Alpha Hydrogen 090812

7/27/2019 Alpha Hydrogen 090812

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ALPHA HYDROGEN


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OBJECTIVES

1. Decsribe the acidity of-hydrogen of carbonyl compounds in the

form of enolate anions (page : 832)

2. Predict the products from alkylation and halogenation (-

bromination and haloform) reaction of -hydrogen of ketone

(page : 837, 842)3. Predict the product from the aldol condensation reaction and be

able to propose synthetic routes to get the target products. (page

: 876-889)

4. Predict the product from the Claisen condensation reaction

(Claisen ester condensation and Dieckmann condensation).(page : 870-874)

5. Predict the product from the addition to , unsaturated carbonyl

compounds and Michael addition. (page : 889, 892)


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1. Decsribe the acidity of-hydrogen of

carbonyl compounds in the form ofenolate anions (page : 832)


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The Acidity of the a Hydrogens of Carbonyl

Compounds: Enolate Anions Hydrogens on carbons a to carbonyls are unusually acidic The resulting anion is stabilized by resonance to the carbonyl

Chapter 17 5


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The enolate anion can be protonated at the carbon or

the oxygen

The resultant enol and keto forms of the carbonyl areformed reversibly and are interconvertible

Chapter 17 7


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REACTION OF -HYDROGEN


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2. Predict the products from alkylation

and halogenation (-bromination andhaloform) reaction of -hydrogen of

ketone (page : 837, 842)


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Direct Alkylation of Ketones via Lithium Enolates

Enolates can also be alkylated with primary alkyl halides via

an SN2 reaction Unsymmetrical ketones can be alkylated at the least substituted

position if LDA is used to form the kinetic enolate

Chapter 17 17


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The a-selenyl ketone is converted to the a,b-unsaturated

carbonyl compound by reaction with hydrogen peroxide

Elimination of the selenoxide produces the unsaturated carbonyl

Chapter 17 19


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Halogenation of Ketones

Ketones can be halogenated at the a position in the

presence of acid or base and X2 Base-promoted halogenation occurs via an enolate

Chapter 17 20


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Acid-catalyzed halogenation proceeds via the enol

Chapter 17 21


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Haloform Reaction

Reaction of methyl ketones with X2 in the presence of base

results in multiple halogenation at the methyl carbon Insert mechanism page 777

Chapter 17 22


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When methyl ketones react with X2 in aqueous hydroxide

the reaction gives a carboxylate anion and a haloform

(CX3H)

The trihalomethyl anion is a relatively good leaving group

because the negative charge is stabilized by the three halogen

atoms

Chapter 17 23


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3. Predict the product from the aldol

condensation reaction and be able topropose synthetic routes to get the target

products. (page : 876-889)


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Chapter 17 29

The Aldol Reaction: The Addition of Enolate

Anions to Aldehydes and Ketones

Acetaldehyde dimerizes in the presence of

dilute sodium hydroxide at room

temperature

The product is called an aldol because it

is both an aldehyde and an alcohol


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Chapter 17 30

The mechanism proceeds through the enolate anion


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Dehydration of the Aldol Product


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Dehydration of the Aldol Product

If the aldol reaction mixture is heated, dehydration to an a,b-

unsaturated carbonyl compound takes place

Dehydration is favorable because the product is stabilized by

conjugation of the alkene with the carbonyl group

In some aldol reactions, the aldol product cannot be isolated

because it is rapidly dehydrated to the a,b-unsaturated

compound


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Synthetic Applications

The aldol reaction links two smaller molecules and creates a new

carbon-carbon bond


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WWUWWU----ChemistryChemistry

Example

CH3 C H

O

CH3 C H

O

+NaOH

CH3 C CH2 C H

OOH

H"Aldol"


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Another Example

CH3 CH2 C H

O

+ CH3 CH2 C H

O

NaOH

CH3 CH2 C CH C H

O

CH3

OH

H


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One More:

CH3 C CH3

O

+ CH3 C CH3

O

NaOH

CH3 C CH2 C CH3

OOH

CH3

"Diacetone alcohol"


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Synthesis Problem

CH3 CH2 CH CH C H

O

CH3

OH

Preparation via Aldol


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Preparation viaAldolCondensation

CH3 CH CH CH2 OH

Preparation via Aldol


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Preparation viaAldolCondensation

CH3 CH2 CH2 CH2 CH CH2 OH

CH2

CH3


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Synthesis Problem

CH2 CH2 CH

OH

CH C

CH2

H

O


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Chalcone Formation

C CH2

OH

H

C

O

CH CH C

O

"spontaneous"

a chalcone

(formed from an aldol

condensation)


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Crossed Aldol Condensations

C H

O

+

CH3 C H

O

NaOHC CH2

OH

H

C H

O

- H2O(spontaneously)

CH CH C H

O

acceptor

donor


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Practical Crossed Aldol Reactions

Crossed aldol reactions give one predictable product when

one of the reaction partners has no ahydrogensThe carbonyl compound without any ahydrogens is put

in basic solution, and the carbonyl with one or two a

hydrogens is added slowly

Dehydration usually occurs immediately, especially if anextended conjugated system results


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Claisen-Schmidt Reactions


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Crossed-aldol reactions in which one partner is a ketone are called

Claisen-Schmidt reactions

The product of ketone self-condensation is not

obtained because the equilibrium is not favorable


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From Experiment 35

C CH3

O

NO2

C H

O

NaOH

NO2

CH CH2

OH

C

O

+

- H2O

(spontaneous)

NO2

CH CH C

O

3-Nitrochalcone


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Do the synthesis of:

CH C C

CH3

H

O

Cyclization via Aldol Condensations


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Cyclization via Aldol Condensations Intramolecular reaction of dicarbonyl compounds proceeds to form

five- and six-membered rings preferentially

In the following reaction the aldehyde carbonyl carbon is attacked

preferentially because an aldehyde is less sterically hindered and

more electrophilic than a ketone


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Also:

CH2

CH2

C

C

CH3

O

CH3

O

NaOH

C2H5OH

25

O

CH3

a

a


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Synthesis of:

C

H

O


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Crossed Aldol Condensations

C H

O

+

CH3 C H

O

NaOHC CH2

OH

H

C H

O

- H2O(spontaneously)

CH CH C H

O

acceptor

donor


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f


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Synthesis of an Insect Repellent

CH3

CH2

CH2

C H

O

CH3

CH2

CH2

C H

O

CH3

CH2

CH2

C

OH

CHCH2

CH3

C H

H

O

CH3

CH2

CH2

C

OH

CHCH2

CH3

C H

H

O

CH3

CH2

CH2

C

OH

CHCH2

CH3

C H

O

HH

H

a

NaOH

H2

Ni

ALDOL

CONDENSATION

HYDROGENATION

2-Ethyl-3-hydroxyhexanal

2-Ethyl-1,3-hexanediol

--used in "6-12" insect repellent


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Synthesis of a Compound used in Perfumery

C

CH3

OCH2

CH2

C

CH2

O

CH2

CH CH CH2

CH3

C

CH3

CH2

CH2

CCH

O

CH2

CH CH CH2

CH3

OH

O

CH3

CH2

C C

CH2

CH3

H H

a cis

KOH

cis

ALDOLCONDENSATION

- H2O

DEHYDRATION

cis-Jasmone

--- used for the scent of jasmine

in perfumes

Biological Synthesis of Fructose


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Biological Synthesis of Fructose

CH2 CH C H

O

OHO

P

OH

OO

CH2 C CH2 O P OH

OH

O O

O

CH2

CH C CH C CH2

O P OH

O

O

O

OH

OH

HOHO

P

OH

O O

+

Glyceraldehyde-3-phosphate

Dihydroxyacetone phosphate

Fructose-1,6-diphosphate

a

ALDOLCONDENSATION

enzyme

The Aldol Condensation Reaction: MechanismThe Aldol Condensation Reaction: Mechanism


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The Aldol Condensation Reaction: MechanismThe Aldol Condensation Reaction: Mechanism

CH3 C H

O

O H OHH CH2 C H

O

CH2

C H

O

CH3

C H

O

CH2

C H

O

CH3

C

O

H

H

CH2

C H

O

CH2

C H

O

CH3

C

O

H

CH2

C H

O

CH3

C

O

H

1)

2)

3)

: :

+ :..

_

..

fast ..

.. +

: : : :

..

_

.. _

an enolate ion: :

: :

.._

slow

:..

:

: :

: :..

: :

+ H2O

fast

:..

: :

+ :OH..

..

_

acceptor

donor


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The Heart of the Mechanism

CH3

C

H

O CH3

C

H

O

CH2

C

H

O

CH2

C

H

O

+ _ _

.._

acceptor

donor


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Chapter 19 69

b-Dicarbonyl compounds can be synthesized by the Claisen

condensation

The acetoacetic ester and malonic acid syntheses use b-

dicarbonyl compounds for carbon-carbon bond forming

reactions

The acetoacetic ester and malonic ester syntheses usually

conclude with decarboxylation of a b-keto acid

The Claisen Condensation: Synthesis of b Keto


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Chapter 19 70

The Claisen Condensation: Synthesis ofb-Keto

Esters Ethyl acetate undergoes a Claisen condensation when

treated with sodium ethoxide The product is commonly called an acetoacetic ester

Ethyl pentanoate undergoes an analogous reaction


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Chapter 19 72


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Chapter 19 73

The alkoxide base must have the same alkyl group as

the alkoxyl group of the ester

The use of a different alkoxide would result in formation of some

transesterification products

Esters with only one ahydrogen do not undergo Claisen

condensation

A second hydrogen on the a carbon is necessary so that it can

be deprotonated in Step 3

This deprotonation drives the reaction to completion


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Chapter 19 74

Crossed Claisen Condensations

Crossed Claisen condensations can lead to one major

product when one of the two esters has no ahydrogen

The Dieckmann condensation is an intramolecular Claisen


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Chapter 19 75

The Dieckmann condensation is an intramolecular Claisen

condensation

Only 5- and 6-membered rings may be prepared in this way


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5. Predict the product from the addition

to , unsaturated carbonyl

compounds and Michael addition.

(page : 889, 892)


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Stronger nucleophiles such as Grignard reagents favor 1,2 addition

h k l hil h id i f 1 4


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whereas weaker nucleophiles such as cyanide or amines favor 1,4

addition

Michael Additions


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Addition of an enolate to an a,b-unsaturated carbonyl compound

usually occurs by conjugate addition

This reaction is called a Michael addition


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6 Predict the products from the

Robinson annulation (ring forming)

(page : 893)

A Robinson annulation can be used to build a new six-membered ring

on an existing ring


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on an existing ring

Robinson annulation involves a Michael addition

followed by an aldol condensation to close the ring


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Chapter 19 84

The Acetoacetic Ester Synthesis: Synthesis of

Methyl Ketones (Substituted Acetones)

Alkylation Alkylation of the enolate derived from acetoacetic ester is

called the acetoacetic ester synthesis

This is an SN2 reaction with the ethyl acetoacetate enolate acting as the

nucleophile


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Chapter 19 85

A second alkylation can be performed

A stronger base such as potassium tert-butoxide must be use to

deprotonate the monoalkyl ester

H d l i f h d h i f h l


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Chapter 19 86

Hydrolysis of the ester and heating of the resultant b-

ketoacid causes decarboxylation

The product is a substituted acetone derivative

E l


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Chapter 19 87

Example:

Ethylacetoacetate serves as a synthetic equivalent of the


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Chapter 19 88

Ethylacetoacetate serves as a synthetic equivalentof the

acetone enolate

It is possible to use acetone enolate directly, but this would require amuch stronger base and special reaction conditions

Ifa-halo esters are used to alkylate the enolate, g-keto acids

are obtained

A t ti E t Di i Alk l ti t th T i l


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Chapter 19 89

Acetoacetic Ester Dianion: Alkylation at the Terminal

Carbon

Treating acetoacetic ester with two equivalents of a very

strong base produces the dianion

Alkylation of the dianion occurs first at the terminal carbon

The terminal carbanion is more nucleophilic and more basicbecause it is stabilized by only one carbonyl group

Th M l i E t S th i S th i f


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Chapter 19 90

The Malonic Ester Synthesis: Synthesis of

Substituted Acetic Acids

Alkylation of diethylmalonate, hydrolysis of the diester to theb-dicarboxylic acid, and decarboxylation can be used to

synthesize mono- and disubstituted acetic acids The mechanism is analogous to that for the acetoacetic ester synthesis

In step 1 the stabilized anion is formed

I t 2 th i i di lk l t d i S 2


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Chapter 19 91

In step 2 the anion is mono- or dialkylated using SN2

reactions

In step 3 the mono or dialkylated product is hydrolyzed and


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Chapter 19 92

In step 3 the mono- or dialkylated product is hydrolyzed and

decarboxylated

Examples


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Documents

Alpha Hydrogen 090812