Organic Chemistry

Section 19.8 Alkylation of the -Carbon of Carbonyl Compoundsa 799

compound is converted into the enolate because hydroxide ion is a weaker base than
the base being formed. (Recall that the equilibrium of an acid–base reaction favors
reaction of the strong acid and formation of the weak acid, Section 1.17.)

In contrast, when lithium diisopropylamide (LDA) is used to remove the
(the of LDA’s conjugate acid is about 35), essentially all the carbonyl compound
is converted to enolate because LDA is a much stronger base than the base being
formed (Section 1.17). Therefore, LDA is the base of choice for those reactions that
require the carbonyl compound to be completely converted to enolate before it reacts
with an electrophile.

Using a nitrogen base to form an enolate can be a problem because a nitrogen base
can also react as a nucleophile and attack the carbonyl carbon (Section 18.6). Howev-
er, the two bulky alkyl substituents bonded to the nitrogen of LDA make it difficult for
the nitrogen to get close enough to the carbonyl carbon to react with it. Consequently,
LDA is a strong base but a poor nucleophile, so it removes an much faster
than it attacks a carbonyl carbon. LDA is easily prepared by adding butyllithium to di-
isopropylamine (DIA) in THF at

19.8 Alkylation of the -Carbon of

Carbonyl Compounds

Alkylation of the of a carbonyl compound is an important reaction because it
gives us another way to form a carbon–carbon bond. Alkylation is carried out by first
removing a proton from the with a strong base such as LDA and then adding
the appropriate alkyl halide. Because the alkylation is an reaction, it works best
with methyl halides and primary alkyl halides (Section 10.2).

Ketones, esters, and nitriles can be alkylated at the in this way. Aldehydes,
however, give poor yields of a-alkylatedproducts (Section 19.11).

a-carbon

O

+ Br−

O

CH 3 CH 2 Br

O

LDA/THF − CH^2 CH^3

O

−

SN 2

a-carbon

a-carbon

A

• 78 °C.

a-hydrogen

+ +

O

−

O O−

LDA DIA

pKa = 17 ∼100% pKa^ =^35

pKa

a-proton

O O−

+ HO− + H 2 O

pKa = 17 < 0.1% pKa = 15.7

O

−

CH 3 CH 3

++CH 3 CH 2 CH 2 CH 2 Li

CH 3 CH 3

− + THF

CH 3 CHNCHCH 3 CH 3 CH 2 CH 2 CH 3

−

Li+

CH 3 CHNHCHCH (^3) − 78 °C
lithium diisopropylamide
LDA
butane
pKa ∼ 50
diisopropylamine butyllithium
pKa = 35
3-D Molecule:
Lithium diisopropylamide
(LDA)