Chm556 alpha hydrogen

8/18/2019 Chm556 alpha hydrogen

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ALPHA HYDROGEN


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OBJECTIVES

1. Decsribe the acidity of α-hydrogen of carbonylcompounds in the form of enolate anions (page : 832)

2. redict the products from al!ylation and halogenation (α-bromination and haloform) reaction of α-hydrogen of

!etone (page : 83"# 8$2)3. redict the product from the aldol condensation reaction

and be able to propose synthetic routes to get the targetproducts. (page : 8"%-88&)

$. redict the product from the 'laisen condensation

reaction ('laisen ester condensation and Diec!manncondensation). (page : 8"-8"$)

. redict the product from the addition to α#* unsaturatedcarbonyl compounds and +ichael addition. (page : 888&2)


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OBJECTIVES

% redict the products from the ,obinson annulation (ringforming) (page : 8&3)

" ble to rite the synthesis of acetoacetic ester andmalonic ester by folloing basic steps /ia al!ylation#

hydrolysis and decarbo0ylation. (page : 8$-8$ 8-83)


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1.Decsribe the acidity of α-hydrogen

of carbonyl compounds in the formof enolate anions (page : 832)


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he cidity of the α ydrogens of 'arbonyl'ompounds: nolate nions

ydrogens on carbons α to carbonyls are unusuallyacidic he resulting anion is stabili4ed by resonance to the

carbonyl

Chapter 17 5


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he enolate anion can be protonated at thecarbon or the o0ygen

he resultant enol and !eto forms of the carbonylare formed re/ersibly and are intercon/ertible

Chapter 17 7


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REACTION OF α-HYDROGEN


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2. Predict the products from alkylation

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

ketone (page ! "#7$ "%2


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Direct l!ylation of 5etones /ia 6ithiumnolates

nolates can also be al!ylated ith primary al!ylhalides /ia an 72 reaction

9nsymmetrical !etones can be al!ylated at the leastsubstituted position if 6D is used to form the !ineticenolate

Chapter 17 17


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α -7elenation: 7ynthesis of α ,β -9nsaturated 'arbonyl 'ompounds

lithium enolate can be selenated ithben4eneselenyl bromide

Chapter 17 1"


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he α -selenyl !etone is con/erted to the α ,β -unsaturated carbonyl compound by reaction ithhydrogen pero0ide limination of the seleno0ide produces the unsaturated

carbonyl

Chapter 17 1&


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alogenation of 5etones 5etones can be halogenated at the α position in the

presence of acid or base and 2 ;ase-promoted halogenation occurs /ia an enolate

Chapter 17 2'


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cid-cataly4ed halogenation proceeds /ia the enol

Chapter 17 21


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aloform ,eaction ,eaction of methyl !etones ith 2 in the presence

of base results in multiple halogenation at themethyl carbon


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=hen methyl !etones react ith 2 in a>ueous

hydro0ide the reaction gi/es a carbo0ylate anionand a haloform ('

3

)

he trihalomethyl anion is a relati/ely good lea/inggroup because the negati/e charge is stabili4ed by thethree halogen atoms

Chapter 17 2#


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#. Predict the product from the aldol

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

products. (page ! "7-""&


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WWUWWU ---- Chemistry Chemistry

1he ldol 'ondensation


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h ld l ' d i


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he ldol 'ondensation,eaction: +echanism

he enolate ion (carbanion) is theactual nucleophilic reagent.

he reaction brea!s don to thefolloing:

he α-carbon of the donor attachesitself to the carbonyl carbon of theacceptor


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Chapter 17 2&

he ldol ,eaction: he ddition ofnolate nions to ldehydes and

5etones

cetaldehyde dimeri4es in thepresence of dilute sodium hydro0ide

at room temperature he product is called an aldol

because it is both an aldehyde and

an alcohol


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Chapter 17 #'

he mechanism proceeds through the enolate anion


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Dehydration of ldol roducts

ldol products are often /ery easilydehydrated# yielding α,β-unsaturated

aldehydes or !etones.fter dehydration# the α,β-unsaturatedaldehydes and !etones are stabili4ed by

resonance# thereby pro/iding a dri/ingforce for the dehydration.


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Dehydration of the ldol roduct


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Dehydration of the ldol roduct


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7ynthetic pplications he aldol reaction lin!s to smaller molecules and

creates a ne carbon-carbon bond


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0ample

CH3 C H

O

CH3 C H

O

+NaOH

CH3 C CH2 C H

OOH

H

"Aldol"


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nother 0ample

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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@ne +ore:

CH3 C CH3

O

+ CH3 C CH3

O

NaOH

CH3 C CH2 C CH3

OOH

CH3

"Diacetone alcohol"


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1he ldol 'ondensation

8@13: 1he must be α-hydrogens in

order to ha/e an aldol condensation.

=ithout α-hydrogens# the only possiblereaction is the 'anni4arro reaction

8@13 67@: 1he aldol condensation is not

an end-to-end condensationA


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7ynthesis roblem

CH3 CH2 CH CH C H

O

CH3

OH

reparation via ldol


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reparation via ldol'ondensation

CH3 CH CH CH2 OH

reparation via ldol


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reparation via ldol'ondensation

CH3 CH2 CH2 CH2 CH CH2 OH

CH2

CH3


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7ynthesis roblem

CH2 CH2 CH

OH

CH C

CH2

H

O


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'halcone Bormation

C CH2

OH

H

C

O

CH CH C

O

"spontaneous"

a chalcone

(formed from an aldol

condensation)

' d ld l , ti


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'rossed ldol ,eactions 'rossed aldol reactions (aldol reactions

in/ol/ing to diCerent aldehydes) are of little

use hen they lead to a mi0ture of products


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'rossed ldol 'ondensation


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'rossed ldol 'ondensations

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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ractical 'rossed ldol ,eactions

'rossed aldol reactions gi/e one predictable product

hen one of the reaction partners has no α hydrogens he carbonyl compound ithout any α hydrogens

is put in basic solution# and the carbonyl ith one

or to α hydrogens is added slolyDehydration usually occurs immediately#

especially if an e0tended con?ugated systemresults


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'laisen-7chmidt ,eactions


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'rossed-aldol reactions in hich one partner is a !etoneare called 'laisen-7chmidt reactions

he product of !etone self-condensation is not

obtained because the e>uilibrium is notfa/orable


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Brom 0periment 3

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


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lso:

CH2

CH2

C

C

CH3

O

CH3

O

NaOH

C2HOH

2!

O

CH3


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7ynthesis of:

C

H

O


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'rossed ldol 'ondensations

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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Brom 0periment 3

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

9ses of the ldol


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9ses of the ldol'ondensation

he aldol condensation is /ery useful in thepreparation of large molecules from simplestarting materials.


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7ynthesis of an


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7ynthesis of a 'ompound used in erfumery

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

cis

.OH

cis

ADOCOND#N$A%&ON

- H2O

D#H'DA%&ON

cis-/asmone

--- used for the scent of 0asmine

in perfumes

;iological 7ynthesis of Bructose


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;iological 7ynthesis of Bructose

CH2 CH C H

O

OHO

1

OH

OO

CH2 C CH2 O 1 OH

OH

O O

O

CH2

CH C CH C CH2

O 1 OH

O

O

O

OH

OH

HOHO

1

OH

O O

+

)lyceraldehyde-3-phosphate

Dihydro*yacetone phosphate

ructose-,-diphosphate

A"DO"COND#N$A%&ON

enyme

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

)

2)

3)

4 4

+ 455

6

55

fast 55

55 +

4 4 4 4

55

6

55 6

an enolate ion4 4

4 4

55 6

slo7

455

4

4 4

4 455

4 4

+ H2O

fast

455

4 4

+ 4OH55

55

6

acceptor

donor


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he FeartG of the +echanism

CH3

C

H

O CH3

C

H

O

CH2

C

H

O

CH2

C

H

O

+ 6 6

55 6

acceptor

donor


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%. Predict the product from the Claisen

condensation reaction (Claisen ester

condensation and )ieckmanncondensation. (page ! "7'-"7%


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Chapter 1& &

β-Dicarbonyl compounds can be synthesi4ed by the'laisen condensation

he acetoacetic ester and malonic acid synthesesuse β-dicarbonyl compounds for carbon-carbon bondforming reactions

he acetoacetic ester and malonic ester synthesesusually conclude ith decarbo0ylation of a β-!etoacid

he 'laisen 'ondensation 7ynthesis of β


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Chapter 1& 7'

he 'laisen 'ondensation: 7ynthesis of β-5eto sters

thyl acetate undergoes a 'laisen condensation

hen treated ith sodium etho0ide he product is commonly called an acetoacetic ester

thyl pentanoate undergoes an analogous reaction


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Chapter 1& 71

he o/erall reaction in/ol/es loss of an α hydrogenfrom one ester and loss of etho0ide from another

he mechanism is an e0ample of the generalprocess of nucleophilic addition-elimination at anester carbonyl


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Chapter 1& 72


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Chapter 1& 7#

he al!o0ide base must ha/e the same al!ylgroup as the al!o0yl group of the ester

he use of a diCerent al!o0ide ould result in formation ofsome transesteriEcation products

sters ith only one α hydrogen do not undergo 'laisencondensation

second hydrogen on the α carbon is necessary so that

it can be deprotonated in 7tep 3

his deprotonation dri/es the reaction to completion


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Chapter 1& 7%

'rossed 'laisen 'ondensations 'rossed 'laisen condensations can lead to one

ma?or product hen one of the to esters has no α

hydrogen

he Diec!mann condensation is an intramolecular


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Chapter 1& 75

he Diec!mann condensation is an intramolecular'laisen condensation @nly - and %-membered rings may be prepared in this ay


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5. Predict the product from the addition

to α$* unsaturated carbonyl

compounds and +ichael addition.

(page ! ""&$ "&2

dditions to α ,β -9nsaturated ldehydes and5etones


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5etonesα ,β -9nsaturated aldehydes and !etones can react by simple

(1#2) or con?ugate (1#$) addition

;oth the carbonyl carbon and the β carbon areelectrophilic and can react ith nucleophiles

7tronger nucleophiles such as Hrignard reagents fa/or 1#2ddi i h ! l hil h id


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addition hereas ea!er nucleophiles such as cyanide oramines fa/or 1#$ addition

+ichael dditions


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ddition of an enolate to an α ,β -unsaturated carbonylcompound usually occurs by con?ugate addition

his reaction is called a +ichael addition


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Predict the products from the

,obinson annulation (ring forming

(page ! "

,obinson annulation can be used to build a ne si0-membered ring on an e0isting ring


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membered ring on an e0isting ring

,obinson annulation in/ol/es a +ichael additionfolloed by an aldol condensation to close the

ring


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7. ble to rite the synthesis of

acetoacetic ester and malonic ester by

folloing basic steps /ia alkylation$hydrolysis and decarbo0ylation. (page !

"%5-"%&$ "5'-"5#


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Chapter 1& "%

he cetoacetic ster 7ynthesis: 7ynthesisof +ethyl 5etones (7ubstituted cetones)

l!ylation l!ylation of the enolate deri/ed from acetoacetic

ester is called the acetoacetic ester synthesis his is an 72 reaction ith the ethyl acetoacetate enolate

acting as the nucleophile


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Chapter 1& "5

second al!ylation can be performed

stronger base such as potassium tert -buto0ide mustbe use to deprotonate the monoal!yl ester

d l i f h d h i f h l


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Chapter 1& "

ydrolysis of the ester and heating of the resultantβ-!etoacid causes decarbo0ylation he product is a substituted acetone deri/ati/e

l


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Chapter 1& "7

0ample:

thylacetoacetate ser/es as a synthetic equivalent


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Chapter 1& ""

thylacetoacetate ser/es as a synthetic equivalent of the acetone enolate uire a much stronger base and special reaction conditions


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Chapter 1& "&

cetoacetic ster Dianion: l!ylation at the erminal 'arbon reating acetoacetic ester ith to e>ui/alents of a

/ery strong base produces the dianion

l!ylation of the dianion occurs Erst at the terminalcarbon he terminal carbanion is more nucleophilic and more

basic because it is stabili4ed by only one carbonyl group

h + l i t 7 th i 7 th i f


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Chapter 1& &'

he +alonic ster 7ynthesis: 7ynthesis of7ubstituted cetic cids

l!ylation of diethylmalonate# hydrolysis of thediester to the β-dicarbo0ylic acid# anddecarbo0ylation can be used to synthesi4e mono-and disubstituted acetic acids he mechanism is analogous to that for the acetoacetic ester synthesis


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Chapter 1& &1


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Chapter 1& &2


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Chm556 alpha hydrogen