Unit 14 Enolates

UNIT 14

ENOLATES

Structure
14.1 Introduction Alkylation of , -unsaturated
Ketones
Expected Learning Outcomes
Alkylation of Aldehydes, Esters,
14.2 Enols and Enolates
Carboxylic acids and Amides
14.3 Generation of Enolates
Control of Enantioselectivity in
Regioslectivity and Alkylation Reactions
Stereoselectivity in Enolate
Nucleophilic Addition of Enolates
Formation
on Carbonyl Compounds
14.4 Reactions of Enolates
Nitrogen Analogs of Enols and
Halogenation Enolates: Enamines and Imines

Enolate Alkylation: Reactions of 14.5 Summary

Relatively Acidic Compounds
14.6 Terminal Questions
Alkylation of Ketone Enolates
14.7 Answers

14.1 INTRODUCTION
In your earlier classes you have studied about the construction of the
molecular framework of organic molecules by carbon-carbon bond formation.
Various types of electrophilic and nucleophilic reagents can be used for this
purpose. In this unit our focus will be on nucleophilic reactions in which
intermediates such as enolates, imine anions and enamines are involved. We
will discuss these intermediates considering following points:

 generation of enolates

 the effect of the reaction conditions on the structure and reactivity of the
enolates.

 the regioslectivity and stereoselectivity of enolates.

 generation and reactions involving nitrogen analogs of enolates, i.e.

imines and enamines 141
Block 4 Organic Synthesis: Some More Approaches

Expected Learning Outcomes

After studying this unit you should be able to:

 list various methods for generating enols and enolates;

 describe various factors which control regioselectivity and stereoselectivity

of enolate formation;

 explain the mechanism of nucleophilic addition reactions of enolates;

 understand the importance of enolate chemistry in stereoselective C−C

bond formation; and

 describe significance of aldol reaction in synthetic organic chemistry.

14.2 ENOLS AND ENOLATES

Enols are isomers of aldehydes or ketones in which an alpha (α) hydrogen has
been removed and placed on the oxygen atom of the carbonyl group. These
molecules have a C=C and an OH group, so they are called an ene/ol i.e.
enols.

H H H CH3
C CH3 C C
H3C C
H3C OH
O

Keto form enol form

The process of converting between the keto and enol forms is called
tautomerism. Tautomerism is rapid interconversion of structural ionsomers. In
most of the cases, the equilibrium lies on the right with Keto form being the
more stable. For example in aqueous solution of acetone at 25C,
concentration of enol form is almost negligible.

O OH
25 oC
C C
H3C CH3 H2O H3C CH2

>99.99 %

The equilibrium between carbonyl compounds and the corresponding enol

form can be acid or base catalysed. This process occurs by a concerted
mechanism in which protonation and deprotonation take place in single step.
Acid catalysed:

O O+ H
-H2O
H3O+ RC C R1 + H2O
RCH2 C R1 +
OH H
-H3O+
1
142 RCH C R
Unit 14 Enolates

Base catalysed

O O-
-BH
RCH C R1 + BH
R CH C R1
B: - H OH
RCH C R1 + B:-

Concerted

O H A OH

R CH C R1 RCH C R1 + BH + A-

B:- H

Once enols are formed, they are nucleophilic like simple alkenes by virtue of
their  electrons, but they are more reactive than simple alkenes due to the
presence of the hydroxyl group which participates as an electron donor during
the reaction process. This can be shown by following resonance structures:

+
OH _ OH
RCH C R 1
RCH C R1

In strong basic conditions, α-hydrogen of an aldehydes or ketone can be

removed to generate resonance stabilized enolate anion or enolate.
O O O -Na+
NaNH2 _
H H + NH3
H
H
H H H
- NH
2

Enolate

Enolate anions are more reactive than enols. The relative lower reactivity of
enols is due to the presence of proton of OH group, which decreases the
electron density of the enol relative to the negative charge on oxygen of
enolate. This relative reactivity of enol and enolate can also be explained on
the basis of Molecular Orbital (MO) theory. Both OH and O- donor
substituent raise the energy of the  HOMO of enolate, but O- group being a
better donor raises this energy little higher.

O-
OH

As mentioned earlier in most of cases, the keto-enolate equilibrium lies on the

right because of the more stability of keto form. Typical strong bases such as
hydroxide or alkoxide are only capable of forming, the enolates in very low 143
Block 4 Organic Synthesis: Some More Approaches

concentration. This leaves a significant concentration of the electrophilic

carbonyl which can react with the base or the enolate. Thus aqueous base
conditions used for the aldol condensation are not suitable because of the very
low concentration of enolate formation form simple carbonyl compounds.
Further, bases like hydroxide or alkoxide are also good nucleophiles.
Therefore, they induce competing reactions such S N2 and E2. Thus it
becomes necessary to achieve complete conversion of aldehydes or ketone
reactants to their enolate forms for their nucleophilic addition reactions. In the
next section we will study various methods to generate enolates in high
concentration.

SAQ 1
Write enol forms of following compounds:
O
i) H3C H
O O
ii) H3C
O
CH3 CH3
iii) CH3

SAQ 2
Why enolate anions are more reactive than enol form?

14.3 GENERATION OF ENOLATES

Acidity of the reactants having -hydrogen such as aldehydes or ketones
determines which base can be used for generating enolates. For complete
conversion, the base must be weaker acid than the reactants. In other words,
the reagent must be a stronger base than the enolate anion of the reactant.
Beside these, solvents and other coordinating or chelating agents also have
strong effect on the formation of enolates. Let is now explain all these points
using some examples.

The pKa values of the CH of acetone and other similar ketones are about
20 (Ka = 1020) while the pKa of typical base like,
- -
-OH- = pK a 15.7 , H3C O , = 16.5 , (CH3)3C O = 19

These bases are much less basic than the enolate ions. As a result, they
convert only a small fraction of ketones, aldehydes or other carboxyl
compound having  hydrogen, to their corresponding enolates. Thus, by
comparing the approximate pKa values of the bases with those of the reactant
of interest, it is possible to estimate the position of the acid-base equilibrium
144 for a given reactant-base combination.
Unit 14 Enolates

If we consider the case of a simple alkyl ketone in a protic solvent such as

ethyl alcohol, for example, we see that hydroxide ion or primary alkoxide ions
will convert only a fraction of a ketone to its anion.

O O-
-
R C CH3 + H3C O , R C CH2 + CH3OH K<1

The slightly more basic tertiary alkoxides are comparable to the enolates in
basicity, and a more favorable equilibrium will be established with such bases.

O O-
-
R C CH3 + (CH3)3C O , R C CH2 + (CH3)3OH K~1

In DMSO, ketones such as acetone are slightly more acidic than in the simple
alcohols. Therefore, use of alkoxide bases in DMSO favors enolate formation.
All these typical bases besides providing low concentration of enolates, they
are also potential neucleophiles in condensation and substitution reactions.

For the amide bases, such as NaH, NaNH2, ((CH3)2CH2)2NLi (lithium

disiopropylamide (LDA) (pKa ~ 36, the equilibrium can be shifted to right
Ka(B−H) << Ka(C−H), and complete formation of the enolate occurs.

O O-
-
R C CH3 + R 2N R C CH2 + R2NH K >> 1

All these bases have higher pKa. The pKa difference between acetone and
LDA is 20 on the other hand it is 1 in case of acetone and tertiary alkoxides.

Solvents also play important role in generation of enolates. Solvent like water
and alcohols act as acids and they can protonate enolates. Therefore,
solvents not having acidic protons are preferred for achieving high
concentration of enolates. Aprotic solvents such as dimethyl sulphoxide
(DMSO), 1,2-dimethoxyethane (DME), tetrahydrofuran (THF) N,N-
dimethylformamide (DMF) and liquid NH3 are commonly used.

O CH3
H C N NH3
CH3OCH2CH2OCH3
O CH3
1,2-dimethoxyethane Tetrahydrofuran N,N-dimethylformamide ammonia
(DME) (THF) (DMF)

From above discussion it can be concluded that both bases and solvents play
very important role in generation of enolates.

SAQ 3
Why do we prefer aprotic solvents for generation of enolates?

145
Block 4 Organic Synthesis: Some More Approaches

14.3.1 Regioselectivity and Stereoselectivity in

Enolates Formation
Deprotonation from the α-position of carbonyl compounds is the basic method
for the generation of enolates. An unsymmetrical dialkyl ketone can form two
regioisomeric enolates on deprotonation. Consider following substituted
ketone:

O O- O-
-
B:
R2CH C CH2R1 R2CH C CHR1 + R2C C CHR1

In this example, there are two sites of deprotonation leading to two different
types of enolates. Although it may not be possible to generate only one type of
enolate, but experimental conditions can be created to favor one of the
regioisomers. The composition of an enolate mixture is regulated by kinetic or
thermodynamic factors. The enolate ratio is determined by the relative rates of
the competing proton abstraction reactions. In the example given below,
secondary protons are more accessible protons for deprotonation.
Deprotonation of these protons will give kinetic control product. On the other
hand deprotonation of tertiary proton leads to more stable enolate because of
higher degree of substitution of the double, thus formation of stable enolate is
thermodynamically controlled.
O
H3C CH3
H3C C C C H
H H
Less acidic and more hindered
More acidic accessible proton
proton

O-
R2CH C CHR1
Ka
O A [A] K
 a
kinetic enolate [B] Kb
R2CH C CH2R1 + B:-
O-
Kb R2C C CH2R1
B
thermodynamic enolate

The regioselectivity of enolate formation can be controlled by following factors:

 Solvent

 Base

 Cation

 Temperature

By controlling reaction conditions for the formation of an enolate, it is possible

to obtain either kinetic or thermodynamic control enolate. Kinetic control
enolate is usually a less substituted enolate. Conditions for kinetic control of
146 enolate formation are those in which deprotonation is rapid, quantitative and
Unit 14 Enolates

irreversible. This can be achieved by using very strong base such as LDA or
LiHMDS in an aprotic solvent such as DMSO in absence of excess ketone.
Lithium ion is better counter ion than sodium or potassium as it maintain a
tighter coordination at oxygen and reduce the rate of proton exchange. H3C
Li
N CH3

H3C CH3
Aprotic solvents also favour the formation of kinetic product as protic solvents
protonate oxygen which gives rise to the thermodynamically controlled Lithiumtetramethylpiperidene
(LTMP)
enolate. Excess ketone also catalyses the equilibrium by proton exchange.
Less hindered hydrogens also favour formation of kinetic enolates as they are Si(CH3)3
more acidic and their removals are faster than removal of more hindered N Li
(H3C)3Si
hydrogen. Higher temperature, weaker base and protic solvent such as ROH
Lithiumhexamethyldisilazide
favour formation of thermodynamic enolates. The equilibrium ratios of enolates (LHMDS)

for some ketone-enolate systems are also shown in Table 14.1.

Table 14.1: Composition of Enolate Mixture Formed under Kinetic and

Thermodynamic Control
O O- O- O-
CH3CH2 C CH3 C H3C C C
o CH3CH2 CH2 CH3 CH3
Kinetic (LDA, 0 C)
CH3
71% 13% Z form 16% E Form
-
O O
- O O
-

CH3(CH2)3 C CH3 C CH3(CH2)2 C C

CH2 CH3 CH3
CH3(CH2)3
(CH2)CH3
o
Kinetic (LDA, -78 C) 100%
o
Thermodynamic (KH,20 C) 42% 46% Z form 12% E Form
O O - O-

(CH3)2CH C CH3 C H3C C

CH2 CH3
(CH3)CH
o
CH3
Kinetic (KHMDS,-78 C) 99% 1%
o
Thermodynamic (KH,20 C) 88% 12%
O O- O-
CH3 CH3 CH3

o
Kinetic (LDA,0 C) 99% 1%
Thermodynamic 26% 74%
o
(NaH,20 C)

In addition to thermodynamic and kinetically formed enolates based on kinetic

conditions as well as degrees of substitution of the double bond there is
another characterization in enolates based on whether the alkyl group is on
the same side of the double bond as the enolate oxygen or on the opposite
side. If the alkyl group is on the same side of the double bond as the oxygen
this is referred to as the Z (zusammen = together) configuration, this
configuration is generally more stable. If the alkyl group is on the opposite side
of the double bond from the oxygen this is referred to as the E (entgegen =
opposite) configuration and is generally less stable. The ratio of E & Z isomers
depends on the nature of base used for enolate formation and nature of
substituents. Consider the formation of enolates using variety of bases in
kinetic control condition. 147
Block 4 Organic Synthesis: Some More Approaches

H3C
O O-
Base
H3C CH3 H3C CH3 + H3C
THF/Hexane
O-
CH3 CH3 CH3

Z enolate E enolate

Base: LDA 56% 44%

LiHMDS 98% 02%
LiNPh2 100%
LiTMP 04% 96%

From above example it can be inferred that LiHMDS generally provides the Z
enolate as the major product and LTMP being a very bulky gives the E enolate
as the major product. Such stereoselectivity can be explained on the basis of
chair-like transition state. Consider following example:

O OLi OLi
LDA
CH3 CH3 +
R 1 R1 R1

Z enolate E enolate CH3

In a ketone shown above Z-enolate is favoured if R1 is large but E-enolate is

favoured if R1 is small. Consider the transition states (TS) formed during the
reaction as given below.
iPr iPr OLi
H CH3
O N + O N+ CH3
Li Li
iPr iPr R1
H H
1 CH3 1 H Z enolate
LDA R R
O OLi
iPr iPr
CH3 CH3 H
O N+ O N+
R1 Li R1
Li
iPr iPr
H H E enolate CH3
1 H R
1 CH3
R

The interactions shown above are important for determining the

stereochemical outcome of the reaction.

 if R1 is large, this TS is destabilised by R1, CH3 interaction and Z

predominates

 if R1 is small, 1,3-diaxial interaction is important as it destabilises this TS

and E predominates. Therefore, bulky bases like LTMP favour the
formation of E-Enolate

Esters and amide also form enolates on treatment with strong bases. In these
cases -proton is less acidic than in a ketone. In case of esters, the formation
of E enolates is favoured whereas tertiary amides tend to form Z enolates.
This again can be explained by formation of cyclic transition states as shown
148 below:
Unit 14 Enolates

iPr OLi
CH3 H3C CH3
O N +
Li O
H3C iPr
H Z enolate
O H
O OLi
iPr
H3C CH3 H H3C
LDA
O N+ O
O Li
iPr
H3C H E enolate CH3
O CH3
predominates

iPr OLi
H CH3
O N+ Et
Li N
Et iPr Z enolate
H Et
N
CH3 OLi
O Et
iPr
CH3 LDA CH3 Et
O N+ N
Et N Li
iPr Et
Et H CH3
Et N H
E enolate
Et predominates

You can see in case of esters 1, 3 diaxial interactions discourage the

formation of Z-enolate. On the other hand in substituded amides its subsituant
and the –CH3 interaction discourages formation of E-enolate.

These arguments are good generalizations and many other factors also affect
stereoselectivity of enolates. For example, use of the additive HMPA
(hexamethylphosphoric triamide) reduces coordination and favours the
thermodynamically more stable enolate.
OLi
OLi H3C
O LDA H3C CH3 + O
CH3
H3C O
O CH3
Z enolate E enolate
THF 6% 94%
82% 18%
THF/HMPA

General observation

 LHMDS generally provides the Z enolate as major product

 LTMP (very bulky) affords the E enolate as the major product
 LDA gives intermediate result
 Use of HMPA as a strong Lewis basic donor-co-solvent can reverse
selectivity.
Enolates can also be prepared by other methods than deprotonation of α-
hydrogen. For example enolates can be obtained by the cleavage of
trimethylsilyl enol ether or enol acetate by methyl lithium. Alkoxides can also
be used to cleave silyl enol ethers and enol acetates. 149
Block 4 Organic Synthesis: Some More Approaches

OTMS O- Li +

CH3Li
DME

OTMS O-K+

t-Bu-K+

Trimethylsilyl enol ethers are readily prepared by trapping lithium enolate with
TMSCl.
O OTMS

LDA, 78oC

TMSCl, THF

SAQ 4
Draw the enolate formed when following compounds are treated in the
specified condition given in each case.
O
C2H5ONa LDA
i) H3C H
C2H5OH THF, -78oC

O
C2H5ONa LDA
ii) H3C CH3
C2H5OH THF, -78oC
CH3

O LDA
C2H5ONa
iii) THF, -78oC
C2H5OH
CH3

LDA O
LDA
iv) H3C CH3
o
THF+ HMPA, -78 C O THF, -78oC

14.4 REACTIONS OF ENOLATES

The enolates are ambident nucleophiles and they can react either by oxygen
150 or carbon ends.
Unit 14 Enolates

Acid-base reaction:

O- OH
-
+ B H + B

enol

Nucleophilic-Electrophilic reaction:

O O O-
O –
O -
C C + C C C C
C C

O-
O O–
C + C C C O C C

vinylether

Soft electrophiles such as carbon electrophiles tend to intract with carbon

centre and hard electrophile such as H+ prefer to intract with oxygen. This can
A soft elecrophile is
also be explained on the basis of MO theory. The highest occupied molecular one in which the
orbital (HOMO) of enolate is delocalized between carbonyl oxygen and - positive charge able
carbon. Both sides can act as nucleophilic centres but the carbon centre is a to spread over a
better nucleophile because the HOMO is distorted towards carbon centre and larger area.
negative charge is centred on oxygen (see Fig. 14.1). Thus reactions which
are dominated by charges and electrostatic interactions occur at the oxygen
and reactions which are dominated by orbital interaction occur at the -carbon.

Fig. 14.1: The charge density map of the highest occupied molecular orbital
(HOMO).

14.4.1 Halogenation
In these reactions, halogens are the electrophiles that react with the
nucleophilic enolate.

O
LDA
O-Li + Cl Cl O
Cl
-Cl-

These reactions occur by a SN2 process. You have already studied such
reaction in quite detail in your under graduate programme. 151
Block 4 Organic Synthesis: Some More Approaches

14.4.2 Enolate Alkylation: Reactions of Relatively

Acidic Compounds
Malonic esters and β-ketoesters are relativity acidic compounds. These
compounds generate enolate equivalent mild reaction conditions using metal
alkoxides as base. The presence of two electron withdrawing substituants
facilitates formation of the enolates. Enolate alkylation reactions occur by a
SN2 process, therefore primary alkyl halides, allylic halides and benzylic
halides are most reactive alkylating agents. Secondary alkyl halides react
more slowly and give only moderate yields because of competing elimination
reactions. Tertiary halides give mainly elimination products.

Two examples of this class extensively used in alkylation reactions are

acetoacetic ester (ethyl acetoacetate) and malonic ester (diethyl malonate)

O
O O C OC2H5 O
H3C C CH C OC2H5 H HC
H C OC2H5 H 2C CH3
ethyl acetoacetate O H
pKa = 11 malonic ester Acetone
pKa = 13 pKa = 20

In both cases, α-hydrogen is alpha to two carbonyl groups, the negative

charge on the anions which are formed on deprotonation (enolates) can be
delocalized by both the C=O groups. Such hydrogens are more acidic than
that of a ketone. Therefore these enolates can be generated in high
concentration even using alkoxide bases in alcoholic solvents.

O O C2H5O Na
- + O O O O-
-
H3C C CH C OC2H5 H3C C CH C OC2H5 H3C C CH C OC2H5
C2H5OH
H O– O
H3C C CH C OC2H5

Similar resonating structures can also be drawn for malonic ester. The
enolates formed by these esters undergo substitution reactions with alkyl
halides.

O O - +
O O
C2H5O Na , C2H5OH
H3C C CH C OC2H5 H3C C CH C OC2H5
RX
H R
Above reaction illustrates the synthetic applications of acetoacetic and molanic
esters in which two factors are important

(i) enolate can be generated using mild bases such as metal allkoxides.

(ii) Higher nucleophilic reactivity of the enolates in displacing halogen from

allyl halides and similar alkylating agents, and

152 (iii) Extreme ease of decarboxylation of -ketoacids.

Unit 14 Enolates

The monoalkyl acetoacetic ester may be treated with a base followed by

addition of a different alkyl or allyl halide, alkaline hydrolysis (saponification)
and decarboxylation (warming with dil.acids) gives a ketone that branched at
the -carbon.
O R O - + O R O
C2 H5O Na , C2H5OH
H3C C C C OC2H5 H3C C C C OC2H5
CH2=CHCH2Br
H H2C CH CH2
1. OH-, H2O O
2. dil.H2SO4 H3C C CH CH2 CH CH2
R

Cyclic products (3, 5, 6 and 7 carbon rings) can be formed if the dialkylation is
done using dihaloalkane.
O CH3
O O H
1. C2H5ONa, C2H5OH
H3C C CH C OC2H5
2. Br(CH2)4Br
H
H
3. OH-, H2O
4. dil.H2SO4,

Malonic ester, like acetoacetic ester, when treated with base, generates the
enolate ions which are also very reactive. Addition of alkylating agents
followed by hydrolysis and decarboxylation gives carboxylic acids. Mono or
dialkyl ethanoic acids are preferably prepared by this method.

1. C2H5ONa, C2H5OH dil. HCl,

CH2(CO2C2H5)2 RCH(CO2C2H5)2 RCH2COOH
2. RX D
1. C2H5ONa, C2H5OH
2. R'X
RCR'(CO C H ) dil. HCl
2 2 5 RCHR'COOH
D
Dicarboxylic acids and keto acids can be prepared using malonic ester.

1. C2H5ONa, C2H5OH
CH2COOH
2. ClCH2CO2C2H5
CH2(CO2C2H5)2
3. OH-, H2O CH2COOH
4. dil. HCl, D

1. C2H5ONa, C2H5OH
2. CH3CO(CH2)3Cl
CH2(CO2C2H5)2 CH3CO(CH2)4CO2H
3. OH-, H2O
4. dil. HCl, D dketo heptanoic acid

Alicylic compounds have been prepared by the reaction of enolate of mulanic

ester with dihaloalkane.

1. C2H5ONa, C2H5OH
2. Br(CH2)3Br
CH2(CO2C2H5)2
3. OH-, H2O COOH
4. dil. HCl, D H 153
Block 4 Organic Synthesis: Some More Approaches

SAQ 5
Predict the products of the following reactions
O O - + H+, H2O
C2H5O Na , C2H5OH
i) H3C C CH2 C OC2H5
BrCH2CH2CH2Br
O O - + H+, H2O
C2 H5O Na , C2H5OH
ii) H3C C CH2 C OC2H5
BrCH2COCH3

O
Br2 Base
iii)
NaOH

1. C2H5ONa, C2H5OH H+, H2O

iv) CH2(CO2C2H5)2
2. CH3CH2CH2Br

14.4.3 Alkylation of Ketone Enolates

Alkylations of ketone enolates are usually more useful than alkylation of
aldehyde enolates. With aldehydes, it is difficult to avoid condensation
reactions because -carbon of aldehydes are better electrophile. We have
seen earlier that selective enolate formations are possible in case of
unsymetrical ketones. It is also possible to develop reaction conditions for
stoichiometric formation of both kinetically and thermodynamically controlled
enolates. All these factors permit us to use of enolate alkylation reactions in
multi step synthesis of complex molecules. One of the important aspects of
the alkylation reaction is that we can achieve stereoselectivity. The alkylation
has a stereo electronic preference for approach of the electrophile
perpendicular to the plane of the enolate, because the π electrons are
involved in bond formation. A major factor in determining the stereoselectivity
of ketone enolate alkylations is the difference in steric hindrance on the two
faces of the enolate. The electrophile approaches from the less hindered of
the two faces and the degree of stereoselectivity depends on the steric
differentiation. Numerous examples of such effects have been observed. For
analyzing the stereoselectivity of enolate alkylation reactions let us consider
following example.

Consider a β,β-disubstituted enolate, in this case alkylation usually takes place

anti to the larger substituent, R.

O- H3C O- H3C O-
CH3Br
CH C CH HC + CH HC
H3C H3C H3 C
CH3 CH3 CH3
R H R H R H
R = Ph or i-Pr Minor Major

Major : Minor
R = Ph 60 : 40
R = i-pr 75 : 25
154
Unit 14 Enolates

In such cases the major factors which decide approach of electrophile are the
conformation of the enolate, the stereoelectronic requirement for an
approximately perpendicular trajectory, the steric preference for the least
hindered path of approach, and minimization of torsional strain. In above case
R being a bulky group, electrophile will preferably approach anti to R group. In
Fig. 14.2 we have shown trajectory of approach of the enolate and alkyl
halide.
d
leaving group Br Br
s* orbital(LUMO) of
electrophile
H H
H H
H H H H  H
Od O
–
O -
-Br
CH C H C C
H3C H3C H3C
CH3 CH3 CH3
R H R H R H

Fig. 14.2 : Attack of enolate on an electrophilic centre.

As mentioned earlier these reactions follow SN2 mechanism, therefore, these

reaction are more feasible for 1 or 2, as well as allylic or benzylic halides. In
the case of 3 alkyl halides, we mainly observed E2 elimination with enolate
ion serving as the base.

Some elimination can occur even in 1 and 2 alkyl halides. This can be
reduced by replacing halogen group with better leaving groups (L = OSO 2R,
-OTs, etc.).

Regioselectivity in alkylation of unsymetrical ketones can be achieved by

preparing regioselective enolate intermediates using reaction conditions as
discussed earlier. This can also be achieved by preparing enol acetates and
silyl enol ethers. Both enol acetate and silyl ethers are readily formed by
trapping enolates with acetyl chloride and TMSCl, respectively. The isomers of
enol acetates and silyl enol ethers can be separated using physical methods
and their pure forms then converted to lithium enolate on treatment with
methyl lithium. Alkylation reaction of each lithium enolates gives the
corresponding -alkylate carbonyl compound (see example below).
O O- O-
R2 strong base R2 R2
R1 CH2 C HC R1 CH C HC R1 CH2 C C
R3 R3 CH3COCl R3
CH3COCl

OCOCH3 OCOCH3 2
R2 R
isolatable, separate and R CH1
C HC 1
R CH2 C C
purify
R3 R3
Enol acetate A Enol acetate B

CH3Li
CH3Li

O-Li + O-Li+
R2 R2
R1 CH C HC R1 CH2 C C
R4X R4X
R3 R3
2
O O R
R2
1 1
R CH C HC R CH2 C C R3
4 3 4
R R R 155
Block 4 Organic Synthesis: Some More Approaches

Both enol acetates and silyl enol esters can also be directly alkylated with alkyl
halides in the presence of Lewis acids. Lewis acid forms a complex to the
halogen atom making it a better leaving group.

OTMS R2X O
R2
R1 CH2 R1
OCOCH3 O
R2X
R2
R1 CH2 R1

These reactions may follow SN1 reaction. Especially in case of tertiary alkyl
halides, allylic and benzylic halides as all there system are capable of
stabilising positive charge.

In cyclic system, ring conformation and nature of substituants are the

dominant factor. In case of 4-t-butylcyclohexanone, there is little steric
differentiation for cis and trans approaches of electrophile. The alkylation
product is a nearly 1:1 mixture of the cis and trans isomers.

-
O O O
CH3I
(CH3) 3C (CH3 ) 3C + (CH3) 3C
H CH3
CH3 H

The introduction of an alkyl substituent at the α-carbon in the enolate

enhances stereoselectivity. This is due to a steric effect in the enolate. In such
cases, the electrophile approaches from an axial trajectory preferably. This
approaches leads directly into chair-like product (A). Equatorial approach
leads to a higher energy twisted-boat conformation (see structure D) which
finally leads to structure B.
-
O O O
CH3I
(CH3) 3C (CH3) 3C + (CH3)3C
R R CH3
CH3
R
70-90% 30-10%

A B

H Axial
tBu A H
CH3I O

tBu +
R O
R tBu
O-
CH3 R
B
C D H3C
equatorial
156
Unit 14 Enolates

SAQ 6
Predict the product(s) for each of the following alkylation reactions:
O
1. LDA/THF, -78 oC
a) H3C CH3
2. C2H5I
O
CH3 1. NaOC H /EtOH
2 5
b) 2. CH3Br

O
CH3 1. LDA, 0 oC
c)
2. CH3Br

O
1. NaH, 20 oC
d) H3C CH3
CH3 2. C2H5I

14.4.4 Alkylation of ,-unsaturated Ketones

In the case of ,-unsaturated ketones, there are three potential sites from
where electrophile attack on the enolate can take place. These are oxygen,
the -carbon, and the  carbon. The  site is kinetically favourable for the
electrophilic attack.

d d d
O 
 

This selectivity may be due to the fact that -carbon has greater negative
charge as compared with  carbon.

O O-Li + O O
CH3 CH3
CH3 CH3 CH I H3C
Li,NH3 3 CH3 CH3
+

60 % 28 %

O O - Li + O
CH2CH=CH2
Li,NH3 CH2=CHCH2Br

CH3 CH3 CH3

45 %
tans/cis 20/1
157
Block 4 Organic Synthesis: Some More Approaches

14.4.5 Alkylation of Aldehydes, Esters, Carboxylic

Acids and Amides
As mentioned earlier alkylation of ketones has wider applications in synthetic
chemistry. Since direct alkylation of aldehydes leads to condensation reactions
mainly in presence of base, we can use the indirect approach as shown below:

Li+
NH2 R2C C H
R2CH C H
(C2H5)2N-Li+ N
N
R2CH C H +
O
R 2C C H NH2
R'
CH3 N
R'X H3O+
R 2C C H +
O

In above reaction, we have converted aldehyde to an imine and then this react
with strong base to give an enolate type ion. Reaction of this ion with alkyl
halide gives an -alkylated imine that can be hydrolyzed to give the -alkyl
aldehydes.

Both esters and amides can also be alkylated. Unlike ketones, they give one
enolate ion on reaction with base and they are less reactive than aldehydes in
aldol reactions.
R'
LDA,THF R'X
R2CH C OEt R2C C OEt R2C C OEt
+
O O- Li O
R'
LDA,THF R'X
R2CH C NR 2 R2C C NR 2 R2C C NR 2
+
O O- Li O

Similar to ketone, the stereochemistry of alkylation of esters and amides

depends on steric factors mainly.
CH3 O CH3 O CH3 O
LDA,THF
CH3 CH3 CH3
Ph O CH3I Ph O + Ph O

CH3 CH3

55 % 45 %

DMPS O DMPS O DMPS O

LHMDS
CH3 CH3 CH3
Ph O CH3I Ph O + Ph O

CH3 CH3
DMPS = -dimethylphenylsilyl 97 % 05 %

158
Unit 14 Enolates

This stereoselectivity is the result of the conformation of the enolate and steric
shielding by the silyl substituent. Such directive effect has been employed in
stereoselective synthesis. In next section we will further elaborate this
concept.

Strong bases convert carboxylic into enolate dianion. This dianion will react
with haloalkane to give the -alkylated carboxylic ion.

R'
LDA,THF R'X
R2CH C OH R2C C O- R2C C O-
O O- Li+ O

14.4.6 Control of Enantioselectivity in Alkylation

Reactions
The alkylation of an enolate generate new stereogenic centre when
 substituents are nonidentical. In enantioselective synthesis, it is necessary
to control the direction of approach and thus the configuration of the new
stereocentre.

OH
O O
R 1 Base CH3 R1
R +
CH3I R R1 R
R2 2 CH3
R R2

Enantioselective enolate alkylation can be achieved using chiral auxiliaries

such as oxazolidinones. Many other chiral auxiliaries have been developed in
past, but here we will consider some exampled of oxazolidinones.

O O O O

O NH O NH O NH O NH

Ph CH3 iPr Ph
CH2Ph
cis-4-methyl-5-phenyl 4-benzyl derivative 4-isopropyl derivative 4-phenyl derivative
detivative

The 4-isopropyle and 4-benzyl oxazolidinones can be obtained from valine

and phenylalanine, respectively. Other derivatives can also be synthesized
easily. These chiral auxiliaries can be attached to an appropriate substrate by
N-acylation reaction using n-BuLi as a base.

O O O
o
n-BuLi, THF, -78 C CH3
O NH O N
O
CH3
Cl
CH2Ph CH2Ph

The above product with LDA generates mainly z-enolate. The electrophiles
have a tendency to attack from the opposite face of the chiral controlling group
at C4 position of oxazolidine ring. The high to excellent diastereoselectivity in 159
Block 4 Organic Synthesis: Some More Approaches

alkylation reactions of oxazolidinones as chiral auxiliary has been well

established.
Li+
O O O O- O O
CH3 CH3
O N CH3
LDA O N R'X O N R'

Ph CH3 H
(I) Ph CH3 Ph CH3
Li+
O O O O- O O
CH3 R'
O N CH3
LDA O N R'X O N CH3
H
(II) CH2Ph
CH2Ph CH2Ph

In (I) the lower face is shielded by the methyl and phenyl groups, whereas in
(II) the upper face is shielded by the benzyl group. As a result, alkylation of the
two derivatives gives products of the opposite configuration. The initial
alkylation product ratios are typically 95:5 in favor of the major isomer. These
diastereomeric mixtures can be separated and purified. Subsequent hydrolysis
or alcoholysis provides acids or esters in enantiomerically enriched form.
Alternatively, the acyl imides can be reduced to alcohols or aldehydes. The
final products can often be obtained in greater than 99% enantiomeric purity.
O O O O O- O O
CH3 CH3
CH3
O NH RCH2COCl O N
LDA, THF O N O N
EtI C2 H 5
n-BuLi
Ph CH3 H
Ph CH3 Ph CH3 Ph CH3
O
LiOH, H2O H3C
OH 97% e.e.

C2 H 5

14.4.7 Nucleophilic Addition of Enolates on Carbonyl

Compounds
In earlier Sub-section we have described reaction of enolates with alkylating
agents such as alkyl halides. In this Sub-section we will discuss chemistry of
the nucleophilic attack by enolates on carbonyl groups of aldehydes or
ketones.

The nucleophilic addition reactions of enolate on carbonyl compounds are

most useful methods for carbon-carbon bond formation. Some important
examples of such reactions are the aldol reaction, the Robinson annulation,
the Claisen condensation, carbon acylation methods, the Wittig reaction and
other olefination methods. Here our focus will be on aldol reactions.

An aldol reaction is the nucleophilic attack on a carbonyl group by an enol or

enolate to create a beta hydroxy carbonyl compound. If the reaction is
followed by dehydration, it results in the formation of a double bond and the
reaction is called an aldol condensation. The aldol reaction is the most
important reaction for lengthening a carbon chain that contains chiral centers.
In most cases, this can be achieved by using enolates of smaller metal ions
160 such as lithium, boron, titanium, tin, and zirconium etc..
Unit 14 Enolates

As we have discussed earlier, the enolates that participate in an aldol reaction

can be formed under two types of conditions, either thermodynamic
deprotonation or kinetic deprotonation. A thermodynamically formed enolate
generally has the most substituted double bond or conjugated double bond
and is more stable because of the substitution. The kinetically formed enolate
is formed by the removal of the most easily (accessible) proton and they are
generally less substituted. If the thermodynamic product is desired, then a
larger or more loosely held counter ion such as sodium or potassium is used
as this allows for proton exchange and the reaction is done in a protic solvent
at warmer temperatures and the enolate is allowed to come to equilibrium with
its most stable form. When the kinetically deprotonated enolate is desired, a
smaller more tightly bound counter ion such as lithium or boron is used as this
decreases the rate of proton exchange, and an aprotic solvent and cold
temperatures (generally from -80°C to -35°C) are also used . Usually a
sterically hindered strong base is employed which cannot act as a nucleophile.

As mentioned earlier, these enolates may be E-enolate or Z-enolate based on

whether the alkyl group is on the same side of the double bond as the enolate
oxygen or on the opposite side. In aldol reactions, it is observed that Z-
enolates predominantly give syn addition whereas the E-enolate
predominantly gives the anti addition product. The anti and syn isomers are
called diastereomers and these terms refer to the orientation of the α and β
substituents and are with respect to the lowest energy conformation of the
molecule.

O
O OH
OH H R2
CH3 R2
R1 R1

Z-Enolate CH3
O syn-aldol

OH O OH
H R2
R1 R1 R2
CH3 CH3 anti-aldol
E-Enolate

Generally the diastereoselectivity of an aldol reaction using thermodynamically

formed Z-enolate is higher than for the kinetically formed E-enolates.
Formation of syn and anti products of aldol reaction can be understood on the
basis of cyclic chair model of transition state. (See Fig. 14.3). The stability of
the transition states is mostly governed by the 1,3 diaxial interactions. In the
case of the most favorable pathway for the reaction of the Z-enolate and an
aldehyde, the 1, 3 interactions are better if R1 is axial and R3 is equatorial [TS
A (Fig. 14.3)] rather than both groups being axial the alkyl groups [TS B (Fig.
14.3)]. For the most favorable reaction pathway for the E-enolate the same 1,3
interactions prevail TS C rather than TS D (Fig. 14.3). Thus, aldol reactions
are stereospecific with respect to the E- or Z-configuration of the enolate. The
E-enolate gives the anti aldol product, whereas the Z-enolate gives the syn-
aldol. 161
Block 4 Organic Synthesis: Some More Approaches

R
1
L O OH
H
O M
H R1 R2
O L
(A) H3C R2 CH3 syn-aldol
OH O
Favoured
CH3 LDA 1
L O OH
R1 + H R2 R 2
R
(B) O M
Z-Enolate H R1 R2
O L
H3C H CH3 anti-aldol

R
1
L O OH
H
O M
H3C R1 R2
O L
CH3 anti-aldol
OH O (C) H R2
Favoured
+ H LDA 1
R 2 L O OH
R1 R2 R
CH3 (D) O M
H3C R1 R2
O L
E-Enolate syn-aldol
H H CH3

+
Fig. 14.3: Cyclic Transition model for E-enolates and Z-enolates; M = Li ion,
Boron or any other metal ion.

Diastereoselection is best when using smaller metal ions such as lithium and
boron that form short metal-oxygen bonds as this gives a tighter transition
state and maximizes steric interactions. The steric interaction can further be
increased by using one bulky group in enolate. Now consider following
example.

OH OH
OLi OLi O O
O C6H5CHO
LDA
R1 + R1 R1 CH3+ R1 CH3
R1 CH2CH3 -78 oC
CH3 CH3 CH3
CH3
E-Enolate Z-Enolate anti-aldol syn-aldol

E:Z 2,3 anti : syn

R1 = -C2H5 70:30 36:64

-CH(CH3)2 40:60 18:82

-C(CH3)3 2:98 2:98

In this case ketone enolates with more bulky substituents show an increasing
stereoselectivity in the order: ethyl < i-propyl < t-butyl.

The enolates derived from cyclic ketones are necessarily E-isomers. The
enolate of cyclohexanone reacts with benzaldehyde to give both possible
stereoisomeric products. The stereoselectivity is about 5:1 in favor of the anti
isomer under optimum conditions.

OLi O OH O OH

-78 oC OH OH
+ PhCHO +
THF

Major Minor

From these and many related examples the following generalizations can be
162 made about stereoselection in aldol additions of lithium enolates.
Unit 14 Enolates

 The chair TS model provides a basis for analyzing the stereoselectivity

observed in aldol reactions of ketone enolates having one bulky substituent.
The preference is Z-enolate→syn aldol; E-enolate→anti aldol.
 When the enolate has no bulky substituent, stereoselectivity is low.
 Z-Enolates are more stereoselective than E-enolates.

Boron Enolates in Aldol Reactions

Stereoselctivity of aldol reaction of boron enlolates is also predicted on the

basis of cyclic TS similar to that for lithium enolates and the same relationship
exists between enolate configuration and product stereochemistry. Boron
enolates much more stereoselective than lithium enolates.The shorter B-O
bond compared to Li-O bond leads to a tighter cyclic T.S. and accounts for the
improved stereoselectivity.

Z-Boron enolate can be prepared by the reaction of ketone with dialkylboron

trifluoromethanesulfonate (triflate) and a tertiary amine. Use of boron triflates
and a bulky amine favors the Z-enolate. The resulting aldol products are
predominantly the syn product.
OH
OB(n-Bu)2 O
O (n-Bu)2BOTf C6H5CHO
CH3 CH3 CH3
Et iPr2NEt, Et2O Et -78 oC Et
o
-78 C , 30 min Z-Enolate CH3 syn-aldol
>97%

The combination of (c-Hex)2BCl and Et3N provides the E-boron enolate

preferentially. Bulkier group such as dicyclohexylboron chloride, favours
formation of E-enolates.
OH
OB(c-Hex) 2 O
O (c-HEx)2BClTf C6H5CHO
CH3 CH3
Et Et2N, Et2O Et -78 oC Et
-78 oC , 10 min CH3 CH3 anti-aldol

E-Enolate >97%

Though 9-BBN (9-borabicyclononane) looks bulky, but most of it is ‘tied-back’

behind boron thus allowing formation of the Z-enolate.
OH
O OBBN O
Et3N C6H5CHO
CH3 + CH3 CH3
Et Et -78 oC Et
B Z-Enolate
TfO CH3 syn-aldol
>95%

The E-boron enolate from cyclohexanone shows a preference for the anti aldol
product. The ratio depends on the boron alkyl groups and is modest (2:1) with
di-n-butylboron but greater than 20:1 for cyclopentyl-n-hexylboron.

OBR2 O OH O OH

R R
+ RCHO +

Major Minor 163

Block 4 Organic Synthesis: Some More Approaches

Beside Lithium and boron enolates aldol reactions can also be conducted
using titanium, tin, and zirconium enolates.

Similar to alkylation reactions, we can also create facial discrimination in aldol

reactions by using either the aldehyde or the enolate, or both, as chiral entities
(substrate control). Also as in to alkylation reactions, this can also be achieved
by attaching chiral auxiliaries to the carbonyl compound before enolization and
then removing after the reaction (auxiliary control). Beside these approaches,
using chiral ligands at the metal centre also provides an alternative approach
to controlling the stereochemical outcome of aldol reactions (reagent control).
In Fig. 14.4 we have summarized all three commonly used approaches for
achieving stereochemical outcome of aldol reactions.

O OH O OH
xMLn 2 R3CHO *
R2 R
R3
R1 R1 R1 *
R2

Fig. 14.4: Substrate control if stereoinduction from R1, R2 or R3; Auxiliary

1
control if stereoinduction from R = a chiral auxiliary; Reagent
control if stereoinduction from MLn or added Lewis Acid.

For mixed aldol reactions, enolates of esters, thiol esters, amides, and imides,
Silyl Enol Ethers can including several that serve as chiral auxiliaries can be prepared similar to
be readily formed by
those for ketones. Lithium, boron, titanium, and tin derivatives have all been
trapping a lithium
enolate with TMSCl. widely used in the synthesis.

O OTMS Silyl Enol Ethers in Aldol Reactions (Mukaiyama Aldol Reaction)

o
LDA, -78 C

TMSCl The Mukaiyama aldol reaction refers to Lewis acid–catalyzed aldol addition
reactions of silyl enol ethers. Silyl enol ethers are much less nucleophilic than
boron or lithium enolates and do not react directly with aldehydes. Therefore,
Lewis acid such as TiCl4 is used to increase the electrophilicity of carbonyl
group to allow aldol reaction.

LA OH
H + O
TMSO O
+ R1 R
2 R CH3
R1 R R2

The reaction mechanism is quite different to that of lithium or boron enolates

described above. These reactions proceed through an open T.S.
Stereoselectivity of these reactions are usually low. But, the use of chiral
Lewis acids in sub-stoichiometric quantities provides important methods for
controlling the stereoselectivity of these reactions and thus these reactions are
rapidly becoming a very useful method.

Beside TiCl4, and SnCl4 quite a number of other Lewis acids can be used for
Mukaiyama aldol reaction, including Bu2Sn(O3SCF3), Bu3SnClO4,
164 Sn(O3SCF3), Zn(O3SCF3) and LiClO4.
Unit 14 Enolates

SAQ 7
Complete following reaction and also indicate the major product.
O
LDA PhCHO
a) CH3
(CH3)3
O

LDA PhCHO
b)

O (C2H5 )3N C6H5CHO

c) CH3 + 9BBN
R -78 oC

14.4.8 Nitrogen Analogs of Enols and Enolates:

Enamines and Imines
The nitrogen analogs of aldehyds and ketones are called imine or Schiff
bases. The imine is prepared by the condensation of aldehyde or ketones with
primary amines.

O N R
C + H2N R C
R R R R
Imine

When we use secondary amines, they react with aldehydes or ketones having
α-hydrogen in the presence of acidic catalyst to give enamines.
R
O R N R
Acid catalyst
+ HN R C + H2O
C
R CH2R R CHR
enamine

The -carbon atom of an enamine is a nucleophilic site because of conjugation

with the nitrogen atom similar to enolate ion.

R R
N R N+ R
C C -
R CHR R CHR
enamine

The nucleophilicity of the -carbon atom, permits enamines to be used for

alkylation reaction similar to enolates. 165
Block 4 Organic Synthesis: Some More Approaches

N+ O
N
H3C CH2CH3 H3C CH2CH3
H3C N+
+ I C2 H5 +
H3O+ H H
I-

In above example of alkylation reaction of pyrorolidine enamine, the less

substituted enamine is formed mainly by the reaction of 2-methyl
cyclohexanone with pyrrolidine because of the steric factor and more acidity of
the C-H on the less substituted carbon. Less substituted enamine is a mixture
of two isomers (I) and (II). The isomer (I) is predominant because of the steric
effect. Conjugation between the nitrogen atom and the π orbitals of the double
bond favors coplanarity of the bonds that are darkened in the structures. In
isomer (I) the methyl group adopts a quasi-axial conformation to avoid steric
interaction with the amine substituents. A serious nonbonded repulsion in (I)
destabilizes this isomer.

H H

H N H N
H H
H H H H H
H
H

(I) (II)

The imine ion resulting from alkylation can be hydrolysed to prepare 2,6-
disbstituted cyclohexanone.
Imines can also be deprotonated at the α-carbon by strong bases to give the
nitrogen analogs of enolates. Grignard reagents and lithium amides can be
used for deprotonation. These anions are referred to as imine anions. Imine
anions are also more nucleophilic than enolates and can be alkylated.
-
NR 1 NR 1 NR 1
Base
-
R C CHR22 R C CR22 R C CR22

One application of imine anions is for the alkylation of aldehydes.

BrMg R1
O NR 1 N
NH2R RMgX
RCH2 C H RCH2 C H RCH C H

NR 1 O
2
H3O R
RX
RCH C H CH C H
H2O
R2 R2

H 1. LDA H
H H2N
R
2. R1X
RCH2 C O RCH2 C N CH C O
3. H2O
166 R1
Unit 14 Enolates

Ketone imine anions can also be alkylated. The prediction of the

regioselectivity of lithioimine formation is somewhat more complex than the
case of kinetic ketone enolate formation. One of the complicating factors is
that there are two imine stereoisomers, each of which can give rise to two
regioisomeric imine anions. The isomers in which the nitrogen substituent R’ is
syn to the double bond are the more stable.

R1 R1
N N

C C
H3C CH2R H3C CH2R
LDA LDA

R1 R1 R1 R1
- + - + +-
+-
Li N N Li N Li Li N
or or
C C C C
H2C CH2R H3C CH2R H2C CH2R H3C CH2R

Regioselectivity of ketimines depends on the α-substituents and N-

substituents. For example, in methyl ketimines deprotonation of methyl is
favoured when reaction is carried out using LDA at −78 oC. With larger N-
substituents, deprotonation at 25 oC occurs anti to the nitrogen substituent.
R1
R1
N N-Li +
o
LDA, -78 C
RCH2 C CH3 RCH2 C CH2

R1
R1 + -
N Li N
o
LDA, 0 C
RCH2 C CH2R2 RCH C CH3

Beside the factors discussed above other factors such as the state of
aggregation and solvation also control regioslectivity of ketimines. One of the
important applications of the imine anions is that they can be prepared from
enantiomerically pure amines. When imines derived from chiral amines are
alkylated, the new carbon-carbon bond is formed with a bias for one of the two
possible stereochemical configurations. Hydrolysis of the imine then leads to
enantiomerically enriched ketone.

H3C
H3C O
O
O N N
CH2Ph 2.RCH X
1.LDA X Li RCH2
+ -
2 -Li X
+ H2N CH2OCH3 R
H H
H
O
RCH2

>99 e.e. 167

Block 4 Organic Synthesis: Some More Approaches

The important aspects of above reaction are: (1) formation of rigid structure
due to the chelation of the methoxy group with the lithium ion; (2) the
interaction of the lithium ion with the bromide leaving group, and (3) the steric
effect of the benzyl group, which makes the underside the preferred direction
of approach for the alkylating agent.

SAQ 8
Complete following reaction:
O
H
H3C N C2H5I H3O+
+

14.5 SUMMARY
You have now seen how enols and enolates are generated. There was a detail
discussion how to achieve regioselectivity and streo selectivity in alkylation
and aldol reactions. We have also briefly covered reactions of imine, enamine
and silyl enol ethers.

14.6 TERMINAL QUESTIONS

1. What are the reaction conditions needed to generate kinetic control
enolates?

2. Starting with either acetoacetic ester or malonic ester how are the
following compounds prepared:

a) 5-Methyl-2-hexanone

b) 3-methyl-2-hexanone

c) 2-Methyl butanoic acid

d) Allylethanoic acid

3. How you will control stereochemical outcome of enolate formation.

4. Write the factors which control stereoselectivity in aldol reactions of

ketones.

14.7 ANSWERS
Self Assessment Questions
1. i) OH

H3C H
ii) O OH
H3C
CH3 CH2
168
Unit 14 Enolates

iii) HO

CH2

2. Enolate anions are more reactive than enols. The relative lower reactivity
of enols is due to the presence of proton of OH group, which decreases
the electron density of the enol relative to the negative charge oxygen of
enolate.

3. Protic solvent like water and alcohols act as acids and they can
protonate enolates. Therefore, solvents, not having acidic protons, are
preferred for achieving high concentration of enolates.

O- O O-
C2H5ONa LDA
4. i) H3C H H3C H H3 C H
C2H5OH THF, -78oC
O- O O-

C2H5ONa LDA
ii) H3C CH3 H3C CH3 H3C CH2
THF, -78oC
CH3 C2H5OH CH3 CH3

O- O LDA O-
C2H5ONa
iii) THF, -78oC
CH3 C2H5OH CH3
CH3
LDA

OH O OH
LDA
iv) H3C CH3 H3C CH3 THF, -78 C o H3C CH3
O O O
THF+ HMPA, -78oC

O O O O O
- +
C2H5 O Na , C2 H5 OH H+, H2O
5. i) H3C C CH2 C OC2H5 H3C C HC C OC2H5 H3C C CH2CH2CH2CH3
BrCH2CH2CH3
CH2CH2CH3

O
O O - +
O O H+, H2O
C2H5 O Na , C2 H5 OH H3C C CH2CH2COCH3
ii) H3C C CH2 C OC2H5 H3C C HC C OC2H5
BrCH2COCH3
CH2COCH3

O O O
Br2 Base
iii) Br
NaOH
CH3 CH3 CH3

1. C2H5ONa, C2H5OH H+, H2O

iv) CH2(CO2C2H5)2 CH3CH2CH2CH(COOCH3)2 CH3CH2CH2CH2COOH
2. CH3CH2CH2Br

169
Block 4 Organic Synthesis: Some More Approaches

O O
1. LDA/THF, -78 oC
6. a) H3C CH3 H3C CH3
2. C2H5I

O O
CH3
CH3 1. NaOC H /EtOH
2 5
b) CH3
2. CH3Br

O O
CH3 1. LDA, 0 oC H3C CH3
c)
2. CH3Br

O O
o
1. NaH, 20 C
d) H3C CH3 H3C CH3
CH3 2. C2H5I CH3
CH3

O O- O-
LDA PhCHO O OH O OH
CH3 CH3 +
7. a) (CH3)3 (CH3)3
+
(CH3)3 (H3C)3 CH3
(H3C)3 CH3
Z-enolat/favoured) E-enolate CH3 OH
2,3-syn CH3
2,3-anti

O O - Li+ O OH
H O H OH
LDA PhCHO Ph
Ph
b) +
E isomer anti 80% syn 16 %

OH
O OBBN O
(C2H5)3N C6H5CHO
c) CH3 + 9BBN CH3
R R R CH3
-78 oC
Z-Enolate CH3 syn-aldol
>95%

H O
O N N N+
H3C H3C C 2H 5 H3C C 2H 5
8. H3C

C2H5I H3O+

Terminal Questions
1. Following conditions favour the formation of kinetic enolate: Proton
attached to α Carbon should be less substituted, strong base like LDA,
low temperature, and aprotic solvent.

2. a) Treatment of acetoacetic ester with: 1. NaOC2H5/C2H5OH +

(CH3)2CHCH2Br; 2. OH-/H2O; 3. H3O+

b) Treatment of acetoacetic ester with: 1. NaOC2H5/C2H5OH +

CH3CH2CH2Br; 2. NaOC2H5/C2H5OH + CH3Br; 3. OH-/H2O; 4. H3O+

c) Treatment of malonic ester with: 1. NaOC2H5/C2H5OH + CH3CH2Br; 2.

170 NaOC2H5/C2H5OH + CH3Br; 3. OH-/H2O; 4. H3O+
Unit 14 Enolates

d) Treatment of malonic ester with: 1. NaOC2H5/C2H5OH + Allyl chloride;

2. OH-/H2O; 3. H3O+

3. Following reaction conditions may be used to control stereochemical

outcome of enolate formations:

 LHMDS generally provides the Z enolate as major product

 LTMP (very bulky) affords the E enolate as the major product

 LDA gives intermediate result

 Use of HMPA as a strong Lewis basic donor-co-solvent can reverse

selectivity.

4. Following factors control stereoselectivity in aldol additions via lithium

enolates and boron enolates.

 aldol reactions of ketone enolates having one bulky substituent. The

preference is Z-enolate→syn aldol; E-enolate→anti aldol.

 when the enolate has no bulky substituent, stereoselectivity is low.

 Z-Enolates are more stereoselective than E-enolates.

171