Organic Chemistry

1.5

1.0

0.5

1

pH

kobsd

(min

−^1

)

234567

Figure 18.2

Dependence of the rate of the

reaction of acetone with

hydroxylamine on the pH of the

reaction mixture.

Section 18.6 Reactions of Aldehydes and Ketones with Nitrogen Nucleophiles 749

Aldehydes and ketones react with

primary amines to form imines.

is present, it will protonate all of the reactant amine. Protonated amines are not nucleo-
philes, so they cannot react with carbonyl groups. Therefore, unlike the acid-catalyzed
reactions we have seen previously (Section 17.11), there is not sufficient acid present
to protonate the carbonyl group in the first step of the reaction (see Problem 17).
A plot of the observed rate constant for the reaction of acetone with hydroxylamine
as a function of the pH of the reaction mixture is shown in Figure 18.2. This type of
plot is called a pH-rate profile. The pH-rate profile in the figure is a bell-shaped curve
with the maximum rate occurring at about pH 4.5, 1.5 pH units below the of
hydroxylamine As the acidity increases below pH 4.5, the rate of the re-
action decreases because more and more of the amine becomes protonated. As a result,
less and less of the amine is present in the nucleophilic nonprotonated form. As the
acidity decreases above pH 4.5, the rate decreases because less and less of the tetrahe-
dral intermediate is present in the reactive protonated form.
Imine formation is reversible: In acidic aqueous solutions, imines are hydrolyzed
back to the carbonyl compound and amine.

In an acidic solution, the amine is protonated and, therefore, is unable to react with the
carbonyl compound to reform the imine.
Imine formation and hydrolysis are important reactions in biological systems
(Sections 19.21, 24.9, and 25.6). Imine hydrolysis is the reason DNA contains A, G, C,
and T nucleotides, whereas RNA contains A, G, C, and U nucleotides (Section 27.14).

PROBLEM 17

The of protonated acetone is about and the of protonated hydroxylamine is 6.0.

a. In its reaction with hydroxylamine at (Figure 18.2), what fraction of acetone

will be present in its acidic, protonated form? (Hint: See Section 1.20.)

b. In its reaction with hydroxylamine at what fraction of acetone will be pres-

ent in its acidic, protonated form?

c. In its reaction with acetone at (Figure 18.2), what fraction of hydroxylamine

will be present in its reactive basic form?

PROBLEM 18

A ketone can be prepared from the reaction of a nitrile with a Grignard reagent. Describe the

intermediate that is formed in this reaction, and explain how it can be converted to a ketone.

Addition of Secondary Amines
Aldehydes and ketones react with secondary amines to form enamines. Like imine for-
mation, the reaction requires a trace amount of an acid catalyst.

an enamine

an enamine

+

CH 3 CH 2 CH 2 CH 3

CH 3 CH 2 CH^2 CH^3

O NH

O

+

N

H 2 O

++H 2 O

N

H

N

cyclopentanone

cyclohexanone pyrrolidine

a secondary amine

diethylamine

a secondary amine

catalytic

H+

catalytic

H+

pH=1.5

pH=1.5,

pH=4.5

pKa -7.5 pKa

HCl

CH NCH 2 CH 3 + H 2 O + CH 3 CH 2 NH 3

+

CH O

1 pKa=6.0 2.

pKa

An imine undergoes acid-catalyzed

hydrolysis to form a carbonyl compound

and a primary amine.

3-D Molecule:

N,N-Diethyl-1-cyclo-

pentenamine