LDA

1.39 LITHIUM Di-ISOoPROPYLAMIDE, 0°C (eq. 1).

and butyllithium in the presence of tetrahydrofuran at
It is prepared from diisopropylamine
THF
/CH-CHÑLi +BuH ...(1)
CH-CHNH+ BuLi 0°C

CH3
 Organic Synthesi,
212
deprotonation can be acnieved witho
strong base with which stution
nindered non-nucleophilic
sa nucleophile and
does not give nu
n t e r f e r e n c e by nucleophilic attack. It is verv n o o r
nucleophilic addituon witn aldehyde
( R - O - T s ) . It does
not give c a r b o n (cq. 2, 3).
halides and tosylates from active
Cwin alkyl that it abstracts hvdrogen
C O n e s and nitriles. It is such a
strong base 2
C H = C = C H 7 + L D A C H 2 = C - H I L i

O
O C H 3 C = C H 2
3
CH3-C-CH +LDA CH3-C-CH2 anion
irom carbonyl groun
enolate
carbanion or
generation of
ideal base for
LDA 1s, therefore,

containing compounds (eq. 4).

NH
R-CH- -RLDA |R H- -R|Li

OLi
R CH- -R forms dianion ina
different acidity
two
activated-CHgroups of markedly
A compound possessing
good yield (cq. 5). O O
very
O O
C HO CoH5 H- -CH3
CoHs C-CH2- CH3 only mono anion

weak base
LDA (2 mole)

O O
...(5)
CGH C H-C1 H, CHs C-CHC-CH2
Dianion
formation of enolate anion has high degree ot
For a ketone with two sets of non-equivalenta-hydrogens,
on experimental conditions (eq. 6).
regioselectivity, and regioselectivity depends
O

CH3 Base
CH3 .(6)
CH3
.

(more stable) (less stable)

O O
CH3
CH3
(less stable) (more stable)
Less substituted enolate More substituted enolate
anion (Kinectically anion (Thermodynamically
controlled product) controlled product)
Reagents in Organic Synthesis 213
Highly hindered strong bases, such as LDA favour formation of the kinetic, less substituted enolate,
whereas unhindered weak bases such as NaH, KH, sodium and potassium salt of primary, secondary and
tertiary alcohols (i.e., sodium and potassium alkoxides) generate the more substituted, thermodynamic
enolate. Nowadays bromomagnesium disopropylamide (BMDA) is used for the generation of more
en
substituted enolates.

other hindered non-nucleophilic bases which generate less substituted enoaltes are:

Me3Si SiMe3
N

Li Li
Lithium hexamethyldisilazane Lithium tetramethyl
(LHMDS) piperidine (LTMP)
Thermodynamic enolate is generated in a polar protic solvent whereas kinetic enolate is generated in
polar aprotic solvents.
When 2-1methylcyclohexanone is treated with LDA in the presence of polar aprotic solvent, DMF, it
removes the hydrogen from the-CH2-a- carbon more rapidly because it is less hindered (and because
there are two times as many hydrogens there to react (eq. 7).

O OLi
LiN<

H DMF
...(7)
Kinetic enolate
This enolate is formed faster because the hindered
strong base removes the less hindered proton faster.

1.39.1. Preparation of Silyl Enol Ethers

Enolate ions are ambident nucleophiles.
This site reacts as an alkoxide anion

-This site reacts as a carbanion

CH3-C=CH2 - CH- -CH2

Halotrialkylsilanes tend to react almost exclusively at the oxygen atom of the enolate (eq. 8).
O O SiMe
(i) Base
CH3 C-CH3 (ii)(CH3),SiC/THF CH-(-CH2 ...(8)
Trimethylisly
enol ether

This reaction is known as silylation. Silylation is a nucleophilic substitution reaction of the silicon atom
by the oxygen atom ofthe enolate, and it takes place as it does because the oxygen-silicon bond that formsin
the trimethylsilyl enol ether is very strong (stronger than carbon-silicon bond). This factor makes formation
of the trimethylsilyl enol ether highly exothermic, and consequently, the free activation energy for reaction at
the oxygen nucleophile is lower than that for reaction at the carbon nucleophile.
This reaction can be used for trapping of enolate anion as trimethylsilyl enol ether. Composition of
enolate anion mixture is also determined by trapping it as trimethylsiyl enol ether (Scheme 1).
O OSiMe3 0-SiMe3 Ratio (A): (B)
Raegent
LDA/DMF (ii) TMSCI 99
Reagent NaH/DME (ii) TMSCI 73:27
BMDA/Et,N (ii) TMSCI 97:3
(A) (B)
Scheme 1
 214 Organie Synthesi,
Lithium enolates of ketones from LDA are very useful compounds for organic synthesis. Some of the
reactions are mentioned below:

1. Direct Alkylation and Acylation of Ketones

successful alkylation curs only when
occur

The alkylation reaction is SN2. Enolate anions strong bases,

are

halides are used in this

reaction. With
econdary and
seco

primary alkyl, primary benzyl and primary alkyl

tertiary, elimination becomes the main course of reaction.
O OLi
LDA/DMF
CH, + Lil

CHs-CH2 Br CH-CH-CH2-Br
CH CH-CH2
CH2 CHs

enolate using LDA

Condensation via the kinetic
>1.39.2. An andol using
carried out in the classical way
ketone and acetaldyde is
between ethyl methyl in significant amount
If the aldol reaction would have been formed
least two cross products
then at each of these
hydroxyl ion as the base, enolates would have been
formed from the ketones, and
Both the kinetic and themrodynaic
carbon of the acetaldehyde (Scheme 2).
would add to the carbonyl

CH-CH,- CH OH/H CH CH- -CH + CH-CH= -CH

Thermodynamic enolate
Kinetic enolate

CHy-H
CHC-H
O
CH3-CHCCH2-CH-CH CH-CH- CH
CH-CH
HOH O

HOH
O OH O

CHy CH CH2 H-CH CH-CH- -CH3

CH-CH
OH
Scheme 2
 in Organic Synthesis 215
Reagents

This reaction isregioselective in the presence of LDA and gives only one cross product instead of two
products (Scheme 3).
O

CH3-CH2-C-CH
LDA/DMF
O
CH-C-CH HOH
CH-CH2-C=CH, CH3-CH2-C-CH2-C-CH3
CH3
O OH

CH3CH2-C-CH2C-CH
CH
A single cross aldol product

Scheme3

>1.39.3. a-Selenation : Synthesis of a , B-unsaturated carbonyl compounds

from isolated carbonyl compounds
Lithium enolates obtained by LDA with benzene
react selenyl chloride or bromide to yield products
containing a C%H5-Se-group at the a-position (eq. 9).
OLi O

LDA/DMF CH Se SeCHs ..(9)

SN reaction at Se

Selenenyl ketone
Selenyl ketone on oxidation with hydrogen peroxide at room
temperature gives
ketone (eq. 10).
an a,
P-unsaturated
O

Se CHs H,0
25°C + CHSeOH 10)

These are very mild conditions for the introduction of a double bond
(room temperature and a neutral
SOlution). This is one reason why this method is a valuable one.
Conversion of selenyl ketone into a, p-unsaturated ketone takes as place follows
O O
Intramoleeular
Se H,O Se CoHs cmnatuon of
Se OH
CH Oxidation

Ethyl phenyl ketone gives a, B-unsaturated ketone in this reaction with the
yield of 90o (eq. 11).
216
Organic Synthenis
O O

(i) LDA/DMF
C,H5-C-CH2-CH (i) CH
(i1) S_Rr
C,HSe-Br
6Hs-C-CH=CH

90% yield
..11)
(iii) H,0,
out in the presence of base LDA
AIkylation of acids, esters, amides, imines and evanides can be carried
The result is given in Table 1.

Table 1 Alkylation of Acids, Esters, Amides, Imines & Nitriles in the Presence of LDA
CH (i) 2LDA
CH-COOH 02LDA
CH3 -COOH
CH3 i ) (ii)RX CH
(ii) H R

(i) LDA. -78°C

CH-(CH,)-COOC,Hs CH-(CH2)3-CH-COOC2Hs
(ii)R-CH,-Br
CH2-R
O
(i) LDA
O FO (ii)R-CHBr/HMPA

CH2R
O

O =O
(i) LDA

(ii) CH=CH-CH-Br
(ii) LDA/DME
(iv) CH3H
O I=O
CH CH-CH=CH
O O O
N-C-CH,-Ph LDA/THF
(ii) R-CH2-X
o

N -CH-Ph
CH-R