Lichens: fungus + photosynthetic partneroakton.chadlandrie.com/resources/Download-Center/OrgoIILectures... · •EnolatesandCarbonylCondensa0ons ... (promote reversibility)

CHM'224'•'Organic'Chemistry'IISpring'2013,'Des'Plaines'•'Prof.'Chad'Landrie

•Enolates*and*Carbonyl*Condensa0ons*(23.1)•Aldol*Condensa0on*(23.2823.6)•Claisen*Condensa0on*(23.7823.9)

Lecture'12:'February'28,'2013

Lichens: fungus + photosynthetic partner

S

OCoA

O

OO

17

35

2 Aldol S

OCoA

OO

17

35

2 OH

O

OHHO

17

35

2

orsellinic acid

© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)

Slide Lecture 12: February 28

Enol%and%Enolate

2

CCO

HC

CO

H

CCO

CCO

tautomerization

resonance

dissociationdissociation

H+ H++ +

• enlolate is the conjugate base of an enol• electron lone-pair is delocalized on C and O atoms



Subs.tu.on%Reac.ons%at%the%α3Carbon

3

Ch. 22: Enols and enolates are nucleophilic at the alpha carbon and undergo substitution with electrophiles.



Acidic%a3Hydrogens

4

αβ

ɣC H

OC

H3CH H

HH

C H

OC

H3C

HH

HC H

OC

H3C

HH

H

Main Points:1.acidic hydrogen is attached to the α-carbon2.simple aldehydes and ketones have pKa = 16-20; similar acidity to

OH group of water or most alcohols3.An α-hydrogen of an ester is less acidic than ketone or aldehyde4.A hydrogen that is α to two carbonyls is more acidic



Acidic%a3Hydrogens

5

Main Points:1.acidic hydrogen is attached to the α-carbon2.simple aldehydes and ketones have pKa = 16-20; similar acidity to

OH group of water or most alcohols3.An α-hydrogen of an ester is less acidic than ketone or aldehyde4.A hydrogen that is α to two carbonyls is more acidic



Factors%Effec.ng%Acidity

6

Inductive Effect• carbonyl group is electron

withdrawing• increases partial positive

charge on H atom• more acidic

Resonance• conjugate base stabilized by

resonance• charge delocalized over two

atoms, one of which is O• ↑ stable CB = more acidic

C

O

Hδ+

C H

O

C H

O



pKa%Values%of%Aldehydes,%Ketones%and%Esters

7

• α-hydrogens are much less acidic than carboxylic acids

• acids delocalization over two oxygens

• perspective: still a fairly weak acid

CO

OH

H CO

OH

CO

OH




8

• α-hydrogens are in the same acidity range as alcohols and water

• hydroxide (pKa H2O = 15.7) and alkoxides can deprotonate many α-Hs compounds



Aqueous%Equilibria%of%Ketones%and%Aldehydes

9

CO

H

H3CH3C

HH O + C

O

HH O+

H

H3C

H3C

hydroxide 2-methylpropanalpKa = 15.5

enolate waterpKa = 15.7






10



CO

H

H3CH3C

HH3C O + C

O

HH3C O+

H

H3C

H3C

methoxide 2-methylpropanalpKa = 15.5

enolate methanolpKa = 16.0




11

• esters are less acidic than ketones or aldehydes

• more competing resonance with ester O-atom = less delocalization of lone-pair on C-atom

C O

OH

H H

C O

OH

H C O

O

C O

OH

H




12

• significant percent of ester exists in equilibria with alkoxides or hydroxides

• this is a key requirement for the Aldol condensation we’ll talk about shortly

CO

OEt

HH

HH3CH2C O + C

O

OEtH3CH2C O+

H

H3C

H3C

ethoxide ethy acetatepKa = 25.6

enolate ethanolpKa = 16.0



pKa%Values%of%Dicarbonyls

13

• Dicarbonyl compounds are significantly more acidic

• additional carbonyl = more resonance = more stable CB = more acidic acid

C

O

CH3H H

O

H3C

C

O

CH3H

O

H3CC

O

CH3

O

H3C C

O

CH3

O

H3CHH



Aqueous%Equilibria%of%Dicarbonyls

14

• 1,3-dicarbonyls completely deprotonated by hydroxide and alkoxides

• even diesters are completely deprotonated

H3CH2C O + H3CH2C O+H

ethoxide diethyl malonatepKa = 13.0

enolate ethanolpKa = 16.0

OEtEtO

O O

H HOEtEtO

O O

H



Complete%Deprotona.on%by%Strong%Bases

15

• LDA is a strong bases capable of completely deprotonating carbonyls

• LDA is made by adding butyl lithium to diisopropyl amine

N

H

NLi+

CH2Li+

+ +

n-butyl lithium(n-BuLi)

diisopropyl amine lithium diisopropyl amide(LDA)

butane



Complete%Deprotona.on%by%Strong%Bases

16

• amides (CBs of amines) fully deprotonate even esters

• this is a key requirement when you want to avoid having any of the reactant carbonyl in solution

CO

OEt

HH

HN + C

O

OEtN+

H

H3C

H3C

LDA ethy acetatepKa = 25.6

enolate diisopropyl aminepKa = 36.0



Enolate%Regiochemistry

18

Kinetic Control• strong base (irreversible

deprotonation)• large base (increase sterics);

usually LDA• aprotic solvent (e.g., THF) to

prevent reprotonation• low temperature (ensure

lower energy TS path followed)

Thermodynamic Control• base whose pKa is close to

carbonyl (reversible)• protic solvent (e.g., EtOH) to

promote reprotonation• room temp or higher

(promote reversibility)• most stable product (more

substituted alkene) is obtained

OHH

CH3H

basesolvent,

temp.

OHH

CH3base

solvent,

temp.

OCH3H

H

kinetic enolate(least substituted)

thermodynamic enolate(most substituted)



Thermodynamic%Enolate

19

OHH

CH3H

CH3O

OHH

CH3thermodynamic enolate(most substituted)

OCH3H

Hkinetic enolate(least substituted)

Thermodynamic Control• base whose pKa is close to carbonyl (Keq~1; reversible)• protic solvent (e.g., EtOH) to promote reprotonation• room temp or higher (promote reversibility)• most stable product (more substituted alkene) is obtained



Kine.c%Enolate

20

OHH

HCH3

N

OHH

CH3thermodynamic enolate(most substituted)

OCH3H

Hkinetic enolate(least substituted)

OH

HCH3H

N

OHH

H

CH3

N

Kinetic Control

• strong base (irreversible deprotonation)

• large base (increase sterics); lower energy TS is the one with least sterics

• aprotic solvent (e.g., THF) to prevent reprotonation

• low temperature (ensure lower energy TS path followed)

δ–δ–

δ–δ–



Chapter%Summary

22

CH

OE Y+

CH

O

E

Enolates are nucleophiles!

Ch. 22: Alpha Substitutions of Carbonyl Compounds

CH

OE Y

CH

O

EYH

Ch. 23: Condensation Reactions of Carbonyls



Chapter%Summary

23

+CH

O

H CH3

O Aldol CondensationCH

O OH

HCH3

+CH

O

H3C OCH3

O Claisen CondensationCH

O O

CH3

+CH

O

H3C Cl

O AcylationCH

O O

CH3

+CH

O

H3CCl

AlkylationCH

OCH3



Aldol%Condensa.on

24

O

H2 KOH, H2O HO H

H

Oheat

elimination H

O

aldehyde β-hydroxyaldehyde α,β-unsaturated aldehyde

• condensation of two aldehyde molecules under alkaline conditions

• usually cannot isolate β-hydroxyaldehyde; it quickly undergoes elimination to the alkene

• alkene is more stable since it is conjugated with the carbonyl

aldol = aldehyde & alcohol

Requirements:

•aldehyde: Keq > 1; much slower for ketones (Keq << 1)

•α-carbon must be 1º or 2º (have two Hs)

•alkaline conditions (hydroxide)



“Aldol”%Condensa.on%for%Ketones

25

•the equilibrium for acyclic ketones lies far to the left

•ketones are more stable and less electrophilic

O

CH32

HO H

CH3

O

ketone β-hydroxyaldehyde

98%

2%



Intramolecular%“Aldol”%of%Diketones%Possible

26

O

OH

O

O

Na2CO3, H2O

heat

OH H H

97%

• Intramolecular aldols (even for diketones) particularly favorable when five- or six-membered rings are formed.




27

• Intramolecular aldols (even for diketones) particularly favorable when five- or six-membered rings are formed.




28

• Many natural products are synthesized through biosynthetic intramolecular aldol condensation of polyketides

• Polyketide = compound with alternating ketone and methylene (CH2) groups

Lichens: fungus + photosynthetic partner O O O

S

OCoA12345678 S

OCoA

O

OO

17

35

2

S

OCoA

OO

17

35

2OH

O

OHHO

17

35

2tautomerization

& hydrolysis

Aldol

orsellinic acid

•orsellinic acid isolated from lichens•shown to block neuronal apoptosis•radical scavenging ability



Aldol%Mechansim

29

Board Work:1. Enolate formation.2. Nucleophilic Addition.3. Elimination of hydroxide (really?)



Mixed%Aldols

31

Problem:Four possible products are

possible with two enolizable aldehydes

Solution1. Only one reactant can form an enolate, or2. One reactant is more reactive toward

addition than the other3. Use LDA to completely deprotonate one

component (preventing self-condensation), then add the second.

H

O

H

O+

H

O

HO

H

O

HOH

OOH

H

OOH



Mixed%Aldols

32

• formaldehyde cannot form an enolate• formaldehyde is highly reactive; reacts faster with enolate than the enolate reacts with another aldehyde (self-condensation)

H H

O

H

O+

K2CO3

H2O, Et2O H

O

OHformaldehyde 3-methylbutanal 2-hydroxymethyl-3-

methylbutanal



Mixed%Aldols

33

• aromatic aldehydes cannot form enolates (no α-hydrogens)• enolate of acetone reacts much faster with aldehyde than with another ketone

• ketones are less electrophilic and more sterically hindered

H3CO

H

O

H3C CH3

O+

NaOH, H2O

30 ºCH3CO

CH3

O

p-methoxybenzaldehyde acetone 4-p-methoxyphenyl-3-buten-2-one



Mixed%Aldols

34

• using a strong bases, such as LDA, will completely deprotonate first component and prevent self-condensation

• enolate will react rapidly with second component (aldehyde)

CH3

O

(H3C)3CH H

LDA, THF

-78 ºCCH3

O

(H3C)3CH

H

O

1.

2. H2OCH3

O

(H3C)3C

HO



Claisen%Condensa.on

36

Aldol: Addition of Enolate to Aldehyde

Claisen: Addition of Enolate to an Ester

aldehydeenolate

β-hydroxycarbonyl

CH

OCO

CH

O

COH

H

CRO

OCO

CRO

O

CO

OR

+

+

enolate ester

β-ketoester

α

β

α

β



Claisen%Condensa.on

37

H3C O

O

CH3+

H3C O

O

CH3 O

O

CH3H3C

O

+ HO CH3

1. NaOCH2CH3

2. H3O+

ethyl acetate ethyl 3-oxobutanoate

ethanol

ethyl acetate

• self-condensation between two molecules of ester• typically use alkoxide base identical to alkyl group on ester to prevent transesterification

• overall: an acylation at the α-carbon



X

Claisen%Condensa.on

38

H3C O

O

CH3 O

O

CH3H3C

O1. NaOCH2CH3

2. H3O+

O

O

CH3 O

O

CH3

O1. NaOCH2CH3

2. H3O+H3C H3C

H3C HH H

O

O

CH3 O

O

CH3

O1. NaOCH2CH3

2. H3O+H3C H3C

H3C CH3H3C H

1º

2º

3º

• the α-carbon must be primary or secondary for Claisen• little to no product formed when α-carbon is tertiary• final product is deprotonated as it is formed



Claisen%Mechanism

39

Board Work:1. Enolate formation by alkoxide.2. Tetrahedral intermediate.3. Addition-Elimination gives β-ketoester4. Final product is deprotonated.



Intramolecular%Claisen:%Dieckmann%Cycliza.on

40

• esters of dicarboxylic acids undergo intramolecular Claisen (aka Dieckmann)

• Used mainly to form 5- and 6-membered rings

OCO

C O

O

H H

CCOO O

OHH

NaOCH2CH3

CCOO O

OHC

C O O

OH

O

CC O

OH

O



Intramolecular%Claisen:%Dieckmann%Cycliza.on

41

• esters of dicarboxylic acids undergo intramolecular Claisen (aka Dieckmann)

• Used mainly to form 5- and 6-membered rings

O

O

O O

O

O

Oα

βα

β



Mixed%Claisen

42

• mixed Claisen analogous to mixed aldol• best results obtained when one ester incapable of forming an enolate

O

OCH3

O

OCH3+

1. NaOCH3

2. H2O/H3O+

O

OCH3

O



Mixed%Claisen

43

• mixed Claisen analogous to mixed aldol• best results obtained when one ester incapable of forming an enolate

H O

O

O O

O

O

O

ethyl formate diethyl carbonate ethyl benzoate

Non-enolizable Esters



Biological%“Claisen”

44

acetoacetyl CoA

cholesterol

• thioesters are common intermediates in biological systems

• condensation of two acetyl-CoAs is a “Claisen-like” reaction

• leaving group is a thiolate instead of alkoxide

• acetoacetyl CoA is an intermediate in mevalonate pathway to cholesterol



Biological%“Claisen”

FaRy3Acid%Bioynthesis

45

reduction

stearic acid



Claisen3Like:%Acyla.on%of%Ketones%with%Esters

46

O

O O

O1. NaH

2. H3O++

O

O

O

O

O O

+1. NaOCH2CH3

2. H3O+

OO

cycloheptanone diethyl carbonate ethyl (2-oxocycloheptane)-carboxylate(a β-ketoester)

ethyl benzoate benzephenone 1,3-diphenyl-1,3-propandione(a 1,3-diketone)

• ketones can be acylated with esters and carbonates• similar to Claisen condensation• works best when ester is non-enolizable



Claisen3Like:%Acyla.on%of%Ketones%with%Esters

47

• ketones can be acylated with esters and carbonates• similar to Claisen condensation• works best when ester is non-enolizable

C C

OH3C

H H O

O CH31. NaOCH2CH3

2. H3O+ CC

OH

H3C

O



Synthesis

48

O

OCH3

O

O

+

H

O

OH

O

O

O

O

+OH

O

Amita & Aaron

Shiloh & Ho Miae & AJ

Andrew & Min

Albert & Chirag

CHM'224'•'Organic'Chemistry'IISpring'2013,'Des'Plaines'•'Prof.'Chad'Landrie

Ch.*22

Next'Lecture.'.'.

Documents

Lichens: fungus + photosynthetic partneroakton.chadlandrie.com/resources/Download-Center/OrgoIILectures... · •Enolates*and*Carbonyl*Condensa0ons* ... (promote reversibility)

Lichens: fungus + photosynthetic partneroakton.chadlandrie.com/resources/Download-Center/OrgoIILectures... · •EnolatesandCarbonylCondensa0ons ... (promote reversibility)