Enols and Enolates (and Enamines) Carbon Nucleophiles · Enols and Enolates : Page 3 • in the...
Transcript of Enols and Enolates (and Enamines) Carbon Nucleophiles · Enols and Enolates : Page 3 • in the...
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
Enols and Enolates : Page 2
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
Enols and Enolates : Page 3
• 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
Enols and Enolates : Page 4
• 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
Enols and Enolates : Page 5
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)
Enols and Enolates : Page 6
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
Enols and Enolates : Page 7
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 (±)*
Enols and Enolates : Page 8
• 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
Enols and Enolates : Page 9
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
Enols and Enolates : Page 10
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
Enols and Enolates : Page 11
• 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"
Enols and Enolates : Page 12
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
Enols and Enolates : Page 13
• 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)
Enols and Enolates : Page 14
• 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(±)
Enols and Enolates : Page 15
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
(±)
Enols and Enolates : Page 16
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