Amines Reactions Overview: Basicity, Nucleophiles & Regioselectivity

1. 22.12Reactions of Amines:A Review and a Preview

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

3. Reactions of Amines Reactions already discussed • basicity (Section 22.5) • reaction with aldehydes and ketones (Sections17.10, 17.11) • reaction with acyl chlorides (Section 20.3),anhydrides (Section 20.5), and esters (Section 20.11)

4. 22.13Reactions of Amines with Alkyl Halides

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

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

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

8. 22.14The Hofmann Elimination

9. 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.

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

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

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

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

14. 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.

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

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

17. 22.15Electrophilic Aromatic Substitutionin Arylamines

18. 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

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

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

21. O NHCCH3 NH2 NO2 NO2 CH(CH3)2 CH(CH3)2 Nitration of Anililne • Strategy: remove the acyl group from the amide by hydrolysis KOH ethanol,heat (100%)

22. NH2 NH2 Br Br Br2 acetic acid CO2H CO2H Halogenation of Arylamines • occurs readily without necessity of protecting amino group, but difficult to limit it to monohalogenation (82%)

23. O O NHCCH3 NHCCH3 CH3 CH3 Cl2 acetic acid Cl Monohalogenation of Arylamines • Decreasing the reactivity of the arylamine by converting the NH2 group to an amide allows halogenation to be limited to monosubstitution (74%)

24. O NHCCH3 O CH2CH3 CH3CCl AlCl3 O CCH3 Friedel-Crafts Reactions • The amino group of an arylamine must be protected as an amide when carrying out a Friedel-Crafts reaction. O NHCCH3 CH3 (57%)