1. Dr. Wolf's CHM 201 & 202 22-1 22.6 Reactions of Amines: A Review and a Preview

2. Dr. Wolf's CHM 201 & 202 22-2 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. Dr. Wolf's CHM 201 & 202 22-3 Methods for C—N Bond Formation Nucleophilic substitution by azide ion (N 3 – ) (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  -halo acids (Section 19.16) Nucleophilic acyl substitution (Sections 20.4, 20.6, and 20.12)

4. Dr. Wolf's CHM 201 & 202 22-4 22.7 Preparation of Amines by Alkylation of Ammonia

5. Dr. Wolf's CHM 201 & 202 22-5 Alkylation of Ammonia Desired reaction is: 2 NH 3 + R—X R—NH 2 + NH4XNH4XNH4XNH4Xvia: H3NH3NH3NH3N R X H3NH3NH3NH3N R + X – + + then: H3NH3NH3NH3N + H N H H R + H3NH3NH3NH3N H + + NHH R

6. Dr. Wolf's CHM 201 & 202 22-6 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. NH3NH3NH3NH3 RXRXRXRX RNH2RNH2RNH2RNH2 RXRXRXRX R2NHR2NHR2NHR2NH RXRXRXRX R3NR3NR3NR3N RXRXRXRX R4NR4NR4NR4N+ X–

7. Dr. Wolf's CHM 201 & 202 22-7 Example CH 3 (CH 2 ) 6 CH 2 Br NH 3 CH 3 (CH 2 ) 6 CH 2 NH 2 (45%)+ CH 3 (CH 2 ) 6 CH 2 NHCH 2 (CH 2 ) 6 CH 3 (43%) As octylamine is formed, it competes with ammonia for the remaining 1-bromooctane. Reaction of octylamine with 1-bromooctane gives N,N-dioctylamine.

8. Dr. Wolf's CHM 201 & 202 22-8 22.8 The Gabriel Synthesis of Primary Alkylamines

9. Dr. Wolf's CHM 201 & 202 22-9 gives primary amines without formation of secondary, etc. amines as byproducts uses an S N 2 reaction on an alkyl halide to form the C—N bond the nitrogen-containing nucleophile is N-potassiophthalimide Gabriel Synthesis

10. Dr. Wolf's CHM 201 & 202 22-10 gives primary amines without formation of secondary, etc. amines as byproducts uses an S N 2 reaction on an alkyl halide to form the C—N bond the nitrogen-containing nucleophile is N-potassiophthalimide Gabriel Synthesis OO N – K +

11. Dr. Wolf's CHM 201 & 202 22-11 the pKa of phthalimide is 8.3 N-potassiophthalimide is easily prepared by the reaction of phthalimide with KOH N-PotassiophthalimideOO N – K + O O NHNHNHNH KOH

12. Dr. Wolf's CHM 201 & 202 22-12 N-Potassiophthalimide as a nucleophile O O N – R X +OO N R + X – SN2SN2SN2SN2

13. Dr. Wolf's CHM 201 & 202 22-13 Cleavage of Alkylated Phthalimide OO N R + H2OH2OH2OH2O H2NH2NH2NH2NR + CO 2 H acid or base imide hydrolysis is nucleophilic acyl substitution

14. Dr. Wolf's CHM 201 & 202 22-14 Cleavage of Alkylated Phthalimide hydrazinolysis is an alternative method of releasing the amine from its phthalimide derivative OO N R H2NH2NH2NH2NR +OO NH NH H 2 NNH 2

15. Dr. Wolf's CHM 201 & 202 22-15 ExampleOO N – K + + C 6 H 5 CH 2 Cl DMFOO N CH 2 C 6 H 5 (74%)

16. Dr. Wolf's CHM 201 & 202 22-16 Example + C 6 H 5 CH 2 NH 2 OO N CH 2 C 6 H 5 H 2 NNH 2 (97%)OO NH NH

17. Dr. Wolf's CHM 201 & 202 22-17 22.9 Preparation of Amines by Reduction

18. Dr. Wolf's CHM 201 & 202 22-18 almost any nitrogen-containing compound can be reduced to an amine, including: azides nitriles nitro-substituted benzene derivatives amides Preparation of Amines by Reduction

19. Dr. Wolf's CHM 201 & 202 22-19 S N 2 reaction, followed by reduction, gives a primary alkylamine. Synthesis of Amines via Azides CH 2 CH 2 Br CH 2 CH 2 N 3 NaN 3 (74%) CH 2 CH 2 NH 2 (89%) 1. LiAlH 4 2. H 2 O azides may also be reduced by catalytic hydrogenation

20. Dr. Wolf's CHM 201 & 202 22-20 S N 2 reaction, followed by reduction, gives a primary alkylamine. Synthesis of Amines via Nitriles CH 3 CH 2 CH 2 CH 2 Br NaCN (69%) CH 3 CH 2 CH 2 CH 2 CN CH 3 CH 2 CH 2 CH 2 CH 2 NH 2 (56%) H 2 (100 atm), Ni nitriles may also be reduced by lithium aluminum hydride

21. Dr. Wolf's CHM 201 & 202 22-21 S N 2 reaction, followed by reduction, gives a primary alkylamine. Synthesis of Amines via Nitriles CH 3 CH 2 CH 2 CH 2 Br NaCN (69%) CH 3 CH 2 CH 2 CH 2 CN CH 3 CH 2 CH 2 CH 2 CH 2 NH 2 (56%) H 2 (100 atm), Ni the reduction also works with cyanohydrins

22. Dr. Wolf's CHM 201 & 202 22-22 Synthesis of Amines via Nitroarenes HNO3HNO3HNO3HNO3 (88-95%) Cl Cl NO2NO2NO2NO2 H 2 SO 4 (95%) 1. Fe, HCl 2. NaOH Cl NH2NH2NH2NH2 nitro groups may also be reduced with tin (Sn) + HCl or by catalytic hydrogenation

23. Dr. Wolf's CHM 201 & 202 22-23 Synthesis of Amines via Amides (86-89%) COHO 1. SOCl 2 2. (CH 3 ) 2 NH CN(CH 3 ) 2 O (88%) 1. LiAlH 4 2. H 2 O CH 2 N(CH 3 ) 2 only LiAlH 4 is an appropriate reducing agent for this reaction

24. Dr. Wolf's CHM 201 & 202 22-24 22.10 Reductive Amination

25. Dr. Wolf's CHM 201 & 202 22-25 The aldehyde or ketone equilibrates with the imine faster than hydrogenation occurs. Synthesis of Amines via Reductive Amination O CRR' + NH3NH3NH3NH3 fast NHNHNHNH CRR' + H2OH2OH2OH2O In reductive amination, an aldehyde or ketone is subjected to catalytic hydrogenation in the presence of ammonia or an amine.

26. Dr. Wolf's CHM 201 & 202 22-26 Synthesis of Amines via Reductive Amination O CRR' + NH3NH3NH3NH3 fast NHNHNHNH CRR' + H2OH2OH2OH2O H 2, Ni NH2NH2NH2NH2RR' C H The imine undergoes hydrogenation faster than the aldehyde or ketone. An amine is the product.

27. Dr. Wolf's CHM 201 & 202 22-27 Example: Ammonia gives a primary amine. O + NH3NH3NH3NH3H NH2NH2NH2NH2 H 2, Ni ethanol (80%) via: NHNHNHNH

28. Dr. Wolf's CHM 201 & 202 22-28 Example: Primary amines give secondary amines H 2, Ni ethanol (65%) CH 3 (CH 2 ) 5 CH 2 NH + H2NH2NH2NH2N CH 3 (CH 2 ) 5 CH O via: N

29. Dr. Wolf's CHM 201 & 202 22-29 Example: Secondary amines give tertiary amines H 2, Ni, ethanol (93%) + CH 3 CH 2 CH 2 CH O N H N CH 2 CH 2 CH 2 CH 3

30. Dr. Wolf's CHM 201 & 202 22-30 Example: Secondary amines give tertiary amines CHCH 2 CH 2 CH 3 N + possible intermediates include: N CH CHCH 2 CH 3 CHCH 2 CH 2 CH 3 N HO

31. Dr. Wolf's CHM 201 & 202 22-31 22.11 Reactions of Amines: A Review and a Preview

32. Dr. Wolf's CHM 201 & 202 22-32 Reactions of Amines Reactions of amines almost always involve the nitrogen lone pair. N H X as a base: N C O as a nucleophile:

33. Dr. Wolf's CHM 201 & 202 22-33 Reactions of Amines basicity (Section 22.4) reaction with aldehydes and ketones (Sections 17.10, 17.11) reaction with acyl chlorides (Section 20.4), anhydrides (Section 20.6), and esters (Section 20.12) Reactions already discussed

34. Dr. Wolf's CHM 201 & 202 22-34 22.12 Reactions of Amines with Alkyl Halides

35. Dr. Wolf's CHM 201 & 202 22-35 Reaction with Alkyl Halides Amines act as nucleophiles toward alkyl halides. X + N R H + X N R H + – + N R H +

36. Dr. Wolf's CHM 201 & 202 22-36 Example: excess amine NH2NH2NH2NH2 + ClCH 2 NHCH 2 (85-87%) NaHCO 3 90°C (4 mol) (1 mol)

37. Dr. Wolf's CHM 201 & 202 22-37 Example: excess alkyl halide + 3CH 3 I (99%) methanolheat CH 2 N (CH 3 ) 3 CH 2 NH 2 + I–

38. Dr. Wolf's CHM 201 & 202 22-38 22.13 The Hofmann Elimination

39. Dr. Wolf's CHM 201 & 202 22-39 The Hofmann Elimination a quaternary ammonium hydroxide is the reactant and an alkene is the product is an anti elimination the leaving group is a trialkylamine the regioselectivity is opposite to the Zaitsev rule.

40. Dr. Wolf's CHM 201 & 202 22-40 Quaternary Ammonium Hydroxides Ag 2 O H 2 O, CH 3 OH CH 2 N (CH 3 ) 3 + HO – are prepared by treating quaternary ammmonium halides with moist silver oxide CH 2 N (CH 3 ) 3 I–

41. Dr. Wolf's CHM 201 & 202 22-41 The Hofmann Elimination 160°C CH 2 N (CH 3 ) 3 + HO – on being heated, quaternary ammonium hydroxides undergo elimination CH 2 (69%) + N(CH 3 ) 3 + H2OH2OH2OH2O

42. Dr. Wolf's CHM 201 & 202 22-42 Mechanism H CH2CH2CH2CH2+ N(CH 3 ) 3 –O H OH H N(CH 3 ) 3 CH2CH2CH2CH2

43. Dr. Wolf's CHM 201 & 202 22-43 Regioselectivityheat Elimination occurs in the direction that gives the less-substituted double bond. This is called the Hofmann rule. N(CH 3 ) 3 + HO – CH 3 CHCH 2 CH 3 H2CH2CH2CH2C CHCH 2 CH 3 CH 3 CH CHCH 3 +(95%)(5%)

44. Dr. Wolf's CHM 201 & 202 22-44 Regioselectivity Steric factors seem to control the regioselectivity. The transition state that leads to 1-butene is less crowded than the one leading to cis or trans-2-butene.

45. Dr. Wolf's CHM 201 & 202 22-45 Regioselectivity N(CH 3 ) 3 + HHH H CH 3 CH 2 largest group is between two H atoms C H CHH CH 3 CH 2 major product

46. Dr. Wolf's CHM 201 & 202 22-46 Regioselectivity N(CH 3 ) 3 +H H H CH 3 largest group is between an H atom and a methyl group C H C CH 3 H minor product CH 3

47. Dr. Wolf's CHM 201 & 202 22-47 22.14 Electrophilic Aromatic Substitution in Arylamines

48. Dr. Wolf's CHM 201 & 202 22-48 Nitration of Anililne NH 2 is a very strongly activating group NH 2 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. Dr. Wolf's CHM 201 & 202 22-49 Nitration of Anililne Strategy: decrease the reactivity of aniline by converting the NH 2 group to an amide CH(CH 3 ) 2 NH2NH2NH2NH2 NHCCH 3 OO CH 3 COCCH 3 O (98%) (acetyl chloride may be used instead of acetic anhydride)

50. Dr. Wolf's CHM 201 & 202 22-50 Nitration of Anililne Strategy: nitrate the amide formed in the first step CH(CH 3 ) 2 NHCCH 3 O HNO 3 CH(CH 3 ) 2 NHCCH 3 O NO 2 (94%)

51. Dr. Wolf's CHM 201 & 202 22-51 Nitration of Anililne Strategy: remove the acyl group from the amide by hydrolysis CH(CH 3 ) 2 NHCCH 3 O NO 2 KOH ethanol, heat CH(CH 3 ) 2 NH2NH2NH2NH2 NO 2 (100%)

52. Dr. Wolf's CHM 201 & 202 22-52 occurs readily without necessity of protecting amino group, but difficult to limit it to monohalogenation Halogenation of Arylamines CO 2 H NH2NH2NH2NH2 Br 2 acetic acid (82%) CO 2 H NH2NH2NH2NH2BrBr

53. Dr. Wolf's CHM 201 & 202 22-53 Monohalogenation of Arylamines Cl NHCCH 3 O CH 3 (74%) Cl 2 acetic acid NHCCH 3 O CH 3 Decreasing the reactivity of the arylamine by converting the NH 2 group to an amide allows halogenation to be limited to monosubstitution

54. Dr. Wolf's CHM 201 & 202 22-54 Friedel-Crafts Reactions The amino group of an arylamine must be protected as an amide when carrying out a Friedel-Crafts reaction. NHCCH 3 O CH 3 CH 3 CCl O AlCl 3 (57%) NHCCH 3 O CH 3 CCH 3 O