216 S11-Expt 1
2
Chem 216 S11 Notes - Dr. Masato Koreeda Date: May 3, 2011 Topic: __Experiment 1 ____ page 1 of 2. Experiment 1: Synthesis of Acetamides from Aniline and Substituted Anilines Many of the acetylated [CH 3 –C(=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 CH 3 O acetaminophen (Tylenol) HO O CH 3 O O HO acetylsalicylic acid (Aspirin) ======================================================================= The reaction to be carried out in this experiment is: Acetylation of aniline H N H aniline (nucleophile) CH 3 O O O H 3 C δ- δ+ acetic anhydride (electrophile) H N CH 3 O acetanilide CH 3 HO O + 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. R' N R" O R CH 3 O acetyl group Note: R' N CH 3 O R amide acetamide R' N + R" O - R The amide N is usually not nucleophilic because of a significant contribution of this resonance form. Reaction mechanism: N CH 3 O H 3 C O O δ- δ+ H H N CH 3 O O O H 3 C H H tetrahedral (sp 3 ) intermediate N O CH 3 H H O CH 3 O + B (including O CH 3 O ) pK a ~ -5 N CH 3 O H acetanilide
Transcript of 216 S11-Expt 1
Chem 216 S11 Notes - Dr. Masato Koreeda Date: May 3, 2011 Topic: __Experiment 1____ page 1 of 2. Experiment 1: Synthesis of Acetamides from Aniline and Substituted Anilines Many of the acetylated [CH3–C(=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:
HN CH3
O
acetaminophen (Tylenol)HO
O CH3
O
OHO
acetylsalicylic acid (Aspirin) ======================================================================= The reaction to be carried out in this experiment is: Acetylation of aniline
HNH
aniline (nucleophile)
CH3
O
O
O
H3C δ-δ+
acetic anhydride
(electrophile)HN CH3
O
acetanilideCH3
HO O+
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.
R'N R"
O
R
CH3
O
acetyl group
Note:R' N CH3
O
R
amideacetamide
R'N+ R"
O-
R
The amide N is usually not nucleophilicbecause of a significant contribution of this resonance form.
Reaction mechanism:
N
CH3
O
H3C
O
Oδ-
δ+H H N
CH3
O O
OH3C
HH
tetrahedral (sp3) intermediate
NO
CH3
H
H
O CH3
O+
B (includingO CH3
O)
pKa ~ -5
N CH3
O
H
acetanilide
Chem 216 S11 Notes - Dr. Masato Koreeda Date: May 3, 2011 Topic: __Experiment 1____ page 2 of 2. 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.
N
CH3OH3C
OOH H
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
H2O
Erlenmeyer flaskDon't use a beaker!
H2OPhNH3
+Cl-(all dissolved)
add 1 mol equiv of conc HCl
homogeneous solution
H2O
H2O
Mostly PhNH3+
and NaCl, acetic anhydride, and CH3C(=O)O-
(dissolved in H2O)
add 1 mol equiv of acetic anhydride
PhNH3+Cl-, acetic anhydride
(still all dissolved in H2O)
no reaction yet!
H3C O- Na+
O
add 1.2 mol equiv of
(sodium acetate) - weak base
By the action of sodium acetate, a small amount of free aniline (PhNH2)is regenrated.
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....
acetanilide as white precipitates (collect by suction filtration)
NaCl, acetic acid and CH3C(=O)O- dissolvedin H2O
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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).
