CARBON AS A NUCLEOPHILE
241
It reacts with aldehydes and ketones in the manner
expected, and after acidification yields an alcohol.
This reaction also extends the carbon chain by
two or more atoms, depending on the acetylide
used, inserting a triple bond for further modification.
C C
R
O
R
O
R
OH
H
+
nucleophilic attack
on carbonyl
Box 7.8
Synthesis of the oral contraceptive ethinylestradiol
A number of steroidal drugs are produced by procedures that include nucleophilic attack of sodium acetylide onto
a ketone, particularly that at position 17 on the five-membered ring of the steroid (see Box 3.19).
O
C CH
OH
C
CH
H +
17
Thus, the natural oestrogen estrone can be converted into the drug ethinylestradiol by nucleophilic addition.
Ethinylestradiol is some 12 times more effective than estradiol when taken orally, and is widely used in oral
contraceptive preparations. In drug nomenclature, the systematic name ethynyl– for the HC≡C– group is usually
presented as ethinyl–.
O
HO
H
H
H
C CH
HC C
HO
H
H
H
OH
H
CH 3
H
H
O
HO
estrone
C CH
liquid NH 3
HO
H
H
H
orally active oestrogen
ethinylestradiol
attack from this face
hindered by methyl
group
estradiol
OH
17
attack from lower face
is not hindered by
substituents
H
+
Na
With a simple aldehyde or ketone substrate, there is an equal probability that the nucleophile will attack the
carbonyl carbon from each face of the planar system, thus producing a racemic product, assuming that there are