800 CHAPTER 19 Carbonyl Compounds III
3-D Molecule:
2-MethylcyclohexanoneTwo different products can be formed when the ketone is not symmetrical, because
either can be alkylated. For example, methylation of 2-methylcyclohexanone
with one equivalent of methyl iodide forms both 2,6-dimethylcyclohexanone and
2,2-dimethylcyclohexanone. The relative amounts of the two products depend on the
reaction conditions.The enolate leading to 2,6-dimethylcyclohexanone is the kineticenolate because the
that is removed to make this enolate is more accessible (particularly if a hin-
dered base like LDA is used) and slightly more acidic. So 2,6-dimethylcyclohexanone is
formed faster and is the major product if the reaction is carried out at
The enolate leading to 2,2-dimethylcyclohexanone is the thermodynamicenolate
because it has the more substituted double bond, making it the more stable enolate.
(Alkyl substitution increases enolate stability for the same reason that alkyl substitu-
tion increases alkene stability, Section 4.11.) Therefore, 2,2-dimethylcyclohexanone is
the major product if the reaction is carried out under conditions that cause enolate for-
mation to be reversible and if a less hindered base (KH) is used.
The less substituted can be alkylated—without having to control the con-
ditions to make certain that the reaction does not become reversible—by first making
the N,N-dimethylhydrazone of the ketone.a-carbon- 78 °C.
a-hydrogenO−
O−LDA
+OCH 3 ICH 3 IO
H 3 C2,6-dimethylcyclohexanoneO2,2-dimethylcyclohexanoneCH 3 CH 3CH 3CH 3CH 3
CH 32-methylcyclohexanonea-carbon- LDA/THF
CH 3 CH 2 CH 2 CN2. CH 3 CH 2 l
CH 2 COCH 3- LDA/THF
- CH 3 l
O OCHCOCH 3CH 3 CH 2 CHC NCH 3CH 2 CH 3CH 3 NNH 2H 2 OCH 3HClNCH 3 NCH 3OBu−Li+an N,N-dimethyl-
hydrazoneO
CH 3CH 3 CH 2 BrCH 3−NCH 3 NCH 3NCH 3 NCH 3CH 3CH 3 CH 3 CH 3CH 3 CH 2 CH 3 CH 2
CH 3 NNH 3 +NCH 3 NCH 3+ Li CH 3
Bu−+