22.12 Reactions of Amines: A Review and a Preview

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

Reactions of Amines basicity (Section 22.5) reaction with aldehydes and ketones (Sections 17.10, 17.11) reaction with acyl chlorides (Section 20.3), anhydrides (Section 20.5), and esters (Section 20.11) Reactions already discussed

22.13 Reactions of Amines with Alkyl Halides

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

Example: excess amine NH2NH2NH2NH2 + ClCH 2 NHCH 2 (85-87%) NaHCO 3 90°C (4 mol) (1 mol)

Example: excess alkyl halide + 3CH 3 I (99%) methanolheat CH 2 N(CH 3 ) 3 CH 2 NH 2 + I–

22.14 The Hofmann Elimination

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.

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–

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

MechanismMechanism H CH2CH2CH2CH2+ –O H OH H N(CH 3 ) 3 CH2CH2CH2CH2

RegioselectivityRegioselectivityheat 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%)

RegioselectivityRegioselectivity 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.

RegioselectivityRegioselectivity N(CH 3 ) 3 + HHH H CH 3 CH 2 C H CHH largest group is between two H atoms major product

RegioselectivityRegioselectivity N(CH 3 ) 3 +H H H CH 3 C H C H largest group is between an H atom and a methyl group minor product CH 3

22.15 Electrophilic Aromatic Substitution in Arylamines

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

Nitration of Anililne Strategy: decrease the reactivity of aniline by converting the NH 2 group to an amide CH(CH 3 ) 2 NH 2 CH(CH 3 ) 2 NHCCH 3 O O CH 3 COCCH 3 O(98%) (acetyl chloride may be used instead of acetic anhydride)

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%)

Nitration of Anililne Strategy: remove the acyl group from the amide by hydrolysis KOH CH(CH 3 ) 2 NHCCH 3 O NO 2 ethanol, heat CH(CH 3 ) 2 NH 2 NO 2 (100%)

occurs readily without necessity of protecting amino group, but difficult to limit it to monohalogenation Halogenation of Arylamines CO 2 H NH 2 Br 2 acetic acid (82%) CO 2 H NH 2 BrBr

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

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 2 CH 3 CH 3 CCl O AlCl 3 (57%) NHCCH 3 O CH 3 CCH 3 O