18.1118.11

Effects of Conjugation in Effects of Conjugation in

-Unsaturated Aldehydes and -Unsaturated Aldehydes and

KetonesKetones

Relative StabilityRelative Stability

aldehydes and ketones that contain a carbon-aldehydes and ketones that contain a carbon-carbon double bond are more stable when the carbon double bond are more stable when the double bond is conjugated with the carbonyl double bond is conjugated with the carbonyl group than when it is notgroup than when it is not

compounds of this type are referred to as compounds of this type are referred to as ,, unsaturated aldehydes and ketonesunsaturated aldehydes and ketones

Relative StabilityRelative Stability

CHCH33CHCH

OO

CHCHCHCH22CCHCCH33 (17%)(17%)

KK = 4.8 = 4.8

(83%)(83%)

OO

CHCH33CHCH22CHCH CHCCHCHCCH33

AcroleinAcrolein

HH22CC CHCHCHCH

OO

AcroleinAcrolein

HH22CC CHCHCHCH

OO

AcroleinAcrolein

HH22CC CHCHCHCH

OO

AcroleinAcrolein

HH22CC CHCHCHCH

OO

Resonance DescriptionResonance Description

CCOO•••• ••••

CCCC

++

––

CCOO•••• ••••

CCCC ••••

Resonance DescriptionResonance Description

CCOO•••• ••••

CCCC

++

––

CCOO•••• ••••

CCCC ••••

++

––

CCOO•••• ••••

CCCC ••••

-Unsaturated aldehydes and ketones are -Unsaturated aldehydes and ketones are more polar than simple aldehydes and ketones. more polar than simple aldehydes and ketones.

-Unsaturated aldehydes and ketones contain -Unsaturated aldehydes and ketones contain two possible sites for nucleophiles to attack two possible sites for nucleophiles to attack

carbonyl carboncarbonyl carbon

-carbon-carbon

PropertiesProperties

-Unsaturated aldehydes and ketones are -Unsaturated aldehydes and ketones are more polar than simple aldehydes and ketones. more polar than simple aldehydes and ketones.

-Unsaturated aldehydes and ketones contain -Unsaturated aldehydes and ketones contain two possible sites for nucleophiles to attack two possible sites for nucleophiles to attack

carbonyl carboncarbonyl carbon

-carbon-carbon

PropertiesProperties

CCOO•••• ••••

CCCC

Dipole MomentsDipole Moments

ButanalButanal transtrans-2-Butenal-2-Butenal

= 2.7 D= 2.7 D = 3.7 D= 3.7 D

OO OO–– ––

++

++

++

greater separation greater separation of positive and of positive and negative chargenegative charge

18.1218.12

Conjugate Addition to Conjugate Addition to

-Unsaturated Carbonyl Compounds-Unsaturated Carbonyl Compounds

1,2-addition (direct addition)1,2-addition (direct addition)

nucleophile attacks carbon of C=Onucleophile attacks carbon of C=O

1,4-addition (conjugate addition)1,4-addition (conjugate addition)

nucleophile attacks nucleophile attacks -carbon-carbon

Nucleophilic Addition to Nucleophilic Addition to -Unsaturated Aldehydes and Ketones -Unsaturated Aldehydes and Ketones

attack is faster at C=Oattack is faster at C=O

attack at attack at -carbon gives the more stable -carbon gives the more stable productproduct

Kinetic versus Thermodynamic ControlKinetic versus Thermodynamic Control

HH YY++CC CC

CC

OO

1,2-addition1,2-addition

CC CC

CC

OOHH

YY

formed fasterformed faster

major product under major product under conditions of kinetic conditions of kinetic control control (i.e. when (i.e. when addition is not readily addition is not readily reversible)reversible)

HH YY++CC CC

CC

OO

1,4-addition1,4-addition

CC CC

CC

OOHH

YY

enolenol

goes to keto form goes to keto form under reaction under reaction conditionsconditions

HH YY++CC CC

CC

OO

1,4-addition1,4-addition

keto form is isolated keto form is isolated product of 1,4-additionproduct of 1,4-addition

is more stable than is more stable than 1,2-addition product1,2-addition product CC CC

CC

OO

HHYY

HH YY++CC CC

CC

OO

1,2-addition1,2-addition

CC CC

CC

OOHH

YY

1,4-addition1,4-addition

CC CC

CC

OO

HHYY

C=O is stronger C=O is stronger

than C=Cthan C=C

C=O is stronger C=O is stronger

than C=Cthan C=C

observed with observed with stronglystrongly basic nucleophiles basic nucleophiles

Grignard reagentsGrignard reagents

LiAlHLiAlH44

NaBHNaBH44

Sodium acetylideSodium acetylide

strongly basic nucleophiles add irreversiblystrongly basic nucleophiles add irreversibly

1,2-Addition1,2-Addition

ExampleExample

OO

CHCH33CHCH CHCHCHCH ++ HCHC CMgBrCMgBr

1. THF1. THF2. H2. H33OO++

OHOH

CHCH33CHCH CHCHCCHCHC CHCH

(84%)(84%)

observed with observed with weaklyweakly basic nucleophiles basic nucleophiles

cyanide ion (CNcyanide ion (CN––))

thiolate ions (RSthiolate ions (RS––))

ammonia and aminesammonia and amines

azide ion (Nazide ion (N33––))

weakly basic nucleophiles add reversiblyweakly basic nucleophiles add reversibly

1,4-Addition1,4-Addition

ExampleExample

KCNKCN ethanol,ethanol,

acetic acidacetic acid

(93-96%)(93-96%)

OO

CC66HH55CHCH CHCCCHCC66HH55

OO

CC66HH55CHCHCHCH22CCCC66HH55

CNCN

ExampleExample

KCNKCN ethanol,ethanol,

acetic acidacetic acid

(93-96%)(93-96%)

OO

CC66HH55CHCH CHCCCHCC66HH55

OO

CC66HH55CHCHCHCH22CCCC66HH55

CNCN

viavia

CC66HH55CHCH CCCC66HH55

CNCN••••

––OO•••• ••••

CHCH

CC66HH55CHCH CCCC66HH55

CNCN

––OO•••• ••••••••

CHCH

ExampleExample

OO CHCH33

CC66HH55CHCH22SHSH HOHO––, H, H22OO

(58%)(58%)

OO CHCH33

SCHSCH22CC66HH55

ExampleExample

viaviaOO

CHCH33

CC66HH55CHCH22SHSH HOHO––, H, H22OO

(58%)(58%)

––OO•••• ••••••••

CHCH33

SCHSCH22CC66HH55

OO CHCH33

SCHSCH22CC66HH55

CHCH33

SCHSCH22CC66HH55

––

OO•••• ••••

••••

18.1318.13

Addition of Carbanions toAddition of Carbanions to

-Unsaturated Carbonyl Compounds:-Unsaturated Carbonyl Compounds:

The Michael ReactionThe Michael Reaction

Stabilized carbanions, such as those Stabilized carbanions, such as those derived from derived from -diketones undergo conjugate-diketones undergo conjugateaddition to addition to ,,-unsaturated ketones.-unsaturated ketones.

Michael AdditionMichael Addition

ExampleExample

(85%)(85%)

OO

HH22CC CHCCHCHCCH33

CHCH33

OO

OO

OO

CHCH33

OO

OO

CHCH22CHCH22CCHCCH33

KOH, methanolKOH, methanol

++

The Michael reaction is a useful method forThe Michael reaction is a useful method forforming carbon-carbon bonds.forming carbon-carbon bonds.

It is also useful in that the product of the It is also useful in that the product of the reaction can undergo an intramolecularreaction can undergo an intramolecularaldol condensation to form a six-membered aldol condensation to form a six-membered ring. One such application is called the Robinsonring. One such application is called the Robinsonannulation.annulation.

Michael AdditionMichael Addition

ExampleExample

OO

CHCH33

OO

OO

CHCH22CHCH22CCHCCH33

NaOHNaOH

heatheat

OHOH

OO CHCH33

OO

not isolated;not isolated;

dehydrates under dehydrates under

reaction conditionsreaction conditions

ExampleExample

(85%)(85%)

OO

CHCH33

OO

OO

CHCH22CHCH22CCHCCH33

NaOHNaOH

heatheat OOOO

CHCH33

OHOH

OO CHCH33

OO

18.1418.14

Conjugate Addition of Organocopper Conjugate Addition of Organocopper

Reagents to Reagents to

-Unsaturated Carbonyl Compounds-Unsaturated Carbonyl Compounds

The main use of organocopper reagents is toThe main use of organocopper reagents is toform carbon-carbon bonds by conjugate form carbon-carbon bonds by conjugate addition to addition to ,,-unsaturated ketones.-unsaturated ketones.

Addition of Organocopper Reagents toAddition of Organocopper Reagents to-Unsaturated Aldehydes and Ketones-Unsaturated Aldehydes and Ketones

ExampleExampleOO CHCH33

(98%)(98%)

++ LiCu(LiCu(CHCH33))22

OO CHCH33

CHCH33

1. diethyl ether1. diethyl ether

2. H2. H22OO

18.1518.15

Alkylation of Enolate AnionsAlkylation of Enolate Anions

Enolate ions are nucleophiles and react withEnolate ions are nucleophiles and react withalkyl halides.alkyl halides.

However, alkylation of simple enolates does However, alkylation of simple enolates does not work well.not work well.

Enolates derived from Enolates derived from -diketones can be-diketones can bealkylated efficiently.alkylated efficiently.

Enolate Ions in SEnolate Ions in SNN2 Reactions2 Reactions

ExampleExample

CHCH33CCHCCH22CCHCCH33

OO OO

++ CHCH33IIKK22COCO33

CHCH33CCHCCHCCHCCH33

OO OO

CHCH33

(75-77%)(75-77%)