22.7 Reactions of Amines: A Review and a Preview

1. 22.7Reactions 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 20.3, 20.5, and 20.11) • Hofmann rearrangement (Section 20.17)

4. 22.8Preparation of Aminesby Alkylation of Ammonia

5. Alkylation of Ammonia Desired reaction is: + 2 NH3 + R—X R—NH2 NH4X

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

7. – + 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

8. 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.

9. 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%) + CH3(CH2)6CH2NHCH2(CH2)6CH3 (43%)

10. 22.9The Gabriel Synthesis of Primary Alkylamines

11. 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

12. 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

13. 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

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

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

16. 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 +

17. O – + K N •• •• O Example + C6H5CH2Cl DMF

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

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

20. 22.10Preparation of Amines by Reduction

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

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

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

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

25. 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 H2 (100 atm), Ni CH3CH2CH2CH2CH2NH2 (56%)

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

27. NO2 Cl NH2 Cl Synthesis of Amines via Nitroarenes HNO3 Cl H2SO4 (88-95%) 1. Fe, HCl 2. NaOH (95%)

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

29. O O COH CN(CH3)2 Synthesis of Amines via Amides 1. SOCl2 2. (CH3)2NH (86-89%) 1. LiAlH4 2. H2O CH2N(CH3)2 (88%)

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

31. 22.11Reductive Amination

32. 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

33. 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

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

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

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

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

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