Organic Chemistry

Section 19.8 Alkylation of the -Carbon of Carbonyl Compoundsa 801

3-D Molecule:

N,N-Dimethylhydrazone of

2-methylcyclohexanone

Hermann Kolbe (1818–1884)and

Rudolph Schmitt (1830–1898)were

born in Germany. Kolbe was a

professor at the Universities of

Marburg and Leipzig. Schmitt

received a Ph.D. from the University

of Marburg and was a professor at

the University of Dresden. Kolbe

discovered how to prepare aspirin in

1859. Schmitt modified the synthesis
      in 1885, making aspirin available in
      large quantities at a low price.

THE SYNTHESIS OF ASPIRIN

The first step in the industrial synthesis of aspirin

is known as the Kolbe–Schmitt carboxylation

reaction. The phenolate ion reacts with carbon dioxide under

pressure to form o-hydroxybenzoic acid, also known as sali-

cylic acid. Acetylation of salicylic acid with acetic acid forms

acetylsalicylic acid (aspirin).

During World War I, the American subsidiary of the Bayer

Company bought as much phenol as it could from the interna-

tional market, knowing that eventually all the phenol could be

converted into aspirin. This left little phenol available for other

countries to purchase for the synthesis of 2,4,6-trinitrophenol

(TNT), a common explosive.

O

(CH 3 C) 2 O

O

+ OCO

− O

C

H

O−

O

OH OH

COH

O

COH

O

CO−

O

HCl

O

C

O

H 3 C

salicylic acid

o-hydroxybenzoic acid

acetylsalicylic acid

aspirin

The N,N-dimethylhydrazone will form so that the dimethylamino group is pointing
away from the more substituted The nitrogen of the dimethylamino group
directs the base to the less substituted carbon by coordinating with the lithium ion of
butyllithium the base generally employed in this reaction. Hydrolysis of the
hydrazone reforms the ketone (Section 18.6).

(Bu-Li+),

a-carbon.

PROBLEM 12

What compound is formed when cyclohexanone is shaken with NaOD in for several

hours?

PROBLEM 13

Explain why alkylation of an works best if the alkyl halide used in the reaction is

a primary alkyl halide and why it does not work at all if it is a tertiary alkyl halide.

PROBLEM-SOLVING STRATEGY

How could you prepare 4-methyl-3-hexanone from a ketone containing no more than six

carbon atoms?

Two sets of ketone and alkyl halide could be used for the synthesis: 3-hexanone and a

methyl halide or 3-pentanone and an ethyl halide.

3-Pentanone and an ethyl halide are the preferred starting materials. Because 3-pentanone

is symmetrical, only one ketone will be formed. In contrast, 3-hexanone can

form two different enolates, so two a-substitutedketones can be formed.

a-substituted

CH 3 CH 2 CCH 2 CH 3 + CH 3 CH 2 Br

O

3-pentanone

CH 3 CH 2 CCH 2 CH 2 CH 3 + CH 3 Br or

O

3-hexanone

CH 3 CH 2 CCHCH 2 CH 3

O

CH 3

4-methyl-3-hexanone

a-carbon

D 2 O