Chem 216 S11 Notes - Dr. Masato Koreeda Topic: __Experiment 1____ page 1 of 2.

Date: May 3, 2011

Experiment 1: Synthesis of Acetamides from Aniline and Substituted Anilines

Many of the acetylated [CH3C(=O)-] derivatives of aromatic amines (aka anilines) and phenols are pharmacologically important compounds. Some of these exhibit distinct analgesic activity. Two of the most representative examples are:
H N HO O CH3 HO O O CH3

acetaminophen (!Tylenol)

O acetylsalicylic acid (!Aspirin)

======================================================================= The reaction to be carried out in this experiment is: Acetylation of aniline
!H3C !+ O O N H H aniline (nucleophile) O CH3 acetic anhydride (electrophile) H N O acetanilide CH3 +

HO

O CH3

acetic acid

Both aniline and acetic anhydride are somewhat viscous liquids. So, simply mixing them together does not result in the efficient formation of acetanilide. Therefore, a solvent (in this case water) is used to dissolve and evenly disperse two reactants in it.
Note:
O CH3 acetyl group R' R N R" R N+ OThe amide N is usually not nucleophilic because of a significant contribution of this resonance form. R" R' R N O acetamide

R'

CH3

O amide

Reaction mechanism:
H N !H H3C !+ O O O CH3 tetrahedral (sp3) H H H3C N O O O CH3 intermediate pKa ~ -5 B (including H N H N H O + CH3
O O CH3

O O )

CH3

CH3

O acetanilide

Chem 216 S11 Notes - Dr. Masato Koreeda Topic: __Experiment 1____ page 2 of 2.

Date: May 3, 2011

Additional comments on the reaction mechanism: 1. Aniline is a strong nucleophile (much stronger than water). 2. Acetic anhydride is a relatively unstable reagent, but does not react with water that easily. 3.
H N H3C H O O O CH3

A direct substitution process at the C=O carbon does not take place. No direct SN2 reaction at the C=O carbon is known. This is not feasible on the basis of the orbital consideration.

Experimental procedure:
Aniline is not soluble in water; so 1 mol. equiv of conc. HCl (37% HCl by weight in water) is added in order to dissolve the aniline in water.

aniline

add 1 mol equiv of conc HCl

add 1 mol equiv of acetic anhydride

H2O

Erlenmeyer flask Don't use a beaker!

PhNH3+Cl(all dissolved)

H2 O

PhNH3+Cl-, acetic anhydride (still all dissolved in H2O)

H2O

homogeneous solution

no reaction yet! add 1.2 mol equiv of

NaCl, acetic acid and CH3C(=O)O- dissolved in H2O

H3C

O- Na+

By the action of sodium acetate, a small amount of free aniline (PhNH2) is regenrated.

O (sodium acetate) - weak base

oo o o o oo o oo o oo o o o o o

acetanilide as white precipitates (collect by suction filtration)

Free aniline has virtually no water solubility. But before aniline comes out of the H2O solution, it quickly collides (i.e., reacts) with acetic anhydride dissolved in H2O. As soon as the acetamide product (acetanilide) is formed, it will precipitate out of the H2O solution and more PhNH3+ gets converted to free aniline....

H2O

Mostly PhNH3+ and NaCl, acetic anhydride, and CH3C(=O)O(dissolved in H2O)

Questions: (1) What would happen if the order of additions of acetic anhydride and sodium acetate is reversed? (2) What would be the outcome if 1 mol equiv of NaOH is used instead of sodium acetate? (3) What would you have to do in order to dissolve p-nitroaniline into water by adding conc. HCl? The pKa of the conjugate acid of p-nitroaniline is 1.00 (see the note on pKa).