Lecture 9

-Alkylation of Carbonyl Compounds

-Alkylation of ketones - via the enolate anion - can be a useful

technique for extending or modifying the alkyl chain in aldehydes and

ketones at the -carbon:

C6H5C

O

CH3

LDA

C6H5C

O

CH2

CH3

I

C6H5C

O

CH2

CH3

C6H5C

O

CH2

_

_

Acetophenone

Propiophenone

The reaction is most useful with 1 alkyl halides - with 2

halides -elimination competes significantly with alkylation.

As we saw earlier a problem here is that the intermediate enolate can be

a strong enough base to deprotonate the alkylated product at an -

carbon. This yields a new enolate which can then itself be alkylated -

hence mixtures which may be difficult to separate can be formed:

H3C CH3

O

CH2

CH2

O

CH3H3C

H3C CH2

O

H3C CH2

O

CH3

H2C CH2

O

CH3

Base _

_

CH3I

CH3I

CH3COCH2-

lkylation of -ketocarboxylic esters provides a clean alternative route

to direct -alkylation of ketones:

CH3C

COEt

O

CH2

O

CH3C CH3

O

CH3C CH2

O

C3H7

CH3C

COEt

O

CH

O

CH3C

COEt

O

CH

O

C3H7

CH3C

COH

O

CH

O

C3H7

_

N.B. Mono-alkylation only - the mono-alkylated product is lessacidic and more stericallyhindered than the -ketoesterstarting material - cannot bedeprotonated by enolate.

- CO2

1 Eq. NaOEt

CH3CH2CH2Br

CH3CH2CH2Br

H3O+

Na+

Claisen condensationof ethyl acetate

[Quantitative]

The activating effect of the ester group increases the acidity of the

'doubly -' CH, directing alkylation to that carbon but di-alkylation is

sterically inhibited. Following removal of the ester group by

hydrolysis/decarboxylation the overall reaction is equivalent to - i.e.

yields the same product as - clean -monoalkylation of acetone.

The strategy of using a -ketoester as a synthetic 'stand-in' for a ketone

in alkylation reactions (in technical language, as a 'synthetic

equivalent' of a ketone) can also be applied to carry out effective

stepwise di-alkylation - to ketone carbonyl:

CH3C

COEt

O

CH2

O

CH3C CH3

O

CH3C

COEt

O

C

O

C3H7

CH3C

COEt

O

C

O

H3C C3H7

CH3C

HC

O

H3C C3H7

CH3C

COEt

O

CH

O

CH3C

COEt

O

CH

O

C3H7

, - CO2

1 Eq. NaOEt

_

1 Eq. NaOEt_

H3O+

CH3I

CH3CH2CH2Br

Na+

- H+

- H+

(i) C3H7I, EtO-

(ii) CH3I, EtO-

Ethyl acetoacetate fromClaisen condensation ofethyl acetate.

Mono-alkylation

[Quantitative]

Although the reactions discussed above involve several steps, the

ability to exercise precise choice of mono- vs. di-alkylation and the

ability to attach two different alkyl groups to the -carbon makes

them significantly more useful than direct alkylation of the ketone

enolate.

Revision: Indirect clean -monoalkylation of ketones via the Claisen

condensation:

CH3C

COEt

O

CH2

O

CH3C CH3

O

CH3C CH2

O

C3H7

CH3C

COEt

O

CH

O

CH3C

COEt

O

CH

O

C3H7

CH3C

COH

O

CH

O

C3H7

_

N.B. Mono-alkylation only - the mono-alkylated product is lessacidic and more stericallyhindered than the -ketoesterstarting material - cannot bedeprotonated by enolate.

- CO2

1 Eq. NaOEt

CH3CH2CH2Br

CH3CH2CH2Br

H3O+

Na+

Claisen condensationof ethyl acetate

[Quantitative]

The activating effect of the ester group, increases the acidity of the

'doubly -' CH, directing alkylation to that carbon but sterically

inhibiting di-alkylation. Following removal of the ester group by

hydrolysis/decarboxylation the overall reaction is equivalent to - i.e.

yields the same product as - clean -monoalkylation of acetone.

Some further examples of indirect ketone monoalkylation:O

CO2Et

Br

O

CO2Et

O O

CO2H

O

CO2Et

O

CO2Et

_

- H+

_

, - CO2

NaOEt

H3O+3-Bromopropene

Allyl bromide

[Equivalent to -allylation of cyclohexanone]

H3O+

CH3C C

H2

O

COEt

O

CH3C

HC

O

COEt

O

(i) NaOEt

CH2CO2Et

CH3C CH2CH2CO2H

O

CH3C

HC

O

COH

O

CH2CO2H

, - CO2

Ethyl Bromoacetate

(ii) BrCH2CO2Et

[Equivalent to alkylation of acetone by BrCH2CO2H]

Malonic Ester Synthesis - A synthesis of -substituted carboxylic

acids - equivalent to clean indirect mono- or di- -alkylation of acetic

acid:

H2C

CO2Et

CO2Et

Diethylmalonateaka Malonic Ester

H2C

CO2H

CO2H

Malonic Acid

(i) Base, RX

(ii) Base, R1X

(iii) H3O+,

C

H

CO2H

R

R1

RR1CHCO2H

C

CO2Et

CO2Et

Me

CH CO2H

CH

CO2Et

CO2Et

Me

EtC

Me CO2Et

CO2Et

HC

CO2Et

CO2Et

EtCH

MeCO2H

H2C

CO2Et

CO2Et

_

_(i) H3O+

(ii) , - CO2

EtO-

EtO-

-2

MeBr

EtBr

(i) MeBr; (ii) EtBr

The CH2 hydrogens in diethylmalonate are 'doubly -' to the two ester

carbonyl groups and therefore have enhanced acidity. One or two

deprotonation/alkylation steps leads cleanly to monoalkylated or

dialkylated products (compare the -ketoester chemistry just studied)

Hydrolysis of both ester groups gives a -dicarboxylic acid which - like

a -keto carboxylic acid - undergoes rapid decarbonylation to a

monocarboxylic acid. The overall reaction is equivalent (i.e. gives the

same product as) the clean indirect di--alkylation of acetic acid.

The Knoevenagel Condensation - The 'doubly -' enolate anion of

diethyl malonate behaves as the nucleophile in an aldol-like reaction

with an aldehyde or ketone forming an ,-unsaturated diester.

Following hydrolysis and decarboxylation, the final product is an ,-

unsaturated carboxylic acid. Here diethyl malonate acts as a synthetic

equivalent of the enolate anion of acetic acid.

PhCH CHCO2H

H2C(CO2Et)2

HC

O

Ph

HC

CO2Et

CO2Et

C

CO2Et

CO2Et

C

OH

H

Ph

C

CO2Et

CO2Et

C

H

Ph

HC(CO2Et)2

H2O

CH

CO2Et

CO2Et

C

O

H

Ph

CH

CO2Et

CO2Et

C

OH

H

Ph

CHCO2HPhHC

PhCH C(CO2Et)2

NH

H2C(CO2Et)2 + PhCHO Mild base

(i) H3O+ (ii) , - CO2

PiperidinePiperidine =

Š

_

_

Base_

(i) H3O+

(ii) , - CO2

- OH-

Tutorial Question:

In the base-catalysed Aldol-Claisen Condensation of a ketone and an

ester the ketone behaves as the nucleophile and the ester behaves as the

electrophile:

CH2C

O

H3C H3CC

O

OEt

CO

H3CCH2 C

O

CH3

CO

H3CCH2 C

O

OEt

CH3

_

_

- OEt-

Etc.

In the base-catalysed Knoevenagel Condensation of malonic ester and a

ketone the ester behaves as the nucleophile and the ketone behaves as

the electrophile:

CH3C

O

Ph

HC

CO2Et

CO2Et

CH

CO2Et

CO2Et

C

O

H

Ph

CH

CO2Et

CO2Et

C

OH

H

Ph

_

_

H2O

Etc.

How do you explain the difference?

Enamines - nitrogen analogues of enols:

C C

OH

C C

O

H

C C

NH2

C C

NH

H

Enol Carbonyl

Enamine Imine

C C

NR2

Isolable because tautomerism is now impossible

Preparation of 3° enamines - acid-catalysed addition of a secondary

amine to an enolisable ketone:

HO NHMe2

H2O NMe2

H

OH

NMe Me

H

OHO

NMe Me

+ +

++

- H2O

Me2NHH3O+

TsOH

Methylene imminium cation

Reactivity of enamines:

C C

NR2

C C

NR2+

_

Nucleophiliccarbon

-Alkylation of enamines - another synthetic equivalent of clean -

monoalkylation of ketones:

Me2NMe2N Me2N

CH3CH3 I

O

CH3

O

+

Me2NH +

The neutral enamine - unlike the anionic

enolate - is a weak base and does not de-

protonate the mono-alkylated product.

Hence no di-alkylation occurs.

Base/CH3I

Poor control - mono & di-alkylation

I-

H2O

+

_

Although a multi-step process, ketone alkylation via enamines may be

more efficient than direct alkylation via the enolate.

Special properties of conjugated carbonyl compounds:

Carbonyl compounds in which other multiple bonds are conjugated

with the C-O double bond are significantly more stable than their non-

conjugated isomers. For this reason ,-unsaturated carbonyl

compounds readily isomerise to the more stable conjugated ,-

unsaturated isomers via enol (acidic conditions) or enolate (basic

conditions) intermediates:

H2C CH

CH2

CO

HH3C C

HCH

CO

H

Catalysis byH+ or OH-

Acid catalysis:

H2C CH

CH2

CO

HH2C C

HCH

COH

H

:

:

H2C CH

CH

COH

H

H+

+_H+

H3C CH

CH

COH

H

+

- H+

H3C CH

CH

CO

H

-Unsaturated carbonyl compounds have two electrophilic carbon

sites - the carbonyl carbon and the -carbon:

H3C CH

CH

CO

H+

-H3C C

HCH

CO

H

_

+

Electrophiliccarbon

Electrophiliccarbon

Addition reactions tto the C=C or C=O double bond alone are called

'normal' or 1,2 additions:

CC

CC

O

X Y CC

CC

O

X

Y

CC

CC

OY

X

or+1

2 1

2

Addition reactions that involve the conjugated system as a whole are

called 'conjugate additions' or 1,4 additions:

CC

CC

O

X Y CC

CC

O

X

Y

+

1

23

4

Note that here '1,2' and '1,4', do not refer to the numbering system for

identifying carbon atoms in the systematic naming of the molecules.

Examples of 1,4 (i.e. conjugate) addition:

H2C CH

C

O

CH3 ClH2C CHH

C

O

CH3+ HCl

This reaction looks like a 'normal' or 1,2 - although anti-Markownikov

- addition of HCl to the C-C double bond. However the mechanism

involves acid-catalysed 1,4-addition:

H2C CH

C

O

CH3

H2C CH

C

OH

CH3

H2C CH

C

OH

CH3

ClH2C CH

C

OH

CH3

Cl-

ClH2C CH

C

O

CH3

+ H3O+

+

+

H

This apparent contradiction arises because 1,4-addition of HZ to the

C=C-C=O structure yields an enol which then tautomerises to the

corresponding keto form which has the same structure as would be

produced by anti-Markovnikov 1,2-addition to the C=C bond.