630
HOW TO APPROACH EXAMINATION QUESTIONS: SELECTED PROBLEMS AND ANSWERS
derivative, and we can not just react with methanol and acid because that would be likely to transesterify the
existing ester. The clue is in the use of base; this will form the carboxylate anion. The reaction then becomes
a base-initiated S N 2 reaction with MeI; the carboxylate anion is the nucleophile.
N
Me
CO 2 Me
O
O
cocaine
N
Me
O
CO 2 H
Ph
O
N
Me
O
CO 2
Ph
O
Me I
NaOMe
Ph
S N 2
(X)
ionization of
carboxylic acid
(b) This problem provides two examples of nucleophilic addition to a ketone; the ketone is the only reacting
functional group in this complex steroidal structure.
Estradiol is formed by lithium aluminium hydride reduction of the ketone. We can formulate this simply
as hydride acting as the nucleophile, though hydride delivery by LAH is strictly more complex than this.
Unless you are specifically asked for details, treat LAH as a source of hydride ion.
HO
O
Nu
HO
O
Nu
H OH
HO
OH
Nu
Nu is either H − or HC≡C −
nucleophilic attack
on carbonyl
protonation from suitable
source
Similarly, acetylide is the nucleophile in the synthesis of ethinylestradiol. In each case the reaction is
finished off by protonation from a suitable source, e.g. water.
Problem 16.09 (level 1; chapter 4)
(a) Provide a reasoned explanation for the relative pK a values determined for the five amines shown.
NH 2
NH 2
HN
HN
CH 3
NH 2
pK a (conjugate acid)
10.6
4.6
0.8
4.9
9.3
cyclohexylamine
aniline
diphenylamine
N-methylaniline
benzylamine
HOW TO APPROACH EXAMINATION QUESTIONS: SELECTED PROBLEMS AND ANSWERS
derivative, and we can not just react with methanol and acid because that would be likely to transesterify the
existing ester. The clue is in the use of base; this will form the carboxylate anion. The reaction then becomes
a base-initiated S N 2 reaction with MeI; the carboxylate anion is the nucleophile.
N
Me
CO 2 Me
O
O
cocaine
N
Me
O
CO 2 H
Ph
O
N
Me
O
CO 2
Ph
O
Me I
NaOMe
Ph
S N 2
(X)
ionization of
carboxylic acid
(b) This problem provides two examples of nucleophilic addition to a ketone; the ketone is the only reacting
functional group in this complex steroidal structure.
Estradiol is formed by lithium aluminium hydride reduction of the ketone. We can formulate this simply
as hydride acting as the nucleophile, though hydride delivery by LAH is strictly more complex than this.
Unless you are specifically asked for details, treat LAH as a source of hydride ion.
HO
O
Nu
HO
O
Nu
H OH
HO
OH
Nu
Nu is either H − or HC≡C −
nucleophilic attack
on carbonyl
protonation from suitable
source
Similarly, acetylide is the nucleophile in the synthesis of ethinylestradiol. In each case the reaction is
finished off by protonation from a suitable source, e.g. water.
Problem 16.09 (level 1; chapter 4)
(a) Provide a reasoned explanation for the relative pK a values determined for the five amines shown.
NH 2
NH 2
HN
HN
CH 3
NH 2
pK a (conjugate acid)
10.6
4.6
0.8
4.9
9.3
cyclohexylamine
aniline
diphenylamine
N-methylaniline
benzylamine