Enols and Enolates (and Enamines) Carbon Nucleophiles · Enols and Enolates : Page 3 • in the acid/base reaction above, the ketone on the left is a much stronger acid than the amine

Enols and Enolates : Page 1

Enols and Enolates (and Enamines) Carbon Nucleophiles • The hydrogen atoms on the carbon that is alpha- to (adjacent to) the carbon of a C=O bond are the ones involved in keto/enol tautomerization and they are unusually acidic for an sp3 hybridized carbon • these hydrogens are ENOLIZABLE (although we didn't call them that when we fist covered enols)

• alpha, beta, gamma terminology refers to relative position, alpha means next to, beta means one position further away etc., in THIS CONTEXT, alpha means the carbon next to the C=O bond 1 Enolizable Hydrogens: What is it all about? • We understand that the majority of the reactions we encounter can be understood terms of Lewis acid/base and electrophile/nucleophile theory, the Lewis base/nucleophile provides the electrons to make a new bond • CARBON nucleophiles/Lewis bases are difficult to make, however, because carbon is not electronegative, it is not possible to have a simple carbon anion, the non-bonding electrons need to be stabilized some how Some STABILIZED Carbon Nucleophiles/Lewis Bases we have already seen:

• The electrons in the actylide anion are stabilized by sp hybridization, those in the Grignard reagent are stabilized in a weak bond to magnesium, those in the ylid by the positively charged phosphorus New NEW Carbon Nucleophiles/Lewis Bases on carbons based on ENOLIZABLE Hydrogen atoms: • Enols and enamines (see previously) and the enolate anion

• the electrons on the nucleophilic carbon in the enolate anion are stabilized by RESONANCE • the nucleophilic carbon in the enamine and enol has a partial negative charge by RESONANCE • Enolate anions, enamines and enols are Lewis bases with NUCLEOPHILIC carbon atoms in the position next to (alpha to) the carbonyl carbon of an aldehyde or ketone • Enolates are formed by deprotonation of an enolizable hydrogen using a Bronsted base • Enamines are formed in reaction between an aldehyde or ketone with a secondary amine (with acid catalysis) and deprotonation of an enolizable hydrogen (we just didn't call it that previously) • Enols are structural isomers of aldehydes/ketones where the position of ONE ENOLIZABLE hydrogen is changed, we just didn't call it that previously

enol

R

O

H

α− β− γ-positions

H

enolizable

acid or base

catalyzedR

O

H HR

O

H

H

enolizable

CH2R CR C CH2R MgBrδ

CH2R PPh3

acetylide Grignardδ

ylid

nucleophilic nucleophilic nucleophilictoo reactive

CO

R CH2CO

R CH2

enolate anion

RCOH

CH2

enol

nucleophilicnucleophilic

RCOH

CH2 RCNR2

CH2

enamine

nucleophilic

RCNR2

CH2


2 What Kinds of things do Enolizable Hydrogens do? Example: There are FOUR (alpha) enolizable hydrogens in cyclopentanone, these can exchange in presence acid • The mechanism for exchange can be revealed using deuterated (in effect labeled) acidic water, D3O+, involves reversible formation if an enol, ALL enolizable H atoms can be exchanged this way

• There are FOUR enolizable hydrogens in the molecule below, exchange of the hydrogen at the asymmetric center can result in inversion of configuration, i.e., formation of a racemic mixture. The base catalyzed mechanism is shown that proceeds via the enolate anion

3 Bronsted Acidity of Enolizable Hydrogens Which bases can be used to make an enolate anion?

• water is stronger acid, therefore equilibrium lies mostly on ketone side • the hydroxide anion can not be used to irreversibly make an enolate, but can be used to produce a SMALL AMOUNT of enolate that is in equilibrium with the neutral aldehyde/ketone Need a Stronger Base: Recall some strong bases that we know….

• Lithium diisopropylamide is a very strong BULKY base

OH

OD

D3O+

DOD

D

HO D

HO D

O DD

DO DD

OD

DO

D

D OD

DOD

α

β

ODD

D D

H3CCO

CCH3Ph

H

H3CCO

CCH3

Ph

H3CCO

CPh

CH3H

–OH/H2O

RacemizationOH

H3CCO

CCH3

Ph

–OH/H2O

O HH

(±)

S-* *

sp2 - "flat"

CH3C

H3C

O

CH2C

H3C

O+ OH + H2O

weaker acidpKa ~19

stronger acidpka ~15weaker base stronger base

N

new stronger bulky base

O H

strong base

NH H

stronger base

O

strong bulky base

hydroxide

t-butoxide

amide

lithiumdiisopropylamide

LDA

Li


• in the acid/base reaction above, the ketone on the left is a much stronger acid than the amine that is formed on the right, therefore equilibrium lies essentially completely on enolate side • LDA can be used to IRREVERSIBLY deprotonate an aldehyde/ketone and form an enolate anion

• LDA will DEPROTONATE an aldehyde or ketone at a carbon alpha-to the C=O, but it will not ADD to the C=O the same way that other strong nucleophiles do, e.g. the acetylide anion, Grignard reagent etc., because it is BULKY and therefore STERICALLY HINDERED • where does this base LDA come from??

• LDA is like NaNH2, but is BULKY BASE, thus less nucleophilic, stronger base than tertiary butoxide Recall, Bu-Li (butyl lithium) reacts like a carbon anion base, it is the strongest base that we see in second semester organic chemistry Summary: • Use –OH if you don't care about forming enolate reversibly • Use LDA if you want to form the enolate irreversibly, using LDA, ALL of the carbonyl is consumed! 3.1 Relative Acidities of Carbonyl Compounds • Compare an aldehyde, a ketone, an ester, and a new structure, a beta-dicarbonyl

CH3C

H3C

O

stronger acidpKa ~19

CH2C

H3C

ON

HN

weaker acidpKa ~40

weaker base100% in enolate form

stronger baseLDA

+

essentiallyirreversible

+Li Li

XCH3C

H3C

ON+

Li

does NOT add to the C=O, strong base but weak nucleophile because it is BULKYLDA

LiN

lithium diisopropylamide (LDA)

N + Bu-Li + butane (g)REALLY strong Base

H

CH

O

CH3C

H

O

CH2

aldehyde, pKa ~17

ester, pKa ~25

+ H3OH2O

CH

O

CH2

CR

O

CH3C

R

O

CH2

ketone, pKa ~20

+ H3OH2O

CR

O

CH2

CRO

O

CH3C

RO

O

CH2

+ H3OH2O

CRO

O

CH2

weakly donating R group destabilizes enolate

strongly donating RO- group further destabilizes enolate

S.D.

W.D.

decreasingacidity


• the acidity order is thus esters (least acidic) < ketones < aldehydes (most acid of these three) • the beta-dicarbonyl is by far the strongest acid because the enolate anion is DOUBLY resonance stabilized in this case and so…

• adding a base such as an alkoxide (ethoxide is shown above) or hydroxide results in formation of only a very small amount of the enolate of an aldehyde or a ketone, most of the carbonyl is not deprotonated but……

• adding a base such as an alkoxide to a beta-dicarbonylresults in essentially COMPLETE formation of the enolate anion 4 Alkylation and Halogenation Reactions of Enols/Enolates • There are many kinds of reactions of enols and enolates that we could examine, in all of them the enol/enolate is the LEWIS BASE/NUCLEOPHILE • We will look at only TWO kinds, C-C bond formation and reaction with Br2 • It isn't that reaction with Br2 is so important, it isn't, but it represents a nice introduction to the basic principles of the reactions of enols and enolates

CC

C

O

O

O

ORR

CC

C

O

O

O

ORR

CC

C

O

O

O

ORR

CC

C

O

O

O

ORR

β-dicarbonyl, pKa ~13

+ H3O

H2O

most resonance contributors

wins!!H

H

H

H H

strongest Bronsted acid

CH3C

H3C

O

CH2C

H3C

O+ OEt + EtOH

weaker acidpKa ~19

stronger acidpka ~15

equilibrium on THIS side

+ OEt

stronger acidpKa ~13

weaker acidpka ~15

CC

CO

OEt

O

EtOH H

+ EtOHCC

CO

OEt

O

EtO

H

equilibrium on THIS side

malonic ester


4.1 Alpha-Halogenation ACID catalyzed: REACTION VIA ENOL Recall

Related

• the reaction is substitution rather than addition, the reaction looks quite different, but it isn't The Mechanism

• although only a small quantity of the enol present at any one time (the equilibrium is on the side of the ketone), as the enol reacts, more is formed (Le Chatelier's principle!), which then reacts, then more enol is formed etc. and eventually all of the ketone is brominated • the enol, it is VERY reactive towards Br2, more than an alkene, because it is ACTIVATED by the electron donating -OH group, the acid catalyzes formation of the enol that is the REACTIVE SPECIES • the second step is the same as the reaction with the alkene above, but the third step is different, the protonated carbonyl is a very strong Bronsted acid (wants to lose the proton) and so deprotonation occurs even to the weak bromide anion base to form a product that has a (relatively) strong C=O bond • An organic acid OR H3O+ could be used as the catalyst, depending upon the solubility of the ketone Example

• CF3CO2H = trifluoroacetic acid (TFA), common strong organic acid used in the example above, other organic acids that may be used include HCl, TsOH (para-toluene sulfonic acid) etc. • the important point here is not so much that this is a reaction that you need to learn, but the under ACID CATALYZED conditions, the reactive species is the ENOL (we will see this again!)

Br–Br

CH2C

Me

Me

Br

CH2C

Me

MeBr

CH2C

Me MeBr

BrLB

LA

ANTI-addition

H (cat.)CH3C

R

O

CH2BrC

R

OsubstitutionBr–Br

viaENOL with

ACID

H (cat.)Br–Br

CH3C

R

O

CH2C

H3C

OH

CH2BrC

R

O

CH2BrC

R

OHLA

Br

enol stronger LB/Nuc than alkene

substitution

ACIDS. Donating

extremelystrong acid

+ Br2

CF3COOH (cat.)

CH3C

Ph

O

CH2BrC

Ph

O

(TFA)


BASIC Conditions: REACTION VIA ENOLATE The Mechanism:

• after substitution by one bromine, making the enolate anion of the brominated ketone is easier since the bromine stabilizes the enolate by the inductive effect (bromine is electronegative), so brominations become progressively easier and multiple additions often occur under base catalyzed conditions • note that the base is not a catalyst in this reaction, AND, even more reactions can happen after 3 substitutions, therefore use acid catalyzed conditions to brominates a carbonyl in the alpha-position The important point here is not so much that these are reactions you need to learn, but: • under ACID conditions, the reactive species is the ENOL (we will see this again!) • under BASIC conditions, the reactive species is the ENOLATE (we will see this again!) 4.2 Alkylation of Aldehydes/Ketones via Enamines/Enolates • Making C-C bonds is a very important reaction for enols, enolates and enamines A Basic Principle Underlying Enol/Enolate and related reactions

• the enamine and enolate are reactive (nucleophilic) enough to do SN2 with an appropriate alkyl halide, AND, these reactions make new C–C bonds!

OH Br–Br

CH3C

R

O

CH2C

H3C

O

CH2BrC

R

O OH

CC

R

O

H

Br

more stable enolate anion

CBr3C

R

O

enolate stronger LB/Nuc than alkene AND enol

stronger acidthan original ketone

Br–Br

CHBr2C

R

O

even stronger acid

OH

CC

R

O

Br

Br

even more stable enolate

Br–Brfurther

reactions.....OH

via ENOLATEwith

BASE

X

X

COH

R CH2

CH3-Br

No reactionalkene not strong enough Lewis BaseC

R

R CH2

CH3-Br

No reactionenol not strong enough Lewis Base

LB

CO

R CH2

CH3-Br

CNR2

R CH2

CH3-Br CNR2

R CH2CH3

CO

R CH2CH3

iminium salt

LA

LBLA

LALB

LALB

increasingLewis base

Nucleophilicitystrength stronger D

strongest D

alkene

enol

enamine

enolateSN2

SN2


Alkylation via the Enolate Anion

• in principle this should work, however, can't use -OH to make the enolate because it ALSO acts as a nucleophile, this problem can be fixed, see below • addition occurs mainly at the CARBON of the enolate anion rather than the oxygen • one way that we can understand this is that addition at oxygen forms a less stable enol ether (c.f. keto/enol equilibrium) (although the explanation is actually more complicated than this) Recall:

How to Fix the Problem of the base competing with the Enolate in the SN2 reaction? • Use LDA!

• 1 Equivalent of LDA completely deprotonates the carbonyl to form a lithium enolate (actually, the lithium ion may play a small role in controlling the reactions of the enolate) • BOTH the carbonyl and the LDA are completely consumed when 1 equivalent is used • Alkyl halide should be 1° or allylic to ensure SN2 Examples

• alpha-alkylation (formation of a new C-C bond) accomplished! • best if there is only one KIND of enolizable hydrogen atom or mixtures of products may result

CH3-Br+ OH

CH3-Br

CH3OHUnwanted side reaction

CO

R CH3 CO

R CH2

CO

R CH2CH3

hardly formedCO

R CH2

CH3

SN2 SN2

SN2

CO

R CH2

CH3-Br

SN2

SN2major product

enol ether

new C-C bond!

CO

R CH2CH3CO

R CH2

CH3CO

R CH2CH3CO

R CHCH3

H

keto-isomer favored enol-isomer not favored ketone favored enol ether not favored

similarly

1 Equiv. LDACH3-BrO O

CH3

O O

SN2H

H

Li

ALL ketone consumed

irreversible

O O

1. LDA

2. CH3CH2I

H

only 1 enolizable H (±)*


• Best if only 1 type of enolizable H, otherwise mixture of products will probably result Alkylation via an Enamine: The Stork Reaction • An enamine is a stronger nucleophile than an enol, but less nucleophilic than an enolate • The Stork enamine alkylation reaction avoids some problems with enolates, specifically, the reactions conditions are milder, more amenable to the presence of other functional groups it avoids using LDA, which is a very strong base and avoids enolate anion intermediates which are also strong Bronsted bases, as we will see, enolates can also react with the carbonyl structures they are formed from The Stork enamine reaction sequence: 1) convert carbonyl to enamine 2) add halide to enamine 3) hydrolyze enamine to carbonyl • seems a bit complicated, but is actually relatively straightforward and is quite and is usually PREFERRED over the LDA method Examples: H+ could be HCl, TFA, TsOH etc., any organic acid, but NOT H3O+

• alkylation is accomplished after hydrolysis of the iminium salt that is formed in the SN2 reaction • the iminium salt has a carbon with two bonds to heteroatoms (nitrogen in this case), and we have learned previously that molecules with this structural feature can be hydrolyzed with water under acidic conditions the hydrolysis mechanism is very similar to those that we have seen previously, in this case the iminium salt STARTS with a formal positive charge, and so protonation is not needed in the first step to get the reaction started, it is a strong enough LA/Electrophile to react directly with water as the weak LB/Nucleophile

O

1. LDA

2. CH3CH2I

H3 enolizable H's (total) HH

but 2 KINDS of enolizable H, thus two possible kinds of product

O O

+(±)*

H+ cat.

CH3Br

PhCH2Br

H3O

H3O

O

N

pyrrolidine

N

NCH3

OCH3

NCH2Ph

OCH2Ph

H

iminium+

iminium

hydrolysis

(±)

(±)SN2

SN2


The Iminium Hydrolysis mechanism

Example

• the enamine alkylation reaction is much preferred over the LDA method here since alkylation of aldehydes is often problematic due to self-Aldol reactions, that are discussed later in this section 5 Aldol and Claisen Reactions of Enols/Enolates 5.1 Aldol Condensation of Aldehydes/Ketones Definition: Condensation reaction liberates a small neutral molecule product, often water, that can be "condensed" Definition: Aldol reaction is another nucleophilic addition to an aldehyde of ketone where the nucleophile is an enol or enolate Summary of the reaction

• product is a conjugated "enone", formed after ELIMINATION of water (E1 or E2 mechanism) • the water that is formed in the reaction is removed irreversibly by heating (it can subsequently be condensed) Mechanism: BASE catalyzed VIA THE ENOLATE ANION 1st part: formation of the ADDITION product

NCH3

O H

H

NCH3

O

H

H

OHH

NCH3

OH

O H

H

H

NCH3

OHH

OCH3

OCH3

HO H

H

H3O+

OCH3

H

(±)

(±)

TsOH(cat.)

H3OH

O N

H

NH Br

H

N

H

O

CH3C CH3

O

CH3C CH2

OC

CH3

H3C

CH3C CH

OC

CH3

heat

H+ or -OHAldol ADDITION

productAldol CONDENSATION

product

H+ or -OH

catalyst

OH CH3

+ H2O


2nd part: formation of the CONDENSATION product • formation of addition product is reversible, BUT, formation of condensation product irreversible due to ELIMINATION of water • irreversible because water is removed by heating - condensation required to make overall reaction "go" • FIRST, hydroxide removes ANOTHER enolizable proton to make another enolate anion, THEN, hydroxide leaves, the elimination occurs in TWO steps

• every time we see an oxygen anion as a leaving group the structure it leaves from is itself an anion (an enolate anion in this case), we need to get high energy electrons into the structure that "kicks out" the hydroxide (it must be an anion), and that means starting the reaction with high energy electrons, usually in the form of strong base for example, when we reduced an ester with LiAlH4, the intermediate anion was able to have an oxygen anion as the leaving group, again we needed to start with a strong base

• A corresponding one-step E2 elimination does NOT occur because the hydroxide oxygen anion is too poor a leaving group

Aldol Condensation Mechanism: ACID catalyzed via THE ENOL

• acid catalyzed reaction, thus proceeds via the ENOL

H3C CH3

O

H3C CH2

O

H3C CH3

O

H3C

O

CH3

O

H3C

O

CH3

OHOH

Addition Product

CH3CH3

base makes enolate

H OH

another molecule of

starting ketone

H3C

O

CH2

OH

Addition Product

H3C CH

OC

CH3

CH3CH3

H OH

H3C

O

CH3

OHCH3

+ H2O (g)

enolate ANION

waterformedin thisstep

heat

+ OH catalyst reformed

OR

O

HAl HHH

ORO

H

H

Oaddition elimination OR+

ANIONstrong baseoxygen anions ONLY eliminate when

we START with an anion reagent

H3C

O

CH2

OH

H3C CH

O

CCH3

CH3CH3

H OH

E2

+ OHXto poor a leaving group

H3C

O

CH3

OH

Addition Product

H3CHC

O

CH3

OH2 CH3CH3

HH3C C

H

OC

CH3

Condensation Product

CH3H3C

HC

O

CH3

CH3

H

CH3C CH3

O

acid catalyzed - enol!

H–OTs

CH3C C

H2

OH

H

OTs

CH3C CH2

OH

H3C CH3

O

H3C

OH

CH3

OCH3

H–OTs

H3C

O

CH3

OHCH3

H

OTs

H–OTs

TsO


• the water elimination reaction could proceed via both E1 and E2 mechanisms (E1 shown here) Examples

IMPORTANT........... • IN BASE CATALYZED REACTIONS THE NUCLEOPHILE IS THE ENOLATE • IN ACID CATALYZED REACTIONS THE NUCLEOPHILE IS THE ENOL

Solving Aldol Problems Without Going Through the Entire Mechanism, Heuristically 5.2 Rationalizing the Various Possible Products, How do Carbonyls Know What to do? • so far we have seen the following acid and base catalyzed reactions for carbonyl compounds

Q. how does the carbonyl know which one to do? A. It doesn't, so it does them all! Depending upon the amount of water, acid and bases catalyst, we would expect some unreacted carbonyl, some enolate, some enol, some hydrate and some Aldol addition product, ALL in equilibrium (all are formed reversibly). However, if the water is removed (for example by heating), then everything

Na OH

Heat

O O

OH

ONa OH

addition product via enolate

condensation product

HCl HCl /HeatO

H

OH

OHaddition

product via enol

condensation products

OH

OH+

OOH

O

OHHO

O OHH+ or –OH H+ or –OH

H+ or –OHH2O

hydrate

enolate

enol Aldol addition

O

Aldol condensation

–H2O

All accumulates here if the water is removed

heat

–OH

not a "product"

not a "product" not a

"product"

not USUALLY a "product"


can eventually be "driven" towards the Aldol condensation product, which is formed IRREVERSIBLY when the water is removed. • NOTE that the enolate can only be made in the presence of base, but BOTH enol and enolate (and also hydrate) can form in the presence of acid and base, HOWEVER, in the presence of base, the enol has to be formed VIA the enolate, in other words both enol and enolate are present in base, and the enolate is considerably more reactive than the enol, which is why the enolate is the active Lewis base/nucleophile under basic conditions, under acid conditions the reactive Lewis base/nucleophile is the enol 5.3 Crossed Aldol Condensations • Aldol reactions between different carbonyl compounds have a potential major problem.....

• more than one possible product, both crossed Aldol and self-Aldol reactions can occur • how to control these reactions and direct towards a controlled crossed Aldol reaction? Select Appropriate Conditions

• can't make an enolate of benzaldehyde, it can't do a self-Aldol and it can't do an Aldol with acetaldehyde • benzaldehyde is in excess to ensure the enolate from acetaldehyde reacts with it, and to minimize the acetaldehyde self Aldol reaction Examples

• abbreviated (incomplete) mechanism shown above • there are two kinds of enolizable hydrogens in the molecule above, but only one gives a six-membered ring • intramolecular reaction wins out over any intermolecular reaction

H+ or -OH

Self AldolCrossed Aldol

CH

OC

H3C H

O+

TWO carbonyls

CH

O

H

HCH

O

H

H3CH

+

heat

benzaldehydeExcess

acetaldehyde

CH

O

CH3C H

O+

heat

Na+ -OH CH2C H

OC

H

O

OHC

H

O

heat

Na+ -OH CH

ONO enolizable

H atoms

Cinnamaldehyde

O

H

O

H

OH O

HOH OH, Heat

+

no enolizable H'sExcess

O

H

O O O O

HOO O

OH OH, Heat


• abbreviated (incomplete) mechanism shown above 5.4 Claisen Condensations : Enolates of Esters • Revisit acidity of carbonyl compounds

The Claisen Reaction: • Every time we have had a STRONG NUCLEOPHILE reacting with an ester, for example a Grignard, hydroxide, hydride in the form of LiAlH4, etc. the reaction has always been addition/elimination • In the Claisen reaction an enolate anion is the nucleophile, which is a strong nucleophile • The Claisen reaction is of a strong nucleophile reaction with an ester, the mechanism, therefore, is ADDITION/ELIMINATION

• addition/elimination mechanism

O

O

O

O

OH

O OOH OH, Heat

CC

CO

O

O

ORR

CC

CO

O

O

ORR

CC

CO

O

O

ORR

CC

CO

O

O

ORR

ester, pKa ~25

β-dicarbonyl, pKa ~11

+ H3O

H2O

CR

O

CH3C

R

O

CH2

ketone, pKa ~20

+ H3OH2O

CR

O

CH2

CRO

O

CH3C

RO

O

CH2+ H3O

H2OC

RO

O

CH2

S.D.

W.D.

H

H

H

H H

esters are harder to deprotonate (weaker Bronsted

acids) than ketones

β-dicarbonyls are relatively easy to deprotonate because the conjugate base anion is

resonance stabilized

CH2RCO

OR'

CHRCO

OR'

CH2RCO

OR'

CHC

OO

R'

CH2RC OO

R'

R

HC

CO

OR'

CH2RCO

R

CCO

OR'

CH2RCO

R

H3OC

CO

OR

CH2RCO

RH

R'OH/R'O

R'O

final product

base makes enolate β-dicarbonyl

deprotonation can not be prevented

addition elimination

stable anion

pKa ~ 25 pKa ~ 11

same

(acid workup)


• the pKa of R'OH is ~ 15, thus the R'O– MUST irreversibly deprotonate the initial beta-dicarbonyl product that is formed, which has a pKa of ca. 11 • H3O+ MUST be added as a last step to reprotonate the final product. This ACID WORKUP step only has to protonate the beta-dicarbonyl enolate, and so simple addition of aqueous acid works - compare the acid workup at the end of the malonic ester synthesis that requires heat to hydrolyze the ester and decarbonylate • however, this LAST deprotonation of the beta-dicarbonyl makes reaction overall irreversible • the base used is the alkoxide of the ester (R'O) to ensure that trans-esterification will not occur Example 1 (only 1 kind of enolizable proton) : Self-Claisen

Example 2 (only 1 kind of enolizable proton) : INTRAmolecular Claisen (Dieckmann condensation)

Example 3 (only 1 kind of enolizable proton) : Crossed Claisen

CH3CO

OEt

CH2CO

OEt

CH3CO

OEt

H2CC

OO

Et

CH3

C OO

EtCH2

CO

OEt

CH3CO

CH

CO

OEt

CH3CO

1. EtOH/EtO

2. H3O (acid workup)

H3O

CH2

CO

OEt

CH3CO

EtO

EtO

same

O

MeO

O OMe

O

MeO

O OMe O

MeOH3O

O12

3 4

56

7 7-membered ring(±)

12

3 45

67

NaOCH3

CH3OH

H3CH2CCO

OCH3 C

CO

OCH3

no enolizable hydrogens

Ph C

O

CH3

O

OCH3H

H3C

Ph OCO

CH3

+

ExcessPh O

CO

CH3

(H3O+)NaOCH3

CH3OH H(±)


Example 4 (crossed Claisen with a ketone)

• both have enolizable protons, but ketone is more acidic, thus this enolate forms and reacts preferentially Example 5 (crossed Claisen with two esters)

5.5 Aldol/Claisens in Reverse Example 1

Example 2

• B is slightly better because there is only one set of enolizable hydrogens, although A is still OK, since the ketone "end" is much more acidic than the ester "end" and thus the desired reaction will probably occur this way too

CH3CO

H3C+

OCH3CO

Et

CH2CO

H3C OCH3CO

Et

CH2

CO

H3C

OCH3

C OEt

CH

CO

H3CCO

Et

CH2

CO

H3CCO

Et

OCH3H3O

-H

ketone more acidic

1. NaOCH3/CH3OH

2. H3O+

ester less acidic

Excess

OCH3CO

H3CO+

OCH3CO

OCH3

OCH3CO

+H3CO

C COCH3

OO

H3Ono enolizable H's

OCH3CO

H3CO

1. NaOCH3/CH3OH

2. H3O+ H3COC C

OCH3

OOExcess

O

Ph

H O

O Ph

Hcame from+

H+ or –OHenone - Aldolheat Excess

OO

Ph

OO

Ph

OCH3

O

H3COO

Ph

OR

+β-dicarbonyl - Claisen A

B

A

B

Excess

1. CH3O–/CH3OH2. H3O+

1. CH3O–/CH3OH2. H3O+

(±)

H3CO

O O

Ph

β-dicarbonyl - Claisen

A BB

A H3CO

O

+ H3CO

O

Ph

H3CO

O

OCH3+

O

PhExcess

Excess

(±)


6 Summary of Reactions of Enols/Enolates Do NOT start studying by trying to memorize the reactions here! Work as many problems as you can, with this list of reactions in front of you if necessary, so that you can get through as many problems as you can without getting stuck on the reagents/conditions, and so that you can learn and practice solving reaction problems. Use this list AFTER you have worked all of the problems, and just before an exam. By then you will have learned a lot of the reagents/conditions just by using them and you will only have to memorize what you haven't learned yet. Then do the following: • Cover the entire page of reagents/conditions with a long vertical strip of paper, see if you can write down the reagents/conditions for each reaction, check to see which you get correct, if COMPLETELY correct, circle Y, if incorrect or even slightly incorrect, circle N. In this way you keep track of what you know and what you don't know. • Keep coming back to this list and so the same thing only for those reactions you circled N, until all are circled Y.

O Br2O

Br HCl

O1. LDA

2. Br

O

O / H+ (cat.)NH

N

2. H3O+

N OBr1.

O Oheat

TsOH or Na+–OH

PhO O

ORO

+Ph

O 1. Na+ –OR2. H3O+

do not use basic conditions for this reaction

enamine formation

Stork reaction

Aldol condensation, many variants

Y / N

Y / N

Y / N seen previously

Y / N

Y / N

Y / N

Claisen condensation, many variants

Documents

Enols and Enolates (and Enamines) Carbon Nucleophiles · Enols and Enolates : Page 3 • in the acid/base reaction above, the ketone on the left is a much stronger acid than the amine