination

39. The Hofmann Elimination • a quaternary ammonium hydroxide is the reactantand an alkene is the product • is an anti elimination • the leaving group is a trialkylamine • the regioselectivity is opposite to the Zaitsev rule.

40. – CH2N (CH3)3 I Ag2O H2O, CH3OH + – CH2N (CH3)3 HO Quaternary Ammonium Hydroxides are prepared by treating quaternary ammmoniumhalides with moist silver oxide

41. + + H2O CH2 N(CH3)3 (69%) CH2N (CH3)3 The Hofmann Elimination on being heated, quaternary ammonium hydroxides undergo elimination 160°C + – HO

42. – •• •• H H O O •• •• •• H CH2 CH2 N(CH3)3 + N(CH3)3 •• Mechanism H

43. (95%) H2C CHCH2CH3 CH3CHCH2CH3 heat + N(CH3)3 + – CH3CH CHCH3 (5%) HO Regioselectivity Elimination occurs in the direction that gives the less-substituted double bond. This is called the Hofmann rule.

44. Regioselectivity Steric factors seem to control the regioselectivity.The transition state that leads to 1-butene isless crowded than the one leading to cisor trans-2-butene.

45. H H H CH3CH2 H C C H H H CH3CH2 + N(CH3)3 major product Regioselectivity largest group is between two H atoms

46. H CH3 C C H CH3 + N(CH3)3 minor product Regioselectivity H CH3 H CH3 H largest group is between anH atom and a methyl group

47. 22.14Electrophilic Aromatic Substitutionin Arylamines

48. Nitration of Anililne • NH2 is a very strongly activating group • NH2 not only activates the ring toward electrophilic aromatic substitution, it also makes it more easily oxidized • attemped nitration of aniline fails because nitric acid oxidizes aniline to a black tar

49. O NH2 NHCCH3 O O CH3COCCH3 (98%) CH(CH3)2 CH(CH3)2 (acetyl chloride may be used instead of acetic anhydride) Nitration of Anililne • Strategy: decrease the reactivity of aniline by converting the NH2 group to an amide

50. O O NHCCH3 NHCCH3 NO2 HNO3 CH(CH3)2 CH(CH3)2 (94%) Nitration of Anililne • Strategy: nitrate the amide formed in the first step