Organic Chemistry

Section 11.12 Designing a Synthesis II: Approaching the Problem 429

Three- and four-membered rings are strained, so they are less stable than five- and six-

membered rings and, therefore, are less easily formed. The higher activation energy

for three- and four-membered ring formation cancels some of the advantage gained by

tethering.

Three-membered ring compounds are formed more easily than four-membered ring

compounds. To form a cyclic ether, the nucleophilic oxygen atom must be oriented so

that it can attack the back side of the carbon bonded to the halogen. Rotation about a

bond in the molecule forms conformations with the groups pointed away from

one another. The molecule leading to formation of a three-membered ring ether has

one bond that can rotate, whereas the molecule leading to formation of a four-

membered ring has two bonds that can rotate. Therefore, molecules that form

three-membered rings are more apt to have their reacting groups in the conformation

required for reaction.

The likelihood of the reacting groups finding each other decreases sharply when the

groups are in compounds that would form seven-membered and larger rings. There-

fore, the intramolecular reaction becomes less favored as the ring size increases beyond

six members.

PROBLEM 26

Which compound, upon treatment with sodium hydride, would form a cyclic ether more

rapidly?

11.12 Designing a Synthesis II:

Approaching the Problem

When you are asked to design a synthesis, one way to approach the problem is to look

at the given starting material to see whether there is an obvious series of reactions that

can get you started on the pathway to the target molecule(the desired product).

Sometimes this is the best way to approach a simplesynthesis. The examples that fol-

low will give you practice in designing a successful synthesis.

HO Br HO Br

HO Br HO Br

HO Br HO Br

a.

b.

c.

or

or

or

Br

O−

Br

O−

one C C bond

can rotate

two C C bonds

can rotate

C¬C

C¬C

C¬C

CH 2

CH 2

Cl + Cl−

Br +

+

Br−

CH 2

CH 2

CH 2

H 2 C

H 2 C

H 3 CCH 3

H 2 C

O O

N

H 2 C

(CH 3 ) 2 N

−

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