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Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 1 of 15. Date: April 4, 2012
Chapter 17: Enols and Enolate Anions as Nucleophiles
!Enols: ! under acidic conditions! 1. H-X, H3O+ acids, (H3C)3Si-X: with enolates react at O !Enolates: !under basic conditions! (Si is oxophilic)
O OH
enol: weakly nucleophlic enolate: highly nucleophilic
I. Nucleophiles Electrophiles
Rx on ORx on C RR'
Oaldehydes/ketones
4. Z = Cl, OR'
5. R X alkyl, allyl, & benzyl halides
with enolates react atcarbanion C
Rx on C
RZ
O
2. Halogens (Cl2; Br2; I2)3.
(1) Generation of enolates
CH
O
HH
B
C
O
H
H(base)
C
O
H
H
H B carbanion enolate
nucleophilic sitenucleophilic site
ambident nucleophilealpha- (α-) carbon
alpha- (α-)hydrogens
• Halogens and most of the carbon electrophiles react at the carbanion center.
• The solution structures of carbanions closely resemble the structures of enolates. In addition, the only reason for the acidity of the α-hydrogen is the presence of a C=O group. Therefore, the following mechanism for the deprotonation of the α-hydrogen by a base is recommended:
CH
O
HH
B
α
O
H
H H B+
Enolate formation vs carbanion addition
CH
O
HH
C
α CH
O
HH
C
vs
CH
O
HH
H3CBrMg
CH
O
HH
H3C
BrMgnot much deprotonation
Kinetically, addition to the C=O carbon favored.
EO
+H3CMgBr
higher ΔEa for deprotonnationlower ΔEafor addition
OMgBrH3C
OMgBr+ CH4
(i) H3C-MgBr
•
Note: A carbanion addition reaction to a C=O is irreversible.
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 2 of 15. Date: April 4, 2012
(ii) When (H3C)3C-Li or H3CCH2CHLi(CH3) is used, enolate formation is greatly favored due to the increased steric energy for the addition.
(iii) Commonly used non-nucleophilic bases:
II. Reactions of Enolates
O
H
H
M O
HHM
O
H
H
ElO
H
HEl
O
H
HEl
O
H
H
El O
H
H
El
Reactions with "slower"-reacting electrophiles.
Reactions with "fast"-reacting electrophiles.
"transition state" resembles the structure of the starting enolate
"transition state" resembles the structure of the more stable, C=O group containing product
The transition states for the reactions of enolates with highly reactive electrophiles, e.g., H-X, H3O*, and (H3C)3Si-Cl, closely resemble the structures of the starting enolates. In contrast, the reactions with slower-reacting carbon electrophiles, e.g., R-X and R-C(=O)-Z, go through the transitions states that have an energetically favorable, strong C=O bond character. This leads to the preferential reactions at the α-carbon.
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 3 of 15. Date: April 4, 2012 Reactions of enolates with alkyl, allyl, and benzyl halides – Exclusive C-alkylation • Enolates readily undergo reactions on the α-carbons with alkyl, allyl, and benzyl halides.
OH
O
(1 mol equiv)NaH
Hα
NH2
diethyl ether(solvent)
OH
Enolate preformed, then treated with allyl bromide.
+ NH3
Br
O
H
+ NaBr60%
OH
OH
Br
Br
mechanistic drawing:
or
Note: Enols are not nucleophilic enough to have reactions with these halides. III. The Regioselectivity of the Enolate Reactions
(1) Kinetic enolates - Use of an extremely strong base; non-nucleophilic base in an aprotic solvent, typically in tetrahydrofuran (THF) - Use of a slight excess of the base at a low temperature (typically at - 78°C) ------ to ensure no equilibrium between the two enolates.
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 4 of 15. Date: April 4, 2012 LDA: an extremely strong base and a bulky base; does not add to the C=O carbon. The bulky LDA approaches from the less-hindered side of the C=O.
OH
HH3C
H
Li N
HH3CH
O
major enolate
More hindered side!
OH
HH3C
H
Less hindered side!
H O
CH3
H
H
LiN
H3C CH3
H3C
H3C
axial α-H on the less-substituted side
O
HLi
N
H3C CH3
H3C
H3C
H3Csevere steric repulsion
More favored for deprotonation
Chair-like TS
Chair-like TS
Lessfavored for deprotonation
(2) Thermodynamic Enolates
OH
HH3C
H
HH3CH H
HH3C
O O+
Si
CH3CH3
CH3Si
CH3CH3
CH3Si
CH3CH3
CH3Cl
N(CH2CH3)3Δ
HCl•N(CH2CH3)3+22% 78% Mechanism:
OH
HH3C
H NR3
pKa 19-20
OHH3C
HH NR3 O
HH3CH
H
OH
HH3C
H
tautomerizationless-stable
enolate(kinetic enolate)reaction with
Cl-Si(CH3)3
HH3CH
OSi
CH3CH3
CH3
R3N
HH
H3CO
Si
CH3CH3
CH3 HH
H3CO
more-stable enolate(thermodynamic enolate)
reaction withCl-Si(CH3)3
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 5 of 15. Date: April 4, 2012 These conditions allow equilibrium to occur and preferentially produce the more stable “thermodynamic enolate,” i.e., under the “thermodynamic control.”
Highly reactive electrophiles such as H-X, (H3C)3Si-X, H3O+ react at the enolate O site.
Thermodynamic enolates can be obtained:
• Nomally using a weak base • High temperatures • Excess ketone or proton source such as an alcohol.
Note: Even if LDA is used as a base, if less than 1.0 mol equiv of LDA is used at a higher temperature, such as 0 °C or room temperature, the equilibrium between the kinetically generated enolate and the starting ketone could be achieved, thus effectively creating the thermodynamic enolate.
(3) Reactions of Enolates: Examples kinetic enolate thermodynamic enolate
OH
H
HO
HH
Li O
H
LiHLDA
(1.1 mol equiv)
H3COOCH3
(1,2-dimethoxy-ethane; solvent)
0 °C
+
H3C
OCH3
H
H OH
CH3
HO
H
H
H3C
+ enantiiomercis trans76%
& +
I
(i)
(ii)
CH3Br
OH
H Br
OH
H
OH
H
HH
Li
CH3
Br
O
H
K
H
O CH3
91%
+ KBr
+ LiBrLDA (1.1 mol equiv)
H3CCH2OCH2CH3- 60 °C
kinetic enolate
thermodynamic enolate
80%(H3C)3C-O K(H3C)3C-OHΔ
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 6 of 15. Date: April 4, 2012
Chapter 17: IV. Base-catalyzed Aldol Reactions and Condensation Reactions
H3C H
O2
NaOHH2O
5 °C, 1 h
H3O+ workup H3C H
HO H O
H Hβ α H3C H
H OH O
H Hβ α+
~50%
(β-hydroxy-aldehyde)Aldol products [aldehyde + ol]
Note these specfic reaction conditions.
Often difficult to stop at the stage of a β-hydroxy-aldehyde or ketone.
Aldol condensation reaction
O
HO
H3C
O
NaOH95% EtOHrt O
O+ H2O+
H
OH3C
OO
HIn this combination,
OC
O
HHH
this is the only "acidic" H (pKa ~18).
Note: H
O O
not acidicbase x
The resulting carbanion is notstabilized by the C=O π-electrons.
orthogonal: no orbital overlap
OC
OC
O
HHH
HO
OO
HH O
OH
H
(resonance stabilized)α-hydrogenspKa of H-OH is 15.7
1.
2. Whenever a nucleophilic base (e.g., HO-, H3CO-) is used, the base adds to the C=O carbon.
H
O OH3C
O
HO HOOH
OH
OH3C
O
OH
However, these adducted compounds are less stable than the original C=O compounds and do not undergo any other reactions but to go back to the original aldehyde/ketone.
The original aldol reaction:
Comments:
H
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 7 of 15. Date: April 4, 2012
The reaction mechanism:
OC
O
HHH
HOO
OH
H
H
O
O OO
H--OR (R = H or C2H5)
HO OO
H HHO
HO OO
H
H OO
H
α,β-unsaturated ketone
or -OC2H5
a highly resonance-stabilizedclass of compound
A
B
C
Comments: (1) The conjugated ketone produced is primarily the more stable trans (or E) isomer. (2) The reaction of the ketone enolate with benzaldehyde takes place exclusively at the α-carbon.
O
OH
H
H
O
O
OH
H
H
OC-alkylation not O-alkylation
O
O
O-
because of the high C=Obond energy in the T.S.
α-carbon
(3) The last dehydration step should go through the ketone enolate intermediate as shown above. The alternative E2 process should require a higher energy of activation than the pathway that involves the enolate formation by deprotonation (i.e., the faster acid-base reaction).
OH OO
H H
HO or -OC2H5
An E2 process less likely. (4) The last dehydration step is thermodynamically driven, i.e., the formation of the highly stable α,β-unsaturated ketone. Problems: Provide in the following boxes the structures of appropriate compounds.
H O
H
O
NaOH/C2H5OH+
OKOt-Bu (base)
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 8 of 15. Date: April 4, 2012
V. Acid-catalyzed Aldol Reactions/Condensation Reactions Acids can catalyze aldol reactions as well.
OCH3
OO
p-TsOH(catalytic)
Δ
mechanism:
OC
OH
H HH
OO H
H Hp-TsO HO
O H
H HH
O HOH H
O HO HH
H
p-TsO H
O HO HH
H
OH
O
OTs OTs
OTs
Alternatively, may use H - B and B for acid and conjugate base, respectively.
+ H2O
VI. Directed Aldol Reactions [In this case, the word “directed” refers to the regiochemistry of the enolate formation]. When a weak base such as NaOH and NaOCH2CH3 is used, only a small amount of an enolate is generated. Therefore, the initial aldol (addition) reaction product (i.e., β-hydroxy ketone) is exposed to such a base, thus often resulting in the formation of the aldol condensation product. The only practical way of ensuring the clean formation of the β-hydroxy ketone product is to use 1.0-1.1 mol equiv of a strong base such as LDA. Since the base will be used up completely for the enolate generation, there is no excess base left when the β-alkoxy ketone is formed, thus preventing the further reaction to form the aldol condensation product.
O O Li
H
O
O O Li
LDA(1.1 mol equiv)THF, -78 °C
H3O+-workup
O OH
α β
β-hydroxy ketone
p-TsOH, benzenereflux
O H
α
β
α,β-unsaturated ketone (mostly trans)
H
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 9 of 15. Date: April 4, 2012
O OH
α β
H
mechanism for the dehydration step:
HH
O OH
α β
H
H
p-TsO H
O O
α β
H
H
H
H O
α β
H
H
H
O H
α
βα,β-unsaturated ketone
H
OTs
OTs
VII. Retro-Aldol Reactions under Basic or Acidic Conditions The Aldol reactions-condensations are reversible both under basic and acidic conditions.
mechanism under basic conditions:
OH
CH3
O
H3C
CH3
pulegone
O
CH3
H3C CH3
O+
NaOH, H2O, Δ
H3O+, H2O, Δ
mechanism under acidic conditions:
CH3
O
H3C
CH3
CH3
O
H3C
CH3
OH
HO
H
CH3
O
H3C
CH3
O
H
H OH
CH3
O
H3C
CH3
O
H
CH3
O
H3CCH3
OHO
H
CH3
O
H3C
CH3
H
HOH
pulegone
H
CH3
O
H3C
CH3
H
HO
H HOH
CH3
O
H3C
CH3
H
HO
HOH
HCH3
OH3C
CH3
H
HO
H
+O
CH3
O
CH3
H
CH3H3C
OH HO
H
H
O
CH3
H OH2
O
CH3
+
OH2
CH3H3C
O
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 10 of 15. Date: April 4, 2012
Chapter 17: VIII. Reactions of Stabilized Enolate Anions with Alkyl Halides
Enolates of Active Methylene Systems. (1) Enolates from 1,3-diketone and β-Keto Esters: Hydrogens alpha to both of the carbonyl groups in 1,3-diketones and β-keto esters are highly acidic. Therefore, those Hs could readily be deprotonated by the use of a relatively weak base and the resulting enolates undergo facile alkylations with alkyl halides. These mono-anions are stabilized by resonance with both of the C=O groups.
H3C O CH2CH3
O O
H H
αβ
"active methylene"
K2CO3100 °C
N H
O
DMF (N,N-dimethyl-
formamide; solvent)
H3C O
O OCH2CH3
H
K H3C O CH2CH3
O O
H
αβ
I
I 99%+ KI
pKa ~ 11-12 (2) Dienolates from 1,3-diketone and β-Keto Esters: Mono-enolates (mono-anions) formed from 1,3-diketone and β-keto esters can further be deprotonated by the use of a stronger base (typically n-butyllithium or LDA) to generate di-enolate (dianions).
ZR'
O O
H H H H
active methylene Hs (highly acidic)
Z = R or OR"
Z
O O
H
R'
H Hmono-anion
(mono-enolate)
Considerably less acidic than typical α-Hs, thus requiring the use of n-butyllithium or LDA to deprotonate
weak base(1 mol equiv)
stronger base(1 mol equiv)
Z
O O
H H
R'
di-anion(di-enolate)
If these dianionic species is treated with one mol equiv of a carbon electrophile, the C-C bond forming reaction takes place selectively at the second deprotonation site.
H3C
O O
H H
HH3C
O O
H H
H
More basic; more nucleophilic!
(3) An example of the mono-alkylation of a dienolate.
H3C CH3
O O
H HH3C CH3
O O
H
Na+ H2
H3C
O O
H
Na
H
HLi
NaH (1 mole equiv)THF (solvent)
-15 °C
Li(n-butyllithium)
1 mol equiv.at around 0 °C
(1 mol equiv)
I H O-THPH O-THP
H3C
OO
Hdienolate
H O-THP
H3C
OO
H H
aq NH4Cl
CH3CH2CH2CH3 +
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 11 of 15. Date: April 4, 2012 IX. Formation of β-Keto Esters and Their Reactions
R OR'
O O
H H
αβ
β-keto esters
"active methylene" pKa ~ 11-12
H3C OCH2CH3
O O
H H
αβ
pKa 10.7
O OCH2CH3
O O
H H
αβ
pKa 13.3
H3CCH2
C C
H H
pKa 11
NNH3C CH3
O O
H H
αβ
pKa 9pKa values of some 1,3-C=O or CN compounds
(1) Synthesis of β-keto esters from ketone enolates
O OLi O
OCH2CH3
O
+ LiClLDA
(1.0 mol equiv)THF, -78 °C
Cl OCH2CH3
O
OLi
Cl OCH2CH3
O
O
Cl
OCH2CH3
O O
O CH2CH3
O
ketone enolateβ-keto ester
mechanism:
(2) Synthesis of β-keto esters from esters
(i) The Claisen Condensation: between two ester compounds; intermolecular reaction
H3C OCH2CH3
O
OCH2CH32 x
(1 mol equiv)
+H3C O
CH2CH3
O
H
O
H O CH2CH3pKa 17
+
H3C OHO
H3C OCH2CH3
O
H
O
Hethyl acetoacetate
Na
Na
OCH2CH3
OHH H
OCH2CH3
OCH2CH3
OH
H
H O CH2CH3+
H3C
OCH2CH3
O
O CH2CH3
OCH2CH3
OH
H
H3CO
O CH2CH3
OH
H
H3C O
OCH2CH3
+
OH
H3C O
H O CH2CH3+
Reaction end-products before acidic workup.
H3C OHO
OH
H3C O HOH
H3C O
H tautomerizationOCH2CH3OCH2CH3OCH2CH3
Na
Na
Na
mechanism:
pKa ~11
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 12 of 15. Date: April 4, 2012 IX. (2) (ii) The Dieckmann Condensation: an intramolecular version of the Claisen condensation.
O
O
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
O
O
KH (1 mol equiv)
THF (solvent) OCH2CH3
O
O
K workup with acetic acid
OCH2CH3
O
OH
+ HOCH2CH3
mechanism:
HH
H
O
O
OCH2CH3
OCH2CH3
H H
OOCH2CH3
OOCH2CH3
H
O
OCH2CH3
O
OCH2CH3
+ H2+
OCH2CH3
O
O
K
+ HOCH2CH3
K
K
K
OCH2CH3
O
OH
OCH2CH3
OH
O
H3C OH
Otautomerism
acidic!
86% yield Reversible reactions observed for the β-keto ester products lacking an active methylene H.
O
O
OCH2CH3
OCH2CH3
H3CH
1. Na OCH2CH3
2. workup with
H3C OH
O
(1 mol equiv)
H3C O
OOCH2CH3
H
H Not formed!
H3C O
OOCH2CH3
H
O
O
OCH2CH3
OCH2CH3
H3C
H3C O
OCH2CH3
O
H3C O
OCH2CH3
O
O
O
OCH2CH3OCH2CH3
H3CH
H
H3C O
OOCH2CH3
H
H
OCH2CH3
OCH2CH3
stable enolate product;reaction endproduct under the basic conditions prior to acidic workup
gets immediately deprotonated
gets destroyed back to the enolate at the left initiated by the attack by the alkoxide anion
No acidic H present!
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 13 of 15. Date: April 4, 2012
Chapter 17: IX. Formation of β-Keto Esters and Their Reactions (cont’d)
(3) Decarboxylation of β-keto acid and malonic acid and substituted malonic acid Carboxylic acids with a C=O group β-to the carboxylic acid C=O are unstable and lose CO2 gas upon warming/heating. These carboxylic acids include b-keto acid and malonic and substituted malonic acids. These acids can be obtained by the acid catalyzed or base catalyzed hydrolysis followed by acidification of the corresponding esters. The decaboxylation is shown to go through a six-membered cyclic transition state. As such, the two carbonyl groups need to be located at the 1,3-positions or the β-position to the carboxylic acid C=O. The resulting enols undergo tautomerization to provide the more stable C=O structures.
R O-H
O O
R'R O
O O
R'
H
R
OH
R'R
O
R'
HHH
HH tautomerizationdecarboxylation!
CO2
six-memberedcyclic transition state
Δ
R O-Ro
O O
R' H
H3O+, Δor i) HO ; ii) H3O+
H-O O-H
O Omalonic acid
H-O O-H
O O substituted malonic acid
R' R"
Example:
OCH2CH3
O O
OCH2CH3
O O
1. KH (1 mol equiv)2. n-butyllithium (1 mol equiv)
KLi
More reactive here!
OCH2CH3
O O
PhCH2-Br(1 mol equiv)
+ KBr/LiBr
KLi or
H3O+
(pH ~2)
OCH2CH3
O O1. NaOH-H2O2. H3O+, Δ
CH3
O
O
O
OH
OH
H H
H
H
CO2
CH3
Otautomerization
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 14 of 15. Date: April 4, 2012
Chapter 17 X: Conjugate Addition to α ,β-Unsaturated Carbonyl Compounds
(1) Conjugate Addition (or 1,4-Addition) – with “weaker” or “softer” nucleophiles
R
O
R
O
ααββ
12
3
4
"electrophilic C""electrophilic alkene"
"electrophilic C"
+
+
+
Examples of conjugate addition reactions1.
H CH3
H O
H
NH
H3C OH
O0 °C
N CH3
O
α
β
β α
68%
Mechanism:
H CH3
H O
H
βα
NH
N CH3
O
H
NH
N CH3
O
HO CH3
ON CH3
Oα
β
HH H H
2.H OCH3
H O
H
β α2 H2S
O CH3
O
Na(catalytic)
H3CO S OCH3
O O
Mechanism:
HS
HO CH3
O
H OCH3
H O
H
β αH S
H OCH3
H O
Hα
SH
O CH3
O
HO CH3
OH
H OCH3
H O
H
SH
O CH3
O
H
O CH3
O
H OCH3
H O
H
S
H
O CH3
OH
HH3CO
HO
H
βαH OCH3
H O
H
S
HHH3CO
HO
Hα
H
H3CO S OCH3
O O
O CH3
O+
re-generationof the catalyst
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 15 of 15. Date: April 4, 2012 Chapter 17 X: Conjugate (or 1,4-) Addition to α ,β-Unsaturated Carbonyl Compounds (2) 1,2- vs 1,4-Addition reactions
ONu
ONu
O
Nu
O
Nukinetic product(1,2-product)
thermodynamic product(1,4-product)
23
4
• 1,4-addition products (thermodynamic products): formed with “weaker” or “softer” nucleophiles; those nucleophiles with pKa of the conjugate acids in the range of 8 – 25 generally produce 1,4-adducts (those nucleophiles include RS-, RR’R”N, and ketone/ester enolates); the conjugate addition reactions with enolates are referred to as the Michael reactions. • 1,2-addition products (kinetic products): formed with strong nucleophiles such as RMgBr and RLi (these addition products are formed irreversibly).
CH3
Oβ
12
3
4
H3C MgBr
H3C MgBr aq NH4Cl
highly nucleophilic(reactive)δ δ
CH3
OH
CH3
+
CH3
O
β
12
3
4
H3C
CH3
OH3CH
H
CH3
OH3CH
"hypothetical, mildly nucleophilic CH3 anion"
H3O+
The most commonly used such mildly nucleophilic reagents are "organocuprates."
RCu
R'Li
organocuprates
H3CCu
H3CLi (H3C)2CuLi
e.g.,
These cuprate reagents are prepared from:2 H3CLi + CuI (H3C)2CuLi + LiIdiethyl ether (solvent)
The organocuprates undergo: conjugate addition (to, e.g., α,β-unsaturated ketones/esters), SN2reactions (onto, e.g., RCH2X and epoxides).
1. Homocuprates (R = R'): only one of these two groups (R=R') works as a nucleophile; H3CCu produced by the reaction is not nucleophilic enough to undergo the reaction.2. Heterocuprates (R R')
e.g., (NC)RCuLi and H3CCH2CH2C CCuRLi: only R group works as a nucleophile.
O (H3CCH2CH2CH2)2CuLi (1 mol equiv)
O(tetrahydrofuran=THF;
solvent)-78 °C
O Li
H3CCH2CH2CH3Cu(not reactive)
(-30 °C)1.
2. aq NH4Cl
OCH3
H3C I
+ enantoimer[mostly trans-diastereomer]
Example:
Conjugate-adding organometallic reagents:
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